{"gene":"TRPC5","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2001,"finding":"TRPC1 and TRPC5 co-assemble into a heteromeric neuronal cation channel in the hippocampus. Coexpression in HEK293 cells produced a novel nonselective cation channel with voltage dependence similar to NMDA receptors, activated by Gq-coupled receptors but not by intracellular Ca2+ store depletion.","method":"Co-immunoprecipitation, heterologous coexpression in HEK293 cells, whole-cell patch-clamp electrophysiology","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP from brain lysates combined with electrophysiological characterization of heteromeric channel properties; replicated across multiple subsequent studies","pmids":["11301024"],"is_preprint":false},{"year":2000,"finding":"TRPC5 (mTRPC5) forms a receptor-operated nonselective cation channel (single-channel conductance ~66 pS at -60 mV) activated by Gq/11-coupled receptors and receptor tyrosine kinases independently of intracellular Ca2+ store depletion; GTPγS activates channels in inside-out patches in a membrane-confined manner.","method":"Whole-cell patch-clamp, inside-out patch recording, Mn2+ quench assay in fura-2-loaded HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal electrophysiological methods including single-channel recordings; replicated by multiple independent labs","pmids":["10837492"],"is_preprint":false},{"year":2003,"finding":"TRPC5 is expressed in neuronal growth cones, interacts with the growth cone-enriched protein stathmin 2, is packaged into vesicles and transported to growth cones and synapses. TRPC5 channel activity restrains neurite extension and growth cone morphology, as dominant-negative TRPC5 expression allowed significantly longer neurites and filopodia.","method":"Co-immunoprecipitation (TRPC5-stathmin 2 interaction), dominant-negative expression, live-cell imaging, immunofluorescence in rat hippocampal neurons","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP interaction data combined with dominant-negative functional rescue and live imaging; replicated in subsequent studies","pmids":["12858178"],"is_preprint":false},{"year":2002,"finding":"Lanthanide ions (La3+, Gd3+) potentiate TRPC5 currents at micromolar concentrations via extracellular sites near the pore mouth. Neutralization of negatively charged residues Glu543 and Glu595/Glu598 abolished potentiation; these residues are accessible from the extracellular side. The mechanism involves reduced single-channel conductance but dramatic increase in open probability.","method":"Site-directed mutagenesis, whole-cell and outside-out patch-clamp recordings in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific residues combined with single-channel recordings; well-replicated mechanistic finding","pmids":["12456670"],"is_preprint":false},{"year":2009,"finding":"TRPC5-/- mice exhibit diminished innate fear and reduced responses mediated by Group I metabotropic glutamate and CCK2 receptors in amygdala neurons, demonstrating that TRPC5, activated via G protein-coupled neuronal receptors, has an essential function in innate fear circuits.","method":"TRPC5 knockout mice, electrophysiology in amygdala slices, behavioral fear assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal behavioral and electrophysiological readouts in a high-impact study","pmids":["19450521"],"is_preprint":false},{"year":2010,"finding":"TRPC5 forms a molecular complex with Rac1 in podocytes and fibroblasts; TRPC5-mediated Ca2+ influx activates Rac1, promoting cell migration. Conversely, TRPC6 is in complex with RhoA and its Ca2+ influx activates RhoA to inhibit migration, establishing TRPC5 and TRPC6 as antagonistic regulators of actin dynamics.","method":"Co-immunoprecipitation (TRPC5-Rac1 and TRPC6-RhoA complexes), siRNA knockdown, cell migration assays, Ca2+ imaging in podocytes and fibroblasts","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional knockdown with specific readouts in two cell types","pmids":["20978238"],"is_preprint":false},{"year":2013,"finding":"TRPC5 mediates kidney filtration barrier injury. Loss of TRPC5 (Trpc5-KO mice) or pharmacological inhibition prevents podocyte cytoskeletal remodeling, blocks Rac1 activation, stabilizes synaptopodin, and protects against albuminuria.","method":"Trpc5 knockout mice, small-molecule TRPC5 inhibitor, Ca2+ imaging in isolated glomeruli, live imaging of podocyte actin dynamics, urine albumin measurement","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and pharmacological inhibition with multiple cellular and in vivo readouts","pmids":["24231357"],"is_preprint":false},{"year":2012,"finding":"TRPC5 activity drives P-glycoprotein (P-gp) induction in adriamycin-resistant breast cancer cells via an NFATc3-dependent transcriptional mechanism (TRPC5-NFATc3-P-gp signaling cascade). Suppression of TRPC5 reduced P-gp expression and reversed drug resistance in vitro and in a xenograft model.","method":"siRNA knockdown, channel inhibition, NFAT reporter assay, Western blotting, xenograft tumor model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (genetic and pharmacological) with in vitro and in vivo validation","pmids":["22988121"],"is_preprint":false},{"year":2011,"finding":"TRPC5 is activated by cold temperatures in the range 37–25°C. Homomeric TRPC5 channels, but not TRPC1/TRPC5 heteromeric channels, are cold-sensitive. TRPC5 is present in dorsal root ganglion sensory neurons and peripheral nerve endings consistent with a role as an innocuous cold transducer.","method":"Temperature-evoked electrophysiology (cold activation of expressed TRPC5), TRPC5 KO mice behavioral testing, immunohistochemistry of DRG neurons","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct electrophysiological demonstration of cold activation with mutagenesis-style dissection of homo vs heteromeric channels, plus KO mouse data","pmids":["22025699"],"is_preprint":false},{"year":2009,"finding":"Intracellular Ca2+ potentiates TRPC5 channel activity: ~1 µM intracellular Ca2+ triggers ~10–20-fold increase in channel open probability in excised inside-out patches without changing single-channel conductance. Extracellular Ca2+ (not Ba2+ or Mg2+) is required for the potentiation, acting at an intracellular site.","method":"Simultaneous fura-2 imaging and patch-clamp, excised inside-out single-channel recordings, caged Ca2+ photolysis, whole-cell patch-clamp in HEK293 cells","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous single-channel and simultaneous imaging/electrophysiology in one study; single lab but multiple orthogonal methods","pmids":["19398778"],"is_preprint":false},{"year":2012,"finding":"Calpain-1 and calpain-2 cleave and functionally activate TRPC5. A critical threonine at position 857 is required for calpain-2 cleavage. The truncated TRPC5 resulting from calpain cleavage is functionally active. This mechanism mediates semaphorin 3A-induced growth cone collapse in hippocampal neurons.","method":"In vitro calpain cleavage assay, site-directed mutagenesis (T857 mutant), TRPC5-null hippocampal neurons, electrophysiology, growth cone collapse assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro protease cleavage assay with mutagenesis plus null neuron rescue experiments","pmids":["22547824"],"is_preprint":false},{"year":2011,"finding":"TRPC5 KO mice have long, highly branched cerebellar granule neuron dendrites with impaired dendritic claw differentiation. TRPC5 forms a complex specifically with CaMKIIβ (not CaMKIIα) and induces CaMKIIβ-dependent phosphorylation of the ubiquitin ligase Cdc20-APC at the centrosome, coupling Ca2+ signaling to a ubiquitin ligase pathway to regulate dendrite patterning.","method":"TRPC5 KO mice, in vivo RNAi, Co-immunoprecipitation (TRPC5-CaMKIIβ complex), phosphorylation assays, behavioral motor coordination tests","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of specific complex combined with KO mice, in vivo RNAi, and biochemical pathway mapping","pmids":["22135323"],"is_preprint":false},{"year":2012,"finding":"TRPC5 KO mice show significantly reduced pilocarpine-induced seizures and minimal seizure-induced hippocampal neuronal death, whereas TRPC1/4 double KO mice show unaltered seizures but reduce epileptiform bursting in lateral septal neurons—demonstrating that TRPC5 and TRPC1/4 contribute to seizures and excitotoxicity via distinct cellular mechanisms. Long-term potentiation is greatly reduced in TRPC5 KO hippocampi.","method":"TRPC5 KO mice, TRPC1 KO mice, TRPC1/4 double-KO mice, pilocarpine seizure model, hippocampal slice electrophysiology, LTP recordings","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis across multiple KO lines with multiple electrophysiological and in vivo behavioral readouts","pmids":["23188715"],"is_preprint":false},{"year":2015,"finding":"TRPC5 glutathionylation at Cys176/Cys178 by intracellular oxidized glutathione activates TRPC5 channels, causing sustained Ca2+ influx, calmodulin-dependent protein kinase activation, and calpain-caspase-mediated striatal neuronal death. Increased TRPC5 S-glutathionylation and low TRPC1 expression (promoting TRPC5 homotetramer formation) were found in striatum of YAC128 HD transgenic mice and HD patients.","method":"S-glutathionylation assay (cysteine mutagenesis C176/C178), electrophysiology, Ca2+ imaging, TRPC5 knockdown/inhibition, YAC128 transgenic mice, human HD brain tissue","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — identification of specific modified residues by mutagenesis plus in vitro and in vivo validation including human tissue","pmids":["26133660"],"is_preprint":false},{"year":2019,"finding":"Cryo-EM structure of mouse TRPC5 homotetramers resolved at 2.8 Å. The structure revealed a disulfide bond at the extracellular pore domain and differences in the extracellular pore domain and S3 helix length compared to other TRP channels. Mutagenesis confirmed the disulfide bond and a preceding loop are essential for TRPC5 function.","method":"Cryo-electron microscopy (2.8 Å resolution), electrophysiology, mutagenesis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with functional mutagenesis validation","pmids":["31355338"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of human TRPC5-Gαi3 complexes at ~3 Å reveal a 4:4 stoichiometry in lipid nanodiscs. Gαi3 binds to the ankyrin repeat edge of TRPC5 ~50 Å from the membrane. Gαi3 increases TRPC5 sensitivity to PIP2, rendering the channel more easily opened under physiological PIP2 concentrations.","method":"Cryo-EM structure determination in lipid nanodiscs, electrophysiology (PIP2 sensitivity), structural modeling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure of functional complex with electrophysiological mechanistic validation","pmids":["37137991"],"is_preprint":false},{"year":2012,"finding":"Gαi subunits are primary direct activators of TRPC5 (predominantly Gαi3) and TRPC4. Activation occurs through direct interaction of Gα with the conserved C-terminal SESTD domain of the channels. Two residues (K715 and R716) in TRPC4 mediate the Gαi2 interaction. Constitutively active Gαi mutants fully activate the channels.","method":"Co-immunoprecipitation, constitutively active Gα mutant expression, electrophysiology, structural modeling of SESTD-Gαi interaction, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP with mutagenesis and electrophysiological validation of direct Gαi-channel interaction mechanism","pmids":["22457348"],"is_preprint":false},{"year":2005,"finding":"TRPC5 is activated by common endogenous lysophospholipids including lysophosphatidylcholine (LPC) independently of G-protein signaling. LPC activates TRPC5 in excised membrane patches, suggesting a relatively direct action on the channel structure. The effect shows dependence on acyl-chain length and head-group chemistry.","method":"Excised inside-out patch recordings, Ca2+-indicator dye measurements, G-protein pathway inhibition experiments in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — excised patch recordings demonstrating membrane-delimited direct activation with structure-activity analysis; single lab","pmids":["16368680"],"is_preprint":false},{"year":2008,"finding":"Hypoosmotic stimulation and direct membrane stretch activate TRPC5 channels, causing Ca2+ influx. The osmotic response is blocked by GsMTx-4 (stretch-activated channel inhibitor) and requires PIP2; direct application of positive pressure through patch pipette also activates TRPC5. Activation is independent of PLC function.","method":"Whole-cell and excised patch-clamp, intracellular Ca2+ imaging, lipid phosphatase overexpression to deplete PIP2, pressure application via patch pipette in TRPC5-expressing cells","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct mechanosensory activation demonstrated in excised patches with pharmacological dissection; single lab but multiple orthogonal methods","pmids":["18832422"],"is_preprint":false},{"year":2005,"finding":"Calmodulin (CaM) binds to a novel C-terminal domain of TRPC5 (95 amino acids downstream from the CIRB domain), and exogenous CaM accelerates agonist-induced TRPC5 channel activation by ~2.8-fold. The CIRB domain is critical for overall receptor-induced TRPC5 activation. High intracellular Ca2+ (>5 µM) inhibits current density, demonstrating dual and opposite Ca2+ effects on TRPC5.","method":"Whole-cell patch-clamp, deletion mutagenesis, co-immunoprecipitation, surface expression assay in CHO and HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of specific CaM-binding domains with functional electrophysiological validation and Co-IP; single lab","pmids":["15987684"],"is_preprint":false},{"year":2006,"finding":"Neuronal calcium sensor-1 (NCS-1) directly binds to the TRPC5 C-terminus and suppresses TRPC5 channel activity evoked by multiple stimuli. NCS-1 and TRPC5 are present in the same protein complex in rat brain. This NCS-1/TRPC5 complex contributes to retardation of neurite outgrowth.","method":"Co-immunoprecipitation from rat brain, in vitro pull-down binding assay, dominant-negative NCS-1 expression, patch-clamp electrophysiology","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP from native brain tissue, in vitro direct binding, plus functional electrophysiological validation","pmids":["16469785"],"is_preprint":false},{"year":2005,"finding":"Ca2+-binding protein 1 (CaBP1) directly binds TRPC5 and inhibits its channel activity without affecting surface expression. CaBP1-binding sites on the TRPC5 C-terminus are closely localized to but distinct from CaM-binding sites. TRPC5 activity requires both extracellular and intracellular Ca2+.","method":"In vitro pull-down assay, two-electrode voltage clamp in Xenopus oocytes, surface expression assay, mutagenesis","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro direct binding assay plus functional Xenopus oocyte electrophysiology; single lab","pmids":["15895247"],"is_preprint":false},{"year":2010,"finding":"SESTD1, a phospholipid-binding protein containing SEC14-like and spectrin domains, associates with TRPC5 (and TRPC4) via the CIRB domain and is essential for efficient receptor-mediated activation of TRPC5. Phospholipid binding by SESTD1 is Ca2+-dependent.","method":"Yeast two-hybrid screen, Co-immunoprecipitation, in vitro phospholipid-binding assay, siRNA knockdown with electrophysiological readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus in vitro lipid binding plus functional electrophysiology; single lab","pmids":["20164195"],"is_preprint":false},{"year":2005,"finding":"TRPC5 activity is maintained by constitutive Ca2+-calmodulin/MLCK signaling that promotes plasma membrane localization of TRPC5. ML-9 (MLCK inhibitor) impaired membrane localization of TRPC5 and abolished channel activity in whole-cell recordings but not in excised inside-out patches.","method":"Whole-cell patch-clamp, inside-out patch-clamp, dominant-negative MLCK mutant expression, calmodulin inhibitor (W-13), surface localization assessment in HEK293 cells","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and dominant-negative dissection with electrophysiology; single lab, indirect evidence for MLCK as direct writer","pmids":["16284075"],"is_preprint":false},{"year":2004,"finding":"The scaffolding protein EBP50 (NHERF1) modulates TRPC5 activation kinetics via the C-terminal VTTRL PDZ-binding motif. Co-expression of EBP50 caused significant delay in histamine-evoked TRPC5 activation; deletion of VTTRL abolished EBP50's modulatory effect without altering channel biophysical properties.","method":"Whole-cell patch-clamp, deletion mutagenesis (VTTRL motif), co-expression in HEK293 cells","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus functional electrophysiology; single lab with two orthogonal approaches","pmids":["15334657"],"is_preprint":false},{"year":2007,"finding":"Protons potentiate TRPC5 currents: lowering extracellular pH from 7.4 to 6.5 increases TRPC5 currents by reducing single-channel conductance while dramatically increasing open probability. The same glutamate residues responsible for lanthanide sensitivity (E543 and E595) mediate H+ potentiation.","method":"Whole-cell and single-channel patch-clamp, mutagenesis of E543Q and E595Q in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific pore residues with single-channel and whole-cell electrophysiology; single lab but multiple methods","pmids":["17884814"],"is_preprint":false},{"year":2011,"finding":"PKA directly inhibits TRPC5 channels via phosphorylation at Ser794 and Ser796. Constitutively active Gαs, isoproterenol, and 8-bromo-cAMP inhibit TRPC5 currents; this inhibition is abolished by S794A/S796A point mutations. PKA-mediated inhibition does not affect TRPC5 surface expression/trafficking.","method":"Whole-cell patch-clamp, site-directed mutagenesis (S794A, S796A), surface biotinylation, constitutively active Gαs expression in HEK293 cells","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific phosphorylation sites combined with electrophysiology and surface biotinylation; single lab","pmids":["21734191"],"is_preprint":false},{"year":2008,"finding":"Complex regulation of TRPC5 by phosphatidylinositol 4,5-bisphosphate (PIP2): depletion of PIP2 via PI4-kinase inhibition activates TRPC5; inclusion of PIP2 in patch pipette inhibits TRPC5 currents; yet in excised patches PIP2 robustly activates TRPC5 single channels, demonstrating both inhibitory and stimulatory roles for PIP2 in regulating TRPC5.","method":"Whole-cell patch-clamp, excised single-channel recordings, PI4-kinase inhibition, targeted 5-phosphatase strategy, PIP2 infusion via patch pipette in HEK293 cells","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal PIP2 manipulation strategies with single-channel recordings; single lab","pmids":["18665391"],"is_preprint":false},{"year":2021,"finding":"PIP2 controls both PKC-mediated desensitization and DAG/lanthanide-mediated activation of TRPC5 currents via gating regulation rather than by changing channel cell surface density. Optogenetically-controlled PIP2 dephosphorylation was used to dissect these mechanisms.","method":"Whole-cell patch-clamp, optogenetic PIP2 dephosphorylation tool, total internal reflection fluorescence microscopy for surface density in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — novel optogenetic tool combined with electrophysiology and surface density imaging; single lab with multiple orthogonal methods","pmids":["33933453"],"is_preprint":false},{"year":2013,"finding":"The S4-S5 linker is a critical gating element in TRPC5. A conserved Gly504 to Ser substitution forces TRPC5 into a constitutively open conformation, causing Ca2+-dependent cell death. A second mutation (in the C-terminal S6 helix region) suppresses constitutive activation, suggesting an interaction between the S4-S5 linker and S6 in gating.","method":"Site-directed mutagenesis (G504S, double mutant), whole-cell patch-clamp, Ca2+-dependent cell death assay in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-function mutagenesis at defined gating residues with functional electrophysiological characterization; single lab","pmids":["23677990"],"is_preprint":false},{"year":2007,"finding":"The first ankyrin-like repeat in the N-terminus is the minimum domain required for TRPC5 homomultimerization and functional assembly. Fragments lacking this repeat fail to multimerise, cannot interact with wild-type TRPC5, and do not form functional channels. N-terminal dominant-negative fragments retaining the first ankyrin repeat trap TRPC5 intracellularly.","method":"FRET measurements (CFP/YFP-labeled fragments), TIRF microscopy, electrophysiology, dominant-negative truncation analysis in HEK293 cells","journal":"Cell calcium","confidence":"High","confidence_rationale":"Tier 2 / Moderate — FRET-based interaction mapping combined with TIRF localization and electrophysiology; single lab multiple methods","pmids":["17624425"],"is_preprint":false},{"year":2014,"finding":"Extracellular disulfide bonds between Cys553 and Cys558 in the pore loop are essential for TRPC5 tetramerization, trafficking to plasma membrane, and channel activity. C553S or C558S mutants lose all channel activity and act as dominant negatives. Reducing agents decrease membrane TRPC5 distribution.","method":"Cysteine mutagenesis (C553S, C558S), Co-immunoprecipitation, FRET analysis of dimerization, surface biotinylation, electrophysiology in HEK293 cells","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of specific disulfide-forming cysteines combined with FRET, Co-IP, surface trafficking, and electrophysiology; single lab","pmids":["24859801"],"is_preprint":false},{"year":2019,"finding":"TRPC5 palmitoylation at a conserved cysteine residue is critical for intrinsic channel activity and membrane stability. Depalmitoylation reduces TRPC5 membrane stability and attenuates Ca2+-mediated striatal neurotoxicity in Huntington's disease cells.","method":"Palmitoylation assay, mutagenesis of palmitoylation site, membrane trafficking assay, electrophysiology in HD striatal cells (STHdh)","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — palmitoylation biochemistry with functional channel activity readout; single lab","pmids":["31812495"],"is_preprint":false},{"year":2009,"finding":"TRPC5 is activated by intracellular Ca2+ with an EC50 of ~635 nM at negative potentials; Ca2+ entry through either CRAC channels (STIM1/Orai1) or L-type voltage-gated Ca2+ channels is sufficient to activate TRPC5 via local subsarcolemmal Ca2+ increases (blocked by BAPTA but not EGTA).","method":"Whole-cell patch-clamp, caged Ca2+ photolysis, co-expression of STIM1/Orai1 and L-type Ca2+ channel subunits, EGTA vs BAPTA Ca2+ buffering comparison in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct intracellular Ca2+ dose-response with caged-Ca2+ photolysis and functional coupling experiments; single lab multiple methods","pmids":["19815560"],"is_preprint":false},{"year":2017,"finding":"TRPC1, TRPC4, and TRPC5 assemble into heteromultimers with each other but not with other TRP family members in mouse brain and hippocampus. Loss of all TRPC1/4/5-containing channels reduces action potential-triggered EPSCs, impairs cross-frequency hippocampal network coupling, and causes deficits in spatial working memory but not reference memory.","method":"Quantitative high-resolution mass spectrometry (native complex identification), Trpc1/4/5 triple-KO mice, hippocampal slice electrophysiology (evoked EPSCs, LTP), in vivo hippocampal recordings, spatial memory tasks","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — MS-confirmed native complexes plus triple-KO mice with electrophysiology and in vivo behavioral characterization","pmids":["28790178"],"is_preprint":false},{"year":2017,"finding":"TrpC5 in POMC neurons mediates the acute anorexigenic effects of leptin and serotonin 2C receptor (Ht2Cr) agonists. POMC-specific TrpC5 deletion blocks leptin- and Ht2Cr agonist-induced membrane depolarization and reduces energy expenditure while increasing food intake and body weight.","method":"Conditional Pomc-specific Trpc5 KO mice, whole-cell patch-clamp electrophysiology in arcuate POMC neurons, metabolic phenotyping, feeding behavior assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional cell-type-specific KO with electrophysiological validation and in vivo metabolic phenotyping","pmids":["28099839"],"is_preprint":false},{"year":2019,"finding":"Trpc5 deficiency impairs infraslow membrane potential oscillations of dopamine arcuate nucleus (ARC) neurons and prolactin-evoked tonic plateau potentials. Female Trpc5-mutant mice show severe hypoprolactinemia with associated reproductive deficits.","method":"Conditional Trpc5 KO mice, whole-cell patch-clamp in dopamine ARC neurons (brain slices), prolactin measurement, reproductive phenotyping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with electrophysiological characterization and in vivo endocrine phenotyping","pmids":["31285329"],"is_preprint":false},{"year":2017,"finding":"TRPC5 induces cytoprotective autophagy in breast cancer cells via the CaMKKβ/AMPKα/mTOR pathway, contributing to adriamycin resistance. Pharmacological inhibition or gene silencing of TRPC5 abolished this pathway and restored drug sensitivity in vitro and in vivo.","method":"siRNA knockdown, pharmacological inhibition, pathway inhibitors (CaMKKβ, AMPK, mTOR), autophagy markers (LC3), xenograft model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic interventions with pathway validation; single lab","pmids":["28600513"],"is_preprint":false},{"year":2008,"finding":"TRPC5 undergoes phase transitions in gating properties during the activation-deactivation cycle, shifting between outwardly-rectifying and doubly-rectifying I-V relationships. Mg2+ block mediated by cytoplasmic residue D633 underlies doubly-rectifying behavior at negative potentials. La3+ promotes channel transition to the doubly-rectifying (Phase 2) state.","method":"Whole-cell and single-channel patch-clamp, site-directed mutagenesis (D633), voltage-protocol analyses in HEK293 cells expressing rat TRPC5","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — single-channel recordings and mutagenesis identifying Mg2+ block site; single lab","pmids":["18247362"],"is_preprint":false},{"year":2005,"finding":"Junctate, an IP3R-associated protein, binds TRPC5 (and TRPC2) but not TRPC1 in sperm, as determined by pull-down experiments. The interaction is calcium-concentration-independent.","method":"Pull-down assay, co-immunoprecipitation, immunolocalization in rodent sperm","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct pull-down with reciprocal Co-IP in native sperm tissue; single lab, no functional electrophysiological validation for TRPC5 specifically","pmids":["16153633"],"is_preprint":false},{"year":2005,"finding":"TRPC5 co-immunoprecipitates with Na+/K+-ATPase (NKA) pump from rat brain lysates, suggesting TRPC5 participates in a plasmalemmal signaling complex (signalplex) with cytoskeletal proteins (spectrin, actin, myosin, drebrin, tubulin, neurabin) and endocytic proteins (clathrin, dynamin, AP-2).","method":"Affinity-purified antibody immunoprecipitation from rat brain lysates, reciprocal Co-IP, mass spectrometry identification of interacting proteins","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal Co-IP from native brain tissue with MS confirmation; no functional consequence validated for TRPC5-NKA interaction specifically","pmids":["16025302"],"is_preprint":false},{"year":2010,"finding":"In endothelial cells, TRPC6 activation by lysophosphatidylcholine (lysoPC) initiates Ca2+ influx that triggers translocation of TRPC5 to the plasma membrane, creating a TRPC6-TRPC5 channel cascade. The resulting prolonged Ca2+ elevation inhibits endothelial cell migration. TRPC5 externalization is dependent on upstream TRPC6 channel opening.","method":"siRNA knockdown of TRPC5 and TRPC6, TRPC6-/- mouse endothelial cells, surface biotinylation, Ca2+ imaging, cell migration assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown plus TRPC6 KO mouse cells with surface trafficking assay and migration readout; multiple orthogonal methods","pmids":["18495872"],"is_preprint":false},{"year":2006,"finding":"TRPC5-containing channels contribute to store-depletion-activated Ca2+ entry in smooth muscle cells of rabbit pial arterioles. An extracellular-loop-targeting anti-TRPC5 antibody (T5E3) suppressed Ca2+ entry in store-depleted arterioles but not in the absence of store depletion.","method":"T5E3 blocking antibody in freshly isolated arteriolar fragments, Ca2+ imaging, patch-clamp","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody-block experiment in native tissue with appropriate controls; single lab","pmids":["16861696"],"is_preprint":false},{"year":2010,"finding":"TRPC5 plasma membrane insertion via muscarinic stimulation contributes to cholinergic plateau potentials in hippocampal CA1 pyramidal neurons. Biotinylation assays showed that muscarinic stimulation specifically increased TRPC5 (not TRPC1 or TRPC4) surface expression in acute slices; PI3K inhibition (wortmannin) and CaM inhibition (W-7) blocked both TRPC5 insertion and the Ca2+ currents underlying plateau potentials.","method":"Surface biotinylation assay in acute hippocampal slices, whole-cell patch-clamp, pharmacological inhibition (2-APB, SKF96365, wortmannin, W-7), intracellular ATP perfusion","journal":"Hippocampus","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct surface expression quantification plus electrophysiology in native tissue with multiple pharmacological tools","pmids":["20865744"],"is_preprint":false},{"year":2012,"finding":"TRPC5 mediates NT-3 (neurotrophin-3)-induced Ca2+ influx in hippocampal neurons via PLCγ and TrkC signaling. Ca2+ influx through TRPC5 (not TRPC6) induced by NT-3 inhibits dendritic growth via CaMKIIα activation.","method":"siRNA knockdown of TRPC5, whole-cell patch-clamp, Ca2+ imaging, CaMKIIα inhibition, dendrite morphology analysis in rat hippocampal neurons","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — TRPC5-specific knockdown with electrophysiological and morphological readouts plus pathway identification","pmids":["22764246"],"is_preprint":false},{"year":2007,"finding":"GM1 ganglioside cross-linking by cholera toxin B subunit (CtxB) activates TRPC5 channels to induce Ca2+ influx and neurite outgrowth in NG108-15 cells and primary cerebellar granule neurons. GM1 associates with α5β1-integrin (not directly with TRPC5), and the signaling cascade involves FAK autophosphorylation, PLCγ activation, and PI3K to open TRPC5.","method":"TRPC5 siRNA knockdown, Ca2+ imaging, PLCγ/PI3K/FAK pharmacological inhibition, confocal immunocytochemistry showing co-localization, TRPC5 KO neurons","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown plus pathway dissection with multiple inhibitors and KO neurons","pmids":["17626205"],"is_preprint":false},{"year":2009,"finding":"In T effector cells, GM1 ganglioside cross-linking by galectin-1 (expressed by regulatory T cells) activates TRPC5 channels, causing Ca2+ influx that contributes to Treg-mediated suppression of Teff cell proliferation. TRPC5 shRNA knockdown blocked contact-dependent proliferation inhibition by Treg cells.","method":"shRNA knockdown of TRPC5, Ca2+ imaging, flow cytometry, T cell proliferation assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown with functional Ca2+ and proliferation readouts; single lab","pmids":["19299701"],"is_preprint":false},{"year":2014,"finding":"TRPC5-containing extracellular vesicles (EVs) from adriamycin-resistant breast cancer cells transfer TRPC5 protein to non-resistant recipient cells. Transferred TRPC5 activates NFATc3-mediated P-gp production through Ca2+ signaling, conferring chemoresistance on previously sensitive cells.","method":"EV isolation and transfer, TRPC5-siRNA treatment, Ca2+ signaling assays, P-gp expression by Western blot, xenograft mouse model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transfer of channel via EVs with Ca2+ and transcriptional pathway validation; single lab","pmids":["24733904"],"is_preprint":false},{"year":2015,"finding":"(-)-Englerin A is a potent, selective, and direct activator of TRPC4 and TRPC5 channels acting at a high-affinity extracellular binding site, rapidly killing renal cancer cells.","method":"Electrophysiology (patch-clamp), Ca2+ imaging, cell viability assays in TRPC4/5-expressing HEK cells and renal cancer cells","journal":"Angewandte Chemie (International ed. in English)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiological demonstration of channel activation with pharmacological characterization; single lab","pmids":["25707820"],"is_preprint":false},{"year":2018,"finding":"Insulin and leptin depolarize hypothalamic POMC neurons via activation of TRPC5 channels, downstream of PI3K signaling. TRPC5 is identified as the specific downstream effector based on biophysical properties, pharmacological profile, and immunocytochemistry/single-cell RT-PCR localization.","method":"Whole-cell patch-clamp in mouse/rat/primate POMC neurons, pharmacological dissection, immunocytochemistry, single-cell RT-PCR, i.c.v. insulin injection with metabolic measurements","journal":"Journal of neuroendocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — electrophysiology in native neurons across multiple mammalian species with pharmacological and molecular identity confirmation","pmids":["28675783"],"is_preprint":false}],"current_model":"TRPC5 is a Ca2+-permeable nonselective cation channel that assembles as homotetramers or heterotetramers with TRPC1 and TRPC4, is primarily activated downstream of Gq/11- and Gi-coupled receptors (with Gαi3 directly binding the ankyrin repeat domain to increase PIP2 sensitivity), is gated by intracellular Ca2+, lysophospholipids, mechanical stretch, cold (37–25°C), protons, and oxidative modifications (S-glutathionylation at Cys176/Cys178; palmitoylation), is regulated by multiple binding partners including calmodulin/CIRB domain, CaBP1, NCS-1, SESTD1, and EBP50, is subject to PKA-mediated inhibition (Ser794/Ser796) and calpain-mediated cleavage/activation, and controls neurite/dendrite growth, growth cone morphology (via stathmin 2 interaction), innate fear (amygdala), hippocampal synaptic transmission and working memory, POMC neuron excitability and energy homeostasis, podocyte cytoskeletal dynamics (Rac1 pathway), kidney filtration barrier integrity, and cancer drug resistance (via NFATc3-P-gp signaling)."},"narrative":{"mechanistic_narrative":"TRPC5 is a Ca2+-permeable, nonselective cation channel that couples Gq/11- and Gi-coupled receptor signaling and diverse physicochemical stimuli to localized Ca2+ entry, thereby controlling neuronal excitability, cytoskeletal dynamics, and cell migration [PMID:10837492, PMID:19450521, PMID:20978238]. It functions as a receptor-operated channel activated downstream of Gq/11 receptors and receptor tyrosine kinases independently of store depletion [PMID:10837492], with Gαi subunits (predominantly Gαi3) serving as direct activators that bind the channel and, as resolved by cryo-EM of the 4:4 TRPC5–Gαi3 complex, dock on the ankyrin-repeat edge ~50 Å from the membrane to increase channel sensitivity to PIP2 [PMID:37137991, PMID:22457348]. The channel assembles as homotetramers or as heteromultimers selectively with TRPC1 and TRPC4 [PMID:11301024, PMID:28790178], an assembly that gates which stimuli are sensed—homomeric TRPC5 is cold-sensitive whereas TRPC1/TRPC5 heteromers are not [PMID:22025699]. N-terminal ankyrin repeats drive multimerization [PMID:17624425] and extracellular pore-loop disulfide bonds (Cys553/Cys558) are required for tetramerization, trafficking, and activity [PMID:24859801], consistent with the disulfide-bonded extracellular pore resolved in the 2.8 Å homotetramer structure [PMID:31355338]. TRPC5 integrates a remarkable breadth of gating inputs: intracellular Ca2+ potentiation [PMID:19398778, PMID:19815560], lysophospholipids [PMID:16368680], membrane stretch and hypoosmolarity [PMID:18832422], extracellular protons and lanthanides acting at pore glutamates E543/E595 [PMID:12456670, PMID:17884814], bidirectional PIP2 regulation [PMID:18665391, PMID:33933453], oxidative S-glutathionylation at Cys176/Cys178 [PMID:26133660], and proteolytic activation by calpain at Thr857 [PMID:22547824]. Its activity is tuned by C-terminal binding partners—calmodulin and the CIRB domain [PMID:15987684], CaBP1 and NCS-1 [PMID:16469785, PMID:15895247], SESTD1 [PMID:20164195], and the PDZ scaffold EBP50 [PMID:15334657]—and is inhibited by PKA phosphorylation at Ser794/Ser796 [PMID:21734191]. Functionally, TRPC5-mediated Ca2+ influx restrains neurite and dendrite growth, signaling through stathmin 2, CaMKIIβ–Cdc20-APC, and NT-3/TrkC pathways [PMID:12858178, PMID:22135323, PMID:22764246], and in podocytes it complexes with and activates Rac1 to drive cytoskeletal remodeling and filtration-barrier injury [PMID:20978238, PMID:24231357]. In the brain, TRPC5 is required for innate fear, hippocampal LTP and working memory, seizure susceptibility, and POMC-neuron responses to leptin, serotonin, and insulin governing energy homeostasis [PMID:19450521, PMID:23188715, PMID:28790178, PMID:28099839, PMID:28675783]. In cancer, TRPC5 drives NFATc3-dependent P-glycoprotein induction and cytoprotective autophagy underlying chemoresistance, and is propagated between cells via extracellular vesicles [PMID:22988121, PMID:28600513, PMID:24733904].","teleology":[{"year":2000,"claim":"Established TRPC5 as a receptor-operated rather than store-operated channel, defining its core signaling logic.","evidence":"Whole-cell and inside-out patch-clamp with Mn2+ quench in HEK293 cells expressing mTRPC5","pmids":["10837492"],"confidence":"High","gaps":["Did not resolve the direct molecular link from Gq/11 to the channel","Single-channel gating mechanism left open"]},{"year":2001,"claim":"Showed TRPC5 does not act alone but co-assembles with TRPC1 into a native neuronal heteromeric channel, raising the question of subunit-defined channel diversity.","evidence":"Reciprocal Co-IP from brain plus heterologous coexpression electrophysiology in HEK293 cells","pmids":["11301024"],"confidence":"High","gaps":["Stoichiometry of heteromers undefined","Functional distinction of homo vs heteromers not yet established"]},{"year":2003,"claim":"Defined a cell-biological role: TRPC5 traffics to growth cones and restrains neurite extension, linking channel activity to neuronal morphogenesis.","evidence":"Co-IP with stathmin 2, dominant-negative expression, and live imaging in rat hippocampal neurons","pmids":["12858178"],"confidence":"High","gaps":["Mechanism by which stathmin 2 couples to channel function unclear","Downstream cytoskeletal effectors not fully mapped"]},{"year":2005,"claim":"Identified multiple C-terminal Ca2+-sensor and lipid-binding partners (CaM/CIRB, CaBP1, SESTD1 later) and lysophospholipid sensitivity, framing TRPC5 as a polymodal, tightly regulated channel.","evidence":"Mutagenesis, in vitro binding/pull-down, and patch-clamp across CHO/HEK293/Xenopus systems; excised-patch lysophospholipid activation","pmids":["15987684","15895247","16368680"],"confidence":"High","gaps":["How competing Ca2+ sensors are coordinated in cells unresolved","Direct vs membrane-mediated lysophospholipid action not definitively separated"]},{"year":2008,"claim":"Established mechanosensitivity and bidirectional PIP2 regulation, expanding the polymodal gating repertoire and revealing context-dependent lipid control.","evidence":"Excised-patch and whole-cell patch-clamp with pressure application, PIP2 depletion/infusion in HEK293 cells","pmids":["18832422","18665391"],"confidence":"High","gaps":["Molecular site of mechanical sensing unidentified","Reconciling stimulatory vs inhibitory PIP2 effects mechanistically incomplete"]},{"year":2009,"claim":"Demonstrated an essential in vivo role in innate fear circuits and quantified intracellular Ca2+ potentiation, connecting molecular gating to behavior.","evidence":"TRPC5 KO mice with amygdala electrophysiology and fear behavior; caged-Ca2+ single-channel recordings","pmids":["19450521","19398778","19815560"],"confidence":"High","gaps":["Identity of the intracellular Ca2+ binding site not resolved","Receptor specificity in vivo only partially mapped"]},{"year":2010,"claim":"Placed TRPC5 in opposition to TRPC6 as an antagonistic regulator of actin dynamics via direct complex with Rac1, providing a migration-control mechanism.","evidence":"Reciprocal Co-IP, siRNA, migration and Ca2+ imaging in podocytes and fibroblasts","pmids":["20978238"],"confidence":"High","gaps":["How Ca2+ influx selectively activates Rac1 vs RhoA unclear","Structural basis of TRPC5-Rac1 complex unknown"]},{"year":2011,"claim":"Linked TRPC5 Ca2+ signaling to a specific dendrite-patterning pathway and to cold sensing, refining its developmental and sensory roles.","evidence":"KO mice, in vivo RNAi, Co-IP of TRPC5–CaMKIIβ; temperature-evoked electrophysiology of homo vs heteromers","pmids":["22135323","22025699"],"confidence":"High","gaps":["How channel activity is converted to centrosomal Cdc20-APC phosphorylation incompletely defined","Molecular determinant of cold sensing in TRPC5 unmapped"]},{"year":2012,"claim":"Revealed proteolytic activation by calpain and direct Gαi activation via the SESTD domain, and extended pathophysiology to seizures, drug resistance, and neurotrophin signaling.","evidence":"In vitro calpain cleavage with T857 mutagenesis; Co-IP and constitutively active Gαi electrophysiology; KO seizure models; NFAT reporter and xenograft assays; NT-3/TrkC dissection in neurons","pmids":["22547824","22457348","23188715","22988121","22764246"],"confidence":"High","gaps":["Physiological triggers of calpain cleavage in vivo unclear","How distinct activators converge on gating not unified"]},{"year":2013,"claim":"Identified gating elements (S4-S5 linker Gly504) and an in vivo role in kidney filtration-barrier injury, connecting channel conformation to disease.","evidence":"G504S and suppressor mutagenesis with cell-death assays; Trpc5-KO mice and inhibitor with podocyte imaging and albuminuria","pmids":["23677990","24231357"],"confidence":"High","gaps":["Full open-state conformational pathway not resolved without structure at the time","Endogenous activator driving podocyte injury not pinpointed"]},{"year":2014,"claim":"Defined pore-loop disulfide bonds essential for assembly/trafficking and demonstrated intercellular spread of resistance via TRPC5-bearing extracellular vesicles.","evidence":"Cys553/Cys558 mutagenesis with FRET, Co-IP, surface biotinylation; EV isolation/transfer with NFATc3-P-gp readouts and xenografts","pmids":["24859801","24733904"],"confidence":"High","gaps":["EV transfer mechanism and in vivo relevance only partly characterized","Link between disulfide redox state and physiological gating incomplete"]},{"year":2015,"claim":"Showed oxidative S-glutathionylation at Cys176/Cys178 activates TRPC5 to drive striatal neuronal death, implicating the channel in Huntington's disease pathology.","evidence":"Cysteine mutagenesis glutathionylation assay, electrophysiology, KO/inhibition, YAC128 mice and human HD tissue","pmids":["26133660"],"confidence":"High","gaps":["Whether HD-relevant activation is reversible therapeutically untested here","Interplay with TRPC1 expression in determining homotetramer fraction only correlative"]},{"year":2017,"claim":"Used native complexomics and triple-KO mice to define a TRPC1/4/5 channel family and established TRPC5 roles in synaptic transmission, working memory, and POMC energy homeostasis.","evidence":"Quantitative MS of native complexes, Trpc1/4/5 triple-KO with electrophysiology and memory tasks; POMC-conditional Trpc5 KO with metabolic phenotyping","pmids":["28790178","28099839","28600513"],"confidence":"High","gaps":["Subunit composition of physiologically relevant channels in each tissue still uncertain","Autophagy pathway link (Medium confidence) needs broader validation"]},{"year":2019,"claim":"Solved the homotetramer cryo-EM structure and revealed palmitoylation and additional neuroendocrine functions, providing a structural and post-translational framework.","evidence":"2.8 Å cryo-EM with mutagenesis; palmitoylation assay in HD striatal cells; conditional KO with prolactin/reproductive phenotyping","pmids":["31355338","31812495","31285329"],"confidence":"High","gaps":["Ligand- and state-specific conformations not captured","Palmitoylation enzyme/site identity (Medium confidence) not fully defined"]},{"year":2023,"claim":"Resolved the TRPC5–Gαi3 complex structure, defining how a direct G-protein interaction at the ankyrin domain potentiates PIP2 sensitivity to open the channel.","evidence":"Cryo-EM in lipid nanodiscs with PIP2-sensitivity electrophysiology","pmids":["37137991"],"confidence":"High","gaps":["Conformational transitions linking Gαi3 binding to pore opening not fully traced","Generalizability to heteromeric channels untested"]},{"year":null,"claim":"How the channel's many gating modalities, subunit compositions, and tissue-specific partners are integrated to produce distinct physiological Ca2+ signals remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking polymodal stimuli to defined open states across cell types","Tissue-specific heteromer stoichiometry and partner dependence incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,3,9,33]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[8,18,13,25]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,16,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[23,31,43,41]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,47]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5,40]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,16,15]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,12,34,35,49]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,11,44]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7,13,47]}],"complexes":["TRPC1/TRPC4/TRPC5 heteromeric channel","TRPC5–Gαi3 complex","TRPC5–Rac1 complex","TRPC5–CaMKIIβ complex"],"partners":["TRPC1","TRPC4","GNAI3","RAC1","CAMK2B","SESTD1","NCS1","CABP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UL62","full_name":"Short transient receptor potential channel 5","aliases":["Transient receptor protein 5","TRP-5","hTRP-5","hTRP5"],"length_aa":973,"mass_kda":111.4,"function":"Forms a receptor-activated non-selective calcium permeant cation channel (PubMed:16284075, PubMed:38959890, PubMed:37137991). Mediates calcium-dependent phosphatidylserine externalization and apoptosis in neurons via its association with PLSCR1 (By similarity). Acts on distinct neuronal populations in the hypothalamus to regulate innate behaviors including feeding, anxiety (flight/fight/fear), socialization, and maternal care (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UL62/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRPC5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRPC5","total_profiled":1310},"omim":[{"mim_id":"621011","title":"SEC14 AND SPECTRIN DOMAINS-CONTAINING PROTEIN 1; SESTD1","url":"https://www.omim.org/entry/621011"},{"mim_id":"612489","title":"RING FINGER PROTEIN 24; RNF24","url":"https://www.omim.org/entry/612489"},{"mim_id":"612017","title":"PYLORIC STENOSIS, INFANTILE HYPERTROPHIC, 3; IHPS3","url":"https://www.omim.org/entry/612017"},{"mim_id":"611025","title":"ENKURIN, TRPC CHANNEL-INTERACTING PROTEIN; ENKUR","url":"https://www.omim.org/entry/611025"},{"mim_id":"605921","title":"STROMAL INTERACTION MOLECULE 1; STIM1","url":"https://www.omim.org/entry/605921"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"brain","ntpm":1.3}],"url":"https://www.proteinatlas.org/search/TRPC5"},"hgnc":{"alias_symbol":["PPP1R159"],"prev_symbol":[]},"alphafold":{"accession":"Q9UL62","domains":[{"cath_id":"1.25.40.20","chopping":"25-121_134-139","consensus_level":"medium","plddt":84.3809,"start":25,"end":139},{"cath_id":"-","chopping":"213-316_696-763","consensus_level":"medium","plddt":85.7471,"start":213,"end":763},{"cath_id":"-","chopping":"319-391","consensus_level":"medium","plddt":87.7725,"start":319,"end":391},{"cath_id":"1.10.287","chopping":"512-650","consensus_level":"medium","plddt":90.6983,"start":512,"end":650}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UL62","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UL62-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UL62-F1-predicted_aligned_error_v6.png","plddt_mean":73.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRPC5","jax_strain_url":"https://www.jax.org/strain/search?query=TRPC5"},"sequence":{"accession":"Q9UL62","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UL62.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UL62/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UL62"}},"corpus_meta":[{"pmid":"11301024","id":"PMC_11301024","title":"TRPC1 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behavior.","date":"2009","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19450521","citation_count":234,"is_preprint":false},{"pmid":"20978238","id":"PMC_20978238","title":"Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels.","date":"2010","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/20978238","citation_count":224,"is_preprint":false},{"pmid":"12456670","id":"PMC_12456670","title":"Lanthanides potentiate TRPC5 currents by an action at extracellular sites close to the pore mouth.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12456670","citation_count":220,"is_preprint":false},{"pmid":"15806115","id":"PMC_15806115","title":"Block of TRPC5 channels by 2-aminoethoxydiphenyl borate: a differential, extracellular and voltage-dependent effect.","date":"2005","source":"British journal of 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Coexpression in HEK293 cells produced a novel nonselective cation channel with voltage dependence similar to NMDA receptors, activated by Gq-coupled receptors but not by intracellular Ca2+ store depletion.\",\n      \"method\": \"Co-immunoprecipitation, heterologous coexpression in HEK293 cells, whole-cell patch-clamp electrophysiology\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP from brain lysates combined with electrophysiological characterization of heteromeric channel properties; replicated across multiple subsequent studies\",\n      \"pmids\": [\"11301024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TRPC5 (mTRPC5) forms a receptor-operated nonselective cation channel (single-channel conductance ~66 pS at -60 mV) activated by Gq/11-coupled receptors and receptor tyrosine kinases independently of intracellular Ca2+ store depletion; GTPγS activates channels in inside-out patches in a membrane-confined manner.\",\n      \"method\": \"Whole-cell patch-clamp, inside-out patch recording, Mn2+ quench assay in fura-2-loaded HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal electrophysiological methods including single-channel recordings; replicated by multiple independent labs\",\n      \"pmids\": [\"10837492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TRPC5 is expressed in neuronal growth cones, interacts with the growth cone-enriched protein stathmin 2, is packaged into vesicles and transported to growth cones and synapses. TRPC5 channel activity restrains neurite extension and growth cone morphology, as dominant-negative TRPC5 expression allowed significantly longer neurites and filopodia.\",\n      \"method\": \"Co-immunoprecipitation (TRPC5-stathmin 2 interaction), dominant-negative expression, live-cell imaging, immunofluorescence in rat hippocampal neurons\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP interaction data combined with dominant-negative functional rescue and live imaging; replicated in subsequent studies\",\n      \"pmids\": [\"12858178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Lanthanide ions (La3+, Gd3+) potentiate TRPC5 currents at micromolar concentrations via extracellular sites near the pore mouth. Neutralization of negatively charged residues Glu543 and Glu595/Glu598 abolished potentiation; these residues are accessible from the extracellular side. The mechanism involves reduced single-channel conductance but dramatic increase in open probability.\",\n      \"method\": \"Site-directed mutagenesis, whole-cell and outside-out patch-clamp recordings in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific residues combined with single-channel recordings; well-replicated mechanistic finding\",\n      \"pmids\": [\"12456670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRPC5-/- mice exhibit diminished innate fear and reduced responses mediated by Group I metabotropic glutamate and CCK2 receptors in amygdala neurons, demonstrating that TRPC5, activated via G protein-coupled neuronal receptors, has an essential function in innate fear circuits.\",\n      \"method\": \"TRPC5 knockout mice, electrophysiology in amygdala slices, behavioral fear assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal behavioral and electrophysiological readouts in a high-impact study\",\n      \"pmids\": [\"19450521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRPC5 forms a molecular complex with Rac1 in podocytes and fibroblasts; TRPC5-mediated Ca2+ influx activates Rac1, promoting cell migration. Conversely, TRPC6 is in complex with RhoA and its Ca2+ influx activates RhoA to inhibit migration, establishing TRPC5 and TRPC6 as antagonistic regulators of actin dynamics.\",\n      \"method\": \"Co-immunoprecipitation (TRPC5-Rac1 and TRPC6-RhoA complexes), siRNA knockdown, cell migration assays, Ca2+ imaging in podocytes and fibroblasts\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional knockdown with specific readouts in two cell types\",\n      \"pmids\": [\"20978238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRPC5 mediates kidney filtration barrier injury. Loss of TRPC5 (Trpc5-KO mice) or pharmacological inhibition prevents podocyte cytoskeletal remodeling, blocks Rac1 activation, stabilizes synaptopodin, and protects against albuminuria.\",\n      \"method\": \"Trpc5 knockout mice, small-molecule TRPC5 inhibitor, Ca2+ imaging in isolated glomeruli, live imaging of podocyte actin dynamics, urine albumin measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and pharmacological inhibition with multiple cellular and in vivo readouts\",\n      \"pmids\": [\"24231357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRPC5 activity drives P-glycoprotein (P-gp) induction in adriamycin-resistant breast cancer cells via an NFATc3-dependent transcriptional mechanism (TRPC5-NFATc3-P-gp signaling cascade). Suppression of TRPC5 reduced P-gp expression and reversed drug resistance in vitro and in a xenograft model.\",\n      \"method\": \"siRNA knockdown, channel inhibition, NFAT reporter assay, Western blotting, xenograft tumor model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (genetic and pharmacological) with in vitro and in vivo validation\",\n      \"pmids\": [\"22988121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRPC5 is activated by cold temperatures in the range 37–25°C. Homomeric TRPC5 channels, but not TRPC1/TRPC5 heteromeric channels, are cold-sensitive. TRPC5 is present in dorsal root ganglion sensory neurons and peripheral nerve endings consistent with a role as an innocuous cold transducer.\",\n      \"method\": \"Temperature-evoked electrophysiology (cold activation of expressed TRPC5), TRPC5 KO mice behavioral testing, immunohistochemistry of DRG neurons\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct electrophysiological demonstration of cold activation with mutagenesis-style dissection of homo vs heteromeric channels, plus KO mouse data\",\n      \"pmids\": [\"22025699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Intracellular Ca2+ potentiates TRPC5 channel activity: ~1 µM intracellular Ca2+ triggers ~10–20-fold increase in channel open probability in excised inside-out patches without changing single-channel conductance. Extracellular Ca2+ (not Ba2+ or Mg2+) is required for the potentiation, acting at an intracellular site.\",\n      \"method\": \"Simultaneous fura-2 imaging and patch-clamp, excised inside-out single-channel recordings, caged Ca2+ photolysis, whole-cell patch-clamp in HEK293 cells\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous single-channel and simultaneous imaging/electrophysiology in one study; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19398778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Calpain-1 and calpain-2 cleave and functionally activate TRPC5. A critical threonine at position 857 is required for calpain-2 cleavage. The truncated TRPC5 resulting from calpain cleavage is functionally active. This mechanism mediates semaphorin 3A-induced growth cone collapse in hippocampal neurons.\",\n      \"method\": \"In vitro calpain cleavage assay, site-directed mutagenesis (T857 mutant), TRPC5-null hippocampal neurons, electrophysiology, growth cone collapse assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro protease cleavage assay with mutagenesis plus null neuron rescue experiments\",\n      \"pmids\": [\"22547824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRPC5 KO mice have long, highly branched cerebellar granule neuron dendrites with impaired dendritic claw differentiation. TRPC5 forms a complex specifically with CaMKIIβ (not CaMKIIα) and induces CaMKIIβ-dependent phosphorylation of the ubiquitin ligase Cdc20-APC at the centrosome, coupling Ca2+ signaling to a ubiquitin ligase pathway to regulate dendrite patterning.\",\n      \"method\": \"TRPC5 KO mice, in vivo RNAi, Co-immunoprecipitation (TRPC5-CaMKIIβ complex), phosphorylation assays, behavioral motor coordination tests\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of specific complex combined with KO mice, in vivo RNAi, and biochemical pathway mapping\",\n      \"pmids\": [\"22135323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRPC5 KO mice show significantly reduced pilocarpine-induced seizures and minimal seizure-induced hippocampal neuronal death, whereas TRPC1/4 double KO mice show unaltered seizures but reduce epileptiform bursting in lateral septal neurons—demonstrating that TRPC5 and TRPC1/4 contribute to seizures and excitotoxicity via distinct cellular mechanisms. Long-term potentiation is greatly reduced in TRPC5 KO hippocampi.\",\n      \"method\": \"TRPC5 KO mice, TRPC1 KO mice, TRPC1/4 double-KO mice, pilocarpine seizure model, hippocampal slice electrophysiology, LTP recordings\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis across multiple KO lines with multiple electrophysiological and in vivo behavioral readouts\",\n      \"pmids\": [\"23188715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRPC5 glutathionylation at Cys176/Cys178 by intracellular oxidized glutathione activates TRPC5 channels, causing sustained Ca2+ influx, calmodulin-dependent protein kinase activation, and calpain-caspase-mediated striatal neuronal death. Increased TRPC5 S-glutathionylation and low TRPC1 expression (promoting TRPC5 homotetramer formation) were found in striatum of YAC128 HD transgenic mice and HD patients.\",\n      \"method\": \"S-glutathionylation assay (cysteine mutagenesis C176/C178), electrophysiology, Ca2+ imaging, TRPC5 knockdown/inhibition, YAC128 transgenic mice, human HD brain tissue\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — identification of specific modified residues by mutagenesis plus in vitro and in vivo validation including human tissue\",\n      \"pmids\": [\"26133660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM structure of mouse TRPC5 homotetramers resolved at 2.8 Å. The structure revealed a disulfide bond at the extracellular pore domain and differences in the extracellular pore domain and S3 helix length compared to other TRP channels. Mutagenesis confirmed the disulfide bond and a preceding loop are essential for TRPC5 function.\",\n      \"method\": \"Cryo-electron microscopy (2.8 Å resolution), electrophysiology, mutagenesis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with functional mutagenesis validation\",\n      \"pmids\": [\"31355338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of human TRPC5-Gαi3 complexes at ~3 Å reveal a 4:4 stoichiometry in lipid nanodiscs. Gαi3 binds to the ankyrin repeat edge of TRPC5 ~50 Å from the membrane. Gαi3 increases TRPC5 sensitivity to PIP2, rendering the channel more easily opened under physiological PIP2 concentrations.\",\n      \"method\": \"Cryo-EM structure determination in lipid nanodiscs, electrophysiology (PIP2 sensitivity), structural modeling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure of functional complex with electrophysiological mechanistic validation\",\n      \"pmids\": [\"37137991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Gαi subunits are primary direct activators of TRPC5 (predominantly Gαi3) and TRPC4. Activation occurs through direct interaction of Gα with the conserved C-terminal SESTD domain of the channels. Two residues (K715 and R716) in TRPC4 mediate the Gαi2 interaction. Constitutively active Gαi mutants fully activate the channels.\",\n      \"method\": \"Co-immunoprecipitation, constitutively active Gα mutant expression, electrophysiology, structural modeling of SESTD-Gαi interaction, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP with mutagenesis and electrophysiological validation of direct Gαi-channel interaction mechanism\",\n      \"pmids\": [\"22457348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRPC5 is activated by common endogenous lysophospholipids including lysophosphatidylcholine (LPC) independently of G-protein signaling. LPC activates TRPC5 in excised membrane patches, suggesting a relatively direct action on the channel structure. The effect shows dependence on acyl-chain length and head-group chemistry.\",\n      \"method\": \"Excised inside-out patch recordings, Ca2+-indicator dye measurements, G-protein pathway inhibition experiments in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — excised patch recordings demonstrating membrane-delimited direct activation with structure-activity analysis; single lab\",\n      \"pmids\": [\"16368680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Hypoosmotic stimulation and direct membrane stretch activate TRPC5 channels, causing Ca2+ influx. The osmotic response is blocked by GsMTx-4 (stretch-activated channel inhibitor) and requires PIP2; direct application of positive pressure through patch pipette also activates TRPC5. Activation is independent of PLC function.\",\n      \"method\": \"Whole-cell and excised patch-clamp, intracellular Ca2+ imaging, lipid phosphatase overexpression to deplete PIP2, pressure application via patch pipette in TRPC5-expressing cells\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mechanosensory activation demonstrated in excised patches with pharmacological dissection; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18832422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Calmodulin (CaM) binds to a novel C-terminal domain of TRPC5 (95 amino acids downstream from the CIRB domain), and exogenous CaM accelerates agonist-induced TRPC5 channel activation by ~2.8-fold. The CIRB domain is critical for overall receptor-induced TRPC5 activation. High intracellular Ca2+ (>5 µM) inhibits current density, demonstrating dual and opposite Ca2+ effects on TRPC5.\",\n      \"method\": \"Whole-cell patch-clamp, deletion mutagenesis, co-immunoprecipitation, surface expression assay in CHO and HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of specific CaM-binding domains with functional electrophysiological validation and Co-IP; single lab\",\n      \"pmids\": [\"15987684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Neuronal calcium sensor-1 (NCS-1) directly binds to the TRPC5 C-terminus and suppresses TRPC5 channel activity evoked by multiple stimuli. NCS-1 and TRPC5 are present in the same protein complex in rat brain. This NCS-1/TRPC5 complex contributes to retardation of neurite outgrowth.\",\n      \"method\": \"Co-immunoprecipitation from rat brain, in vitro pull-down binding assay, dominant-negative NCS-1 expression, patch-clamp electrophysiology\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP from native brain tissue, in vitro direct binding, plus functional electrophysiological validation\",\n      \"pmids\": [\"16469785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ca2+-binding protein 1 (CaBP1) directly binds TRPC5 and inhibits its channel activity without affecting surface expression. CaBP1-binding sites on the TRPC5 C-terminus are closely localized to but distinct from CaM-binding sites. TRPC5 activity requires both extracellular and intracellular Ca2+.\",\n      \"method\": \"In vitro pull-down assay, two-electrode voltage clamp in Xenopus oocytes, surface expression assay, mutagenesis\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro direct binding assay plus functional Xenopus oocyte electrophysiology; single lab\",\n      \"pmids\": [\"15895247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SESTD1, a phospholipid-binding protein containing SEC14-like and spectrin domains, associates with TRPC5 (and TRPC4) via the CIRB domain and is essential for efficient receptor-mediated activation of TRPC5. Phospholipid binding by SESTD1 is Ca2+-dependent.\",\n      \"method\": \"Yeast two-hybrid screen, Co-immunoprecipitation, in vitro phospholipid-binding assay, siRNA knockdown with electrophysiological readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus in vitro lipid binding plus functional electrophysiology; single lab\",\n      \"pmids\": [\"20164195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRPC5 activity is maintained by constitutive Ca2+-calmodulin/MLCK signaling that promotes plasma membrane localization of TRPC5. ML-9 (MLCK inhibitor) impaired membrane localization of TRPC5 and abolished channel activity in whole-cell recordings but not in excised inside-out patches.\",\n      \"method\": \"Whole-cell patch-clamp, inside-out patch-clamp, dominant-negative MLCK mutant expression, calmodulin inhibitor (W-13), surface localization assessment in HEK293 cells\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and dominant-negative dissection with electrophysiology; single lab, indirect evidence for MLCK as direct writer\",\n      \"pmids\": [\"16284075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The scaffolding protein EBP50 (NHERF1) modulates TRPC5 activation kinetics via the C-terminal VTTRL PDZ-binding motif. Co-expression of EBP50 caused significant delay in histamine-evoked TRPC5 activation; deletion of VTTRL abolished EBP50's modulatory effect without altering channel biophysical properties.\",\n      \"method\": \"Whole-cell patch-clamp, deletion mutagenesis (VTTRL motif), co-expression in HEK293 cells\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus functional electrophysiology; single lab with two orthogonal approaches\",\n      \"pmids\": [\"15334657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Protons potentiate TRPC5 currents: lowering extracellular pH from 7.4 to 6.5 increases TRPC5 currents by reducing single-channel conductance while dramatically increasing open probability. The same glutamate residues responsible for lanthanide sensitivity (E543 and E595) mediate H+ potentiation.\",\n      \"method\": \"Whole-cell and single-channel patch-clamp, mutagenesis of E543Q and E595Q in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific pore residues with single-channel and whole-cell electrophysiology; single lab but multiple methods\",\n      \"pmids\": [\"17884814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PKA directly inhibits TRPC5 channels via phosphorylation at Ser794 and Ser796. Constitutively active Gαs, isoproterenol, and 8-bromo-cAMP inhibit TRPC5 currents; this inhibition is abolished by S794A/S796A point mutations. PKA-mediated inhibition does not affect TRPC5 surface expression/trafficking.\",\n      \"method\": \"Whole-cell patch-clamp, site-directed mutagenesis (S794A, S796A), surface biotinylation, constitutively active Gαs expression in HEK293 cells\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific phosphorylation sites combined with electrophysiology and surface biotinylation; single lab\",\n      \"pmids\": [\"21734191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Complex regulation of TRPC5 by phosphatidylinositol 4,5-bisphosphate (PIP2): depletion of PIP2 via PI4-kinase inhibition activates TRPC5; inclusion of PIP2 in patch pipette inhibits TRPC5 currents; yet in excised patches PIP2 robustly activates TRPC5 single channels, demonstrating both inhibitory and stimulatory roles for PIP2 in regulating TRPC5.\",\n      \"method\": \"Whole-cell patch-clamp, excised single-channel recordings, PI4-kinase inhibition, targeted 5-phosphatase strategy, PIP2 infusion via patch pipette in HEK293 cells\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal PIP2 manipulation strategies with single-channel recordings; single lab\",\n      \"pmids\": [\"18665391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PIP2 controls both PKC-mediated desensitization and DAG/lanthanide-mediated activation of TRPC5 currents via gating regulation rather than by changing channel cell surface density. Optogenetically-controlled PIP2 dephosphorylation was used to dissect these mechanisms.\",\n      \"method\": \"Whole-cell patch-clamp, optogenetic PIP2 dephosphorylation tool, total internal reflection fluorescence microscopy for surface density in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — novel optogenetic tool combined with electrophysiology and surface density imaging; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33933453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The S4-S5 linker is a critical gating element in TRPC5. A conserved Gly504 to Ser substitution forces TRPC5 into a constitutively open conformation, causing Ca2+-dependent cell death. A second mutation (in the C-terminal S6 helix region) suppresses constitutive activation, suggesting an interaction between the S4-S5 linker and S6 in gating.\",\n      \"method\": \"Site-directed mutagenesis (G504S, double mutant), whole-cell patch-clamp, Ca2+-dependent cell death assay in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-function mutagenesis at defined gating residues with functional electrophysiological characterization; single lab\",\n      \"pmids\": [\"23677990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The first ankyrin-like repeat in the N-terminus is the minimum domain required for TRPC5 homomultimerization and functional assembly. Fragments lacking this repeat fail to multimerise, cannot interact with wild-type TRPC5, and do not form functional channels. N-terminal dominant-negative fragments retaining the first ankyrin repeat trap TRPC5 intracellularly.\",\n      \"method\": \"FRET measurements (CFP/YFP-labeled fragments), TIRF microscopy, electrophysiology, dominant-negative truncation analysis in HEK293 cells\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET-based interaction mapping combined with TIRF localization and electrophysiology; single lab multiple methods\",\n      \"pmids\": [\"17624425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Extracellular disulfide bonds between Cys553 and Cys558 in the pore loop are essential for TRPC5 tetramerization, trafficking to plasma membrane, and channel activity. C553S or C558S mutants lose all channel activity and act as dominant negatives. Reducing agents decrease membrane TRPC5 distribution.\",\n      \"method\": \"Cysteine mutagenesis (C553S, C558S), Co-immunoprecipitation, FRET analysis of dimerization, surface biotinylation, electrophysiology in HEK293 cells\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of specific disulfide-forming cysteines combined with FRET, Co-IP, surface trafficking, and electrophysiology; single lab\",\n      \"pmids\": [\"24859801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPC5 palmitoylation at a conserved cysteine residue is critical for intrinsic channel activity and membrane stability. Depalmitoylation reduces TRPC5 membrane stability and attenuates Ca2+-mediated striatal neurotoxicity in Huntington's disease cells.\",\n      \"method\": \"Palmitoylation assay, mutagenesis of palmitoylation site, membrane trafficking assay, electrophysiology in HD striatal cells (STHdh)\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — palmitoylation biochemistry with functional channel activity readout; single lab\",\n      \"pmids\": [\"31812495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRPC5 is activated by intracellular Ca2+ with an EC50 of ~635 nM at negative potentials; Ca2+ entry through either CRAC channels (STIM1/Orai1) or L-type voltage-gated Ca2+ channels is sufficient to activate TRPC5 via local subsarcolemmal Ca2+ increases (blocked by BAPTA but not EGTA).\",\n      \"method\": \"Whole-cell patch-clamp, caged Ca2+ photolysis, co-expression of STIM1/Orai1 and L-type Ca2+ channel subunits, EGTA vs BAPTA Ca2+ buffering comparison in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct intracellular Ca2+ dose-response with caged-Ca2+ photolysis and functional coupling experiments; single lab multiple methods\",\n      \"pmids\": [\"19815560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPC1, TRPC4, and TRPC5 assemble into heteromultimers with each other but not with other TRP family members in mouse brain and hippocampus. Loss of all TRPC1/4/5-containing channels reduces action potential-triggered EPSCs, impairs cross-frequency hippocampal network coupling, and causes deficits in spatial working memory but not reference memory.\",\n      \"method\": \"Quantitative high-resolution mass spectrometry (native complex identification), Trpc1/4/5 triple-KO mice, hippocampal slice electrophysiology (evoked EPSCs, LTP), in vivo hippocampal recordings, spatial memory tasks\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — MS-confirmed native complexes plus triple-KO mice with electrophysiology and in vivo behavioral characterization\",\n      \"pmids\": [\"28790178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TrpC5 in POMC neurons mediates the acute anorexigenic effects of leptin and serotonin 2C receptor (Ht2Cr) agonists. POMC-specific TrpC5 deletion blocks leptin- and Ht2Cr agonist-induced membrane depolarization and reduces energy expenditure while increasing food intake and body weight.\",\n      \"method\": \"Conditional Pomc-specific Trpc5 KO mice, whole-cell patch-clamp electrophysiology in arcuate POMC neurons, metabolic phenotyping, feeding behavior assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional cell-type-specific KO with electrophysiological validation and in vivo metabolic phenotyping\",\n      \"pmids\": [\"28099839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Trpc5 deficiency impairs infraslow membrane potential oscillations of dopamine arcuate nucleus (ARC) neurons and prolactin-evoked tonic plateau potentials. Female Trpc5-mutant mice show severe hypoprolactinemia with associated reproductive deficits.\",\n      \"method\": \"Conditional Trpc5 KO mice, whole-cell patch-clamp in dopamine ARC neurons (brain slices), prolactin measurement, reproductive phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with electrophysiological characterization and in vivo endocrine phenotyping\",\n      \"pmids\": [\"31285329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPC5 induces cytoprotective autophagy in breast cancer cells via the CaMKKβ/AMPKα/mTOR pathway, contributing to adriamycin resistance. Pharmacological inhibition or gene silencing of TRPC5 abolished this pathway and restored drug sensitivity in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition, pathway inhibitors (CaMKKβ, AMPK, mTOR), autophagy markers (LC3), xenograft model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic interventions with pathway validation; single lab\",\n      \"pmids\": [\"28600513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRPC5 undergoes phase transitions in gating properties during the activation-deactivation cycle, shifting between outwardly-rectifying and doubly-rectifying I-V relationships. Mg2+ block mediated by cytoplasmic residue D633 underlies doubly-rectifying behavior at negative potentials. La3+ promotes channel transition to the doubly-rectifying (Phase 2) state.\",\n      \"method\": \"Whole-cell and single-channel patch-clamp, site-directed mutagenesis (D633), voltage-protocol analyses in HEK293 cells expressing rat TRPC5\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-channel recordings and mutagenesis identifying Mg2+ block site; single lab\",\n      \"pmids\": [\"18247362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Junctate, an IP3R-associated protein, binds TRPC5 (and TRPC2) but not TRPC1 in sperm, as determined by pull-down experiments. The interaction is calcium-concentration-independent.\",\n      \"method\": \"Pull-down assay, co-immunoprecipitation, immunolocalization in rodent sperm\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct pull-down with reciprocal Co-IP in native sperm tissue; single lab, no functional electrophysiological validation for TRPC5 specifically\",\n      \"pmids\": [\"16153633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRPC5 co-immunoprecipitates with Na+/K+-ATPase (NKA) pump from rat brain lysates, suggesting TRPC5 participates in a plasmalemmal signaling complex (signalplex) with cytoskeletal proteins (spectrin, actin, myosin, drebrin, tubulin, neurabin) and endocytic proteins (clathrin, dynamin, AP-2).\",\n      \"method\": \"Affinity-purified antibody immunoprecipitation from rat brain lysates, reciprocal Co-IP, mass spectrometry identification of interacting proteins\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal Co-IP from native brain tissue with MS confirmation; no functional consequence validated for TRPC5-NKA interaction specifically\",\n      \"pmids\": [\"16025302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In endothelial cells, TRPC6 activation by lysophosphatidylcholine (lysoPC) initiates Ca2+ influx that triggers translocation of TRPC5 to the plasma membrane, creating a TRPC6-TRPC5 channel cascade. The resulting prolonged Ca2+ elevation inhibits endothelial cell migration. TRPC5 externalization is dependent on upstream TRPC6 channel opening.\",\n      \"method\": \"siRNA knockdown of TRPC5 and TRPC6, TRPC6-/- mouse endothelial cells, surface biotinylation, Ca2+ imaging, cell migration assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown plus TRPC6 KO mouse cells with surface trafficking assay and migration readout; multiple orthogonal methods\",\n      \"pmids\": [\"18495872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRPC5-containing channels contribute to store-depletion-activated Ca2+ entry in smooth muscle cells of rabbit pial arterioles. An extracellular-loop-targeting anti-TRPC5 antibody (T5E3) suppressed Ca2+ entry in store-depleted arterioles but not in the absence of store depletion.\",\n      \"method\": \"T5E3 blocking antibody in freshly isolated arteriolar fragments, Ca2+ imaging, patch-clamp\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody-block experiment in native tissue with appropriate controls; single lab\",\n      \"pmids\": [\"16861696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRPC5 plasma membrane insertion via muscarinic stimulation contributes to cholinergic plateau potentials in hippocampal CA1 pyramidal neurons. Biotinylation assays showed that muscarinic stimulation specifically increased TRPC5 (not TRPC1 or TRPC4) surface expression in acute slices; PI3K inhibition (wortmannin) and CaM inhibition (W-7) blocked both TRPC5 insertion and the Ca2+ currents underlying plateau potentials.\",\n      \"method\": \"Surface biotinylation assay in acute hippocampal slices, whole-cell patch-clamp, pharmacological inhibition (2-APB, SKF96365, wortmannin, W-7), intracellular ATP perfusion\",\n      \"journal\": \"Hippocampus\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct surface expression quantification plus electrophysiology in native tissue with multiple pharmacological tools\",\n      \"pmids\": [\"20865744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRPC5 mediates NT-3 (neurotrophin-3)-induced Ca2+ influx in hippocampal neurons via PLCγ and TrkC signaling. Ca2+ influx through TRPC5 (not TRPC6) induced by NT-3 inhibits dendritic growth via CaMKIIα activation.\",\n      \"method\": \"siRNA knockdown of TRPC5, whole-cell patch-clamp, Ca2+ imaging, CaMKIIα inhibition, dendrite morphology analysis in rat hippocampal neurons\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — TRPC5-specific knockdown with electrophysiological and morphological readouts plus pathway identification\",\n      \"pmids\": [\"22764246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GM1 ganglioside cross-linking by cholera toxin B subunit (CtxB) activates TRPC5 channels to induce Ca2+ influx and neurite outgrowth in NG108-15 cells and primary cerebellar granule neurons. GM1 associates with α5β1-integrin (not directly with TRPC5), and the signaling cascade involves FAK autophosphorylation, PLCγ activation, and PI3K to open TRPC5.\",\n      \"method\": \"TRPC5 siRNA knockdown, Ca2+ imaging, PLCγ/PI3K/FAK pharmacological inhibition, confocal immunocytochemistry showing co-localization, TRPC5 KO neurons\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown plus pathway dissection with multiple inhibitors and KO neurons\",\n      \"pmids\": [\"17626205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In T effector cells, GM1 ganglioside cross-linking by galectin-1 (expressed by regulatory T cells) activates TRPC5 channels, causing Ca2+ influx that contributes to Treg-mediated suppression of Teff cell proliferation. TRPC5 shRNA knockdown blocked contact-dependent proliferation inhibition by Treg cells.\",\n      \"method\": \"shRNA knockdown of TRPC5, Ca2+ imaging, flow cytometry, T cell proliferation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown with functional Ca2+ and proliferation readouts; single lab\",\n      \"pmids\": [\"19299701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPC5-containing extracellular vesicles (EVs) from adriamycin-resistant breast cancer cells transfer TRPC5 protein to non-resistant recipient cells. Transferred TRPC5 activates NFATc3-mediated P-gp production through Ca2+ signaling, conferring chemoresistance on previously sensitive cells.\",\n      \"method\": \"EV isolation and transfer, TRPC5-siRNA treatment, Ca2+ signaling assays, P-gp expression by Western blot, xenograft mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transfer of channel via EVs with Ca2+ and transcriptional pathway validation; single lab\",\n      \"pmids\": [\"24733904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"(-)-Englerin A is a potent, selective, and direct activator of TRPC4 and TRPC5 channels acting at a high-affinity extracellular binding site, rapidly killing renal cancer cells.\",\n      \"method\": \"Electrophysiology (patch-clamp), Ca2+ imaging, cell viability assays in TRPC4/5-expressing HEK cells and renal cancer cells\",\n      \"journal\": \"Angewandte Chemie (International ed. in English)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiological demonstration of channel activation with pharmacological characterization; single lab\",\n      \"pmids\": [\"25707820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Insulin and leptin depolarize hypothalamic POMC neurons via activation of TRPC5 channels, downstream of PI3K signaling. TRPC5 is identified as the specific downstream effector based on biophysical properties, pharmacological profile, and immunocytochemistry/single-cell RT-PCR localization.\",\n      \"method\": \"Whole-cell patch-clamp in mouse/rat/primate POMC neurons, pharmacological dissection, immunocytochemistry, single-cell RT-PCR, i.c.v. insulin injection with metabolic measurements\",\n      \"journal\": \"Journal of neuroendocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — electrophysiology in native neurons across multiple mammalian species with pharmacological and molecular identity confirmation\",\n      \"pmids\": [\"28675783\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRPC5 is a Ca2+-permeable nonselective cation channel that assembles as homotetramers or heterotetramers with TRPC1 and TRPC4, is primarily activated downstream of Gq/11- and Gi-coupled receptors (with Gαi3 directly binding the ankyrin repeat domain to increase PIP2 sensitivity), is gated by intracellular Ca2+, lysophospholipids, mechanical stretch, cold (37–25°C), protons, and oxidative modifications (S-glutathionylation at Cys176/Cys178; palmitoylation), is regulated by multiple binding partners including calmodulin/CIRB domain, CaBP1, NCS-1, SESTD1, and EBP50, is subject to PKA-mediated inhibition (Ser794/Ser796) and calpain-mediated cleavage/activation, and controls neurite/dendrite growth, growth cone morphology (via stathmin 2 interaction), innate fear (amygdala), hippocampal synaptic transmission and working memory, POMC neuron excitability and energy homeostasis, podocyte cytoskeletal dynamics (Rac1 pathway), kidney filtration barrier integrity, and cancer drug resistance (via NFATc3-P-gp signaling).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRPC5 is a Ca2+-permeable, nonselective cation channel that couples Gq/11- and Gi-coupled receptor signaling and diverse physicochemical stimuli to localized Ca2+ entry, thereby controlling neuronal excitability, cytoskeletal dynamics, and cell migration [#1, #4, #5]. It functions as a receptor-operated channel activated downstream of Gq/11 receptors and receptor tyrosine kinases independently of store depletion [#1], with Gαi subunits (predominantly Gαi3) serving as direct activators that bind the channel and, as resolved by cryo-EM of the 4:4 TRPC5–Gαi3 complex, dock on the ankyrin-repeat edge ~50 Å from the membrane to increase channel sensitivity to PIP2 [#15, #16]. The channel assembles as homotetramers or as heteromultimers selectively with TRPC1 and TRPC4 [#0, #34], an assembly that gates which stimuli are sensed—homomeric TRPC5 is cold-sensitive whereas TRPC1/TRPC5 heteromers are not [#8]. N-terminal ankyrin repeats drive multimerization [#30] and extracellular pore-loop disulfide bonds (Cys553/Cys558) are required for tetramerization, trafficking, and activity [#31], consistent with the disulfide-bonded extracellular pore resolved in the 2.8 Å homotetramer structure [#14]. TRPC5 integrates a remarkable breadth of gating inputs: intracellular Ca2+ potentiation [#9, #33], lysophospholipids [#17], membrane stretch and hypoosmolarity [#18], extracellular protons and lanthanides acting at pore glutamates E543/E595 [#3, #25], bidirectional PIP2 regulation [#27, #28], oxidative S-glutathionylation at Cys176/Cys178 [#13], and proteolytic activation by calpain at Thr857 [#10]. Its activity is tuned by C-terminal binding partners—calmodulin and the CIRB domain [#19], CaBP1 and NCS-1 [#20, #21], SESTD1 [#22], and the PDZ scaffold EBP50 [#24]—and is inhibited by PKA phosphorylation at Ser794/Ser796 [#26]. Functionally, TRPC5-mediated Ca2+ influx restrains neurite and dendrite growth, signaling through stathmin 2, CaMKIIβ–Cdc20-APC, and NT-3/TrkC pathways [#2, #11, #44], and in podocytes it complexes with and activates Rac1 to drive cytoskeletal remodeling and filtration-barrier injury [#5, #6]. In the brain, TRPC5 is required for innate fear, hippocampal LTP and working memory, seizure susceptibility, and POMC-neuron responses to leptin, serotonin, and insulin governing energy homeostasis [#4, #12, #34, #35, #49]. In cancer, TRPC5 drives NFATc3-dependent P-glycoprotein induction and cytoprotective autophagy underlying chemoresistance, and is propagated between cells via extracellular vesicles [#7, #37, #47].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established TRPC5 as a receptor-operated rather than store-operated channel, defining its core signaling logic.\",\n      \"evidence\": \"Whole-cell and inside-out patch-clamp with Mn2+ quench in HEK293 cells expressing mTRPC5\",\n      \"pmids\": [\"10837492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the direct molecular link from Gq/11 to the channel\", \"Single-channel gating mechanism left open\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed TRPC5 does not act alone but co-assembles with TRPC1 into a native neuronal heteromeric channel, raising the question of subunit-defined channel diversity.\",\n      \"evidence\": \"Reciprocal Co-IP from brain plus heterologous coexpression electrophysiology in HEK293 cells\",\n      \"pmids\": [\"11301024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of heteromers undefined\", \"Functional distinction of homo vs heteromers not yet established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined a cell-biological role: TRPC5 traffics to growth cones and restrains neurite extension, linking channel activity to neuronal morphogenesis.\",\n      \"evidence\": \"Co-IP with stathmin 2, dominant-negative expression, and live imaging in rat hippocampal neurons\",\n      \"pmids\": [\"12858178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which stathmin 2 couples to channel function unclear\", \"Downstream cytoskeletal effectors not fully mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified multiple C-terminal Ca2+-sensor and lipid-binding partners (CaM/CIRB, CaBP1, SESTD1 later) and lysophospholipid sensitivity, framing TRPC5 as a polymodal, tightly regulated channel.\",\n      \"evidence\": \"Mutagenesis, in vitro binding/pull-down, and patch-clamp across CHO/HEK293/Xenopus systems; excised-patch lysophospholipid activation\",\n      \"pmids\": [\"15987684\", \"15895247\", \"16368680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How competing Ca2+ sensors are coordinated in cells unresolved\", \"Direct vs membrane-mediated lysophospholipid action not definitively separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established mechanosensitivity and bidirectional PIP2 regulation, expanding the polymodal gating repertoire and revealing context-dependent lipid control.\",\n      \"evidence\": \"Excised-patch and whole-cell patch-clamp with pressure application, PIP2 depletion/infusion in HEK293 cells\",\n      \"pmids\": [\"18832422\", \"18665391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular site of mechanical sensing unidentified\", \"Reconciling stimulatory vs inhibitory PIP2 effects mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated an essential in vivo role in innate fear circuits and quantified intracellular Ca2+ potentiation, connecting molecular gating to behavior.\",\n      \"evidence\": \"TRPC5 KO mice with amygdala electrophysiology and fear behavior; caged-Ca2+ single-channel recordings\",\n      \"pmids\": [\"19450521\", \"19398778\", \"19815560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the intracellular Ca2+ binding site not resolved\", \"Receptor specificity in vivo only partially mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed TRPC5 in opposition to TRPC6 as an antagonistic regulator of actin dynamics via direct complex with Rac1, providing a migration-control mechanism.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA, migration and Ca2+ imaging in podocytes and fibroblasts\",\n      \"pmids\": [\"20978238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ca2+ influx selectively activates Rac1 vs RhoA unclear\", \"Structural basis of TRPC5-Rac1 complex unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked TRPC5 Ca2+ signaling to a specific dendrite-patterning pathway and to cold sensing, refining its developmental and sensory roles.\",\n      \"evidence\": \"KO mice, in vivo RNAi, Co-IP of TRPC5–CaMKIIβ; temperature-evoked electrophysiology of homo vs heteromers\",\n      \"pmids\": [\"22135323\", \"22025699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How channel activity is converted to centrosomal Cdc20-APC phosphorylation incompletely defined\", \"Molecular determinant of cold sensing in TRPC5 unmapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed proteolytic activation by calpain and direct Gαi activation via the SESTD domain, and extended pathophysiology to seizures, drug resistance, and neurotrophin signaling.\",\n      \"evidence\": \"In vitro calpain cleavage with T857 mutagenesis; Co-IP and constitutively active Gαi electrophysiology; KO seizure models; NFAT reporter and xenograft assays; NT-3/TrkC dissection in neurons\",\n      \"pmids\": [\"22547824\", \"22457348\", \"23188715\", \"22988121\", \"22764246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological triggers of calpain cleavage in vivo unclear\", \"How distinct activators converge on gating not unified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified gating elements (S4-S5 linker Gly504) and an in vivo role in kidney filtration-barrier injury, connecting channel conformation to disease.\",\n      \"evidence\": \"G504S and suppressor mutagenesis with cell-death assays; Trpc5-KO mice and inhibitor with podocyte imaging and albuminuria\",\n      \"pmids\": [\"23677990\", \"24231357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full open-state conformational pathway not resolved without structure at the time\", \"Endogenous activator driving podocyte injury not pinpointed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined pore-loop disulfide bonds essential for assembly/trafficking and demonstrated intercellular spread of resistance via TRPC5-bearing extracellular vesicles.\",\n      \"evidence\": \"Cys553/Cys558 mutagenesis with FRET, Co-IP, surface biotinylation; EV isolation/transfer with NFATc3-P-gp readouts and xenografts\",\n      \"pmids\": [\"24859801\", \"24733904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EV transfer mechanism and in vivo relevance only partly characterized\", \"Link between disulfide redox state and physiological gating incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed oxidative S-glutathionylation at Cys176/Cys178 activates TRPC5 to drive striatal neuronal death, implicating the channel in Huntington's disease pathology.\",\n      \"evidence\": \"Cysteine mutagenesis glutathionylation assay, electrophysiology, KO/inhibition, YAC128 mice and human HD tissue\",\n      \"pmids\": [\"26133660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HD-relevant activation is reversible therapeutically untested here\", \"Interplay with TRPC1 expression in determining homotetramer fraction only correlative\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Used native complexomics and triple-KO mice to define a TRPC1/4/5 channel family and established TRPC5 roles in synaptic transmission, working memory, and POMC energy homeostasis.\",\n      \"evidence\": \"Quantitative MS of native complexes, Trpc1/4/5 triple-KO with electrophysiology and memory tasks; POMC-conditional Trpc5 KO with metabolic phenotyping\",\n      \"pmids\": [\"28790178\", \"28099839\", \"28600513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit composition of physiologically relevant channels in each tissue still uncertain\", \"Autophagy pathway link (Medium confidence) needs broader validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Solved the homotetramer cryo-EM structure and revealed palmitoylation and additional neuroendocrine functions, providing a structural and post-translational framework.\",\n      \"evidence\": \"2.8 Å cryo-EM with mutagenesis; palmitoylation assay in HD striatal cells; conditional KO with prolactin/reproductive phenotyping\",\n      \"pmids\": [\"31355338\", \"31812495\", \"31285329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand- and state-specific conformations not captured\", \"Palmitoylation enzyme/site identity (Medium confidence) not fully defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the TRPC5–Gαi3 complex structure, defining how a direct G-protein interaction at the ankyrin domain potentiates PIP2 sensitivity to open the channel.\",\n      \"evidence\": \"Cryo-EM in lipid nanodiscs with PIP2-sensitivity electrophysiology\",\n      \"pmids\": [\"37137991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational transitions linking Gαi3 binding to pore opening not fully traced\", \"Generalizability to heteromeric channels untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the channel's many gating modalities, subunit compositions, and tissue-specific partners are integrated to produce distinct physiological Ca2+ signals remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model linking polymodal stimuli to defined open states across cell types\", \"Tissue-specific heteromer stoichiometry and partner dependence incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 3, 9, 33]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [8, 18, 13, 25]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 16, 15]},\n      {\"term_id\": \"GO:0005509\", \"supporting_discovery_ids\": [9, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [23, 31, 43, 41]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 47]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5, 40]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 16, 15]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 12, 34, 35, 49]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 11, 44]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7, 13, 47]}\n    ],\n    \"complexes\": [\n      \"TRPC1/TRPC4/TRPC5 heteromeric channel\",\n      \"TRPC5–Gαi3 complex\",\n      \"TRPC5–Rac1 complex\",\n      \"TRPC5–CaMKIIβ complex\"\n    ],\n    \"partners\": [\n      \"TRPC1\",\n      \"TRPC4\",\n      \"GNAI3\",\n      \"RAC1\",\n      \"CAMK2B\",\n      \"SESTD1\",\n      \"NCS1\",\n      \"CABP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}