{"gene":"TRPC1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1995,"finding":"TRPC1 was cloned as a human homolog of Drosophila TRP, predicted to be a non-voltage-gated plasma membrane Ca2+ channel (lacks charged residues in S4 proposed for voltage sensing), and identified as the founding member of the mammalian TRPC family.","method":"Molecular cloning, sequence analysis, expression profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — sequence-based structural inference replicated across subsequent studies; no direct electrophysiology in this paper","pmids":["7568191"],"is_preprint":false},{"year":2004,"finding":"Biogenesis and transmembrane topology of human TRPC1 was determined: hydrophobic regions (HRs) 1, 4, and 6 cross the membrane cytosol-to-ER lumen; HRs 2, 5, and 8 have opposite orientation; HR 3 remains cytosolic; HR 7 forms a pore-like re-entrant loop. The C-terminal sequence downstream of HR 8 anchors the cytosolic end and prevents HR 7 from fully spanning the bilayer, creating the channel pore.","method":"Truncation mutant approach combined with N-linked glycosylation site insertions in HEK-293T cells; glycosylation used as lumenal topology reporter","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis-based topology mapping with multiple orthogonal constructs in a single rigorous study","pmids":["14707123"],"is_preprint":false},{"year":2004,"finding":"PKCα phosphorylates TRPC1 in human endothelial cells downstream of thrombin or thapsigargin stimulation, and this phosphorylation is required for store-operated Ca2+ entry and the resulting increase in endothelial permeability. Genetic or pharmacological inhibition of PKCα blocked IP3-induced cationic current and Ca2+ entry, and thrombin failed to phosphorylate TRPC1 when PKCα was inactive.","method":"Whole-cell patch clamp, Fura-2 Ca2+ imaging, kinase-defective PKCα mutants, pharmacological inhibition (Gö6976), TRPC1-specific extracellular antibody block, phosphorylation assays, transendothelial resistance","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (electrophysiology, Ca2+ imaging, mutagenesis, phosphorylation assay) in a single study, single lab","pmids":["15016832"],"is_preprint":false},{"year":2005,"finding":"TRPC1 protein was identified as a component of the vertebrate mechanosensitive cation channel (MscCa): purification of frog oocyte membrane proteins followed by liposome reconstitution and patch-clamp identified an ~80 kDa protein as TRPC1 by immunological methods. Heterologous expression of human TRPC1 in oocytes increased MscCa patch density >1000%, and TRPC1-specific antisense RNA abolished endogenous MscCa activity. Transfection into CHO-K1 cells also increased MscCa expression. The channel is gated by tension in the lipid bilayer.","method":"Detergent solubilization + liposome reconstitution + patch-clamp; immunological identification; heterologous overexpression; antisense RNA knockdown; CHO-K1 transfection","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstitution and gain/loss-of-function in multiple systems; subsequent paper (PMID:17957383) failed to replicate in COS/CHO cells, reducing confidence","pmids":["15665854"],"is_preprint":false},{"year":2006,"finding":"The cytosolic C-terminus of STIM1 is sufficient to activate TRPC1 channels. STIM1 binds TRPC1, TRPC2, and TRPC4 selectively (not TRPC3, 6, or 7) via its ERM domain, and gates TRPC1 through a cationic lysine-rich region. Deletion of either domain in constitutively active STIM1(D76A) produces dominant-negative mutants that block native SOC and TRPC1 channel activity.","method":"Co-immunoprecipitation, siRNA knockdown of STIM1, constitutively active and dominant-negative STIM1 mutants expressed in HEK293 cells, electrophysiology, Ca2+ imaging","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of interaction domains, dominant-negative functional rescue, replicated across multiple channel types and cell lines","pmids":["16906149"],"is_preprint":false},{"year":2007,"finding":"Overexpression of TRPC1 or TRPC6 in COS or CHO cells did not significantly alter the amplitude of mechanosensitive currents measured with a fast pressure clamp, contradicting a simple model in which TRPC1 alone forms the vertebrate MscCa.","method":"Transient transfection of TRPC1 or TRPC6 in COS/CHO cells; fast pressure-clamp patch-clamp recordings; Western blot confirmation of protein expression","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous electrophysiological assay directly contradicting PMID:15665854; single lab but controlled overexpression with protein verification","pmids":["17957383"],"is_preprint":false},{"year":2008,"finding":"TRPC1 and caveolin-3 co-localize and co-immunoprecipitate in muscle cells; direct binding was confirmed by FRET between TRPC1-CFP and caveolin-3-YFP in C2 myoblasts. Caveolin-3 targeted TRPC1 to the plasma membrane. ROS increased Src kinase activity and enhanced Ca2+ influx only in cells co-expressing TRPC1 and caveolin-3, revealing a ROS–Src–TRPC1/caveolin-3 pathway in Duchenne muscular dystrophy pathogenesis.","method":"Co-immunoprecipitation, FRET, confocal microscopy, Src inhibitor PP2, ROS scavenger Tiron, Ca2+ influx measurements in mdx muscle","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — FRET-confirmed direct binding plus functional Ca2+ entry assays and in vivo mdx rescue; multiple orthogonal methods","pmids":["18544631"],"is_preprint":false},{"year":2008,"finding":"TRPP2 and TRPC1 assemble into a heteromeric receptor-operated channel with unique properties distinct from either subunit alone: different single-channel conductance, amiloride sensitivity, and ion permeability. Native TRPP2/TRPC1 channel activity was demonstrated in kidney cells by gain- and loss-of-function experiments; the complex co-localizes at the primary cilium and co-immunoprecipitates from kidney membranes.","method":"Heterologous expression, electrophysiology, co-immunoprecipitation from kidney membranes, gain/loss-of-function in kidney cells, immunolocalization to primary cilium","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP from native tissue, electrophysiological characterization of heteromeric channel, gain and loss-of-function, single lab with multiple orthogonal methods","pmids":["18323855"],"is_preprint":false},{"year":2008,"finding":"STIM1 association converts TRPC1 from a receptor-operated channel (ROC) to a store-operated channel (SOC) by promoting insertion of TRPC1 into lipid rafts. In the absence of STIM1, TRPC1 associates with other TRPC members to form ROCs. TIRFM-FRET demonstrated the dynamic association between STIM1 and TRPC1 at ER-PM junctions and lipid rafts.","method":"TIRFM-FRET, lipid raft fractionation, co-immunoprecipitation, Ca2+ imaging, siRNA knockdown of STIM1","journal":"Cell calcium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET-based direct interaction plus biochemical fractionation and Ca2+ functional assays; single lab","pmids":["18420269"],"is_preprint":false},{"year":2008,"finding":"Caveolin-1 scaffold domain (CSD, residues 82–101) directly interacts with TRPC1 C-terminal residues 781–789 and also with IP3R3. The TRPC1-CΔ781-789 mutant abolishes Ca2+ store release-induced Ca2+ influx and disrupts binding to both IP3R3 and caveolin-1. Caveolin-1ΔCSD shows gain-of-function Ca2+ entry. WT caveolin-1 but not ΔCSD interacts with IP3R3 and TRPC1.","method":"Co-immunoprecipitation, deletion mutagenesis of TRPC1 C-terminus and CSD, Ca2+ imaging, Fura-2, confocal co-localization, Cav-1 KO mouse lung endothelial cells","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain-mapping mutagenesis plus Co-IP and functional Ca2+ assays in multiple cell types and KO mice; multiple orthogonal methods","pmids":["19052258"],"is_preprint":false},{"year":2008,"finding":"STIM1 and TRPC1 interact in vascular smooth muscle cells (VSMCs); TRPC1 contributes to a component of store-operated cation current and cell migration. Extracellular STIM1 N-terminus was detected, and extracellular STIM1 antibody rapidly inhibited store-depletion-evoked current. TRPC1-containing channels also contributed to cell proliferation independently of STIM1.","method":"siRNA knockdown of STIM1 and TRPC1, co-immunoprecipitation, extracellular antibody block, patch-clamp, Fura-2 Ca2+ imaging, cell migration and proliferation assays, cell surface localization studies","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus electrophysiology and functional cell assays; single lab","pmids":["18802022"],"is_preprint":false},{"year":2008,"finding":"TRPC1 depletion in skeletal myoblasts reduces store-operated Ca2+ entry and abolishes the transient calpain activity peak at the onset of differentiation. This leads to accumulation of the calpain substrate MARCKS, slowed cell migration, and impaired myotube fusion. IGF-1-stimulated migration and calpain activation were also dependent on TRPC1 expression.","method":"siRNA knockdown of TRPC1 in primary myoblasts, Ca2+ imaging, calpain activity assay, immunofluorescence for MARCKS, time-lapse migration assay, GsMTx4 and calpain inhibitor pharmacology","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple downstream readouts (Ca2+, calpain activity, MARCKS, migration) plus pharmacological validation in a single thorough study","pmids":["19001499"],"is_preprint":false},{"year":2009,"finding":"TRPC1 knockout mice lack the TRPC-associated non-selective cation current observed after pressure overload and are protected from maladaptive cardiac hypertrophy. Mechanosensitive signaling through calcineurin/NFAT, mTOR, and Akt is altered in Trpc1−/− mice subjected to hemodynamic stress, placing TRPC1 upstream of these hypertrophic pathways.","method":"Trpc1−/− mouse model, pressure overload (transverse aortic constriction), whole-cell patch-clamp of cardiomyocytes, cardiac function measurements, Western blot/immunostaining for calcineurin/NFAT/mTOR/Akt","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal phenotypic and signaling readouts; independent from the culture-based PMID:17174323 study","pmids":["19797170"],"is_preprint":false},{"year":2009,"finding":"TRPC1 operates as a Ca2+ leak channel in the sarcoplasmic reticulum (SR) of skeletal muscle fibers, not at the sarcolemma as previously proposed. Immunostaining colocalizes TRPC1-YFP with SR Ca2+ pump markers in a striated pattern. Overexpression increases resting SR Ca2+, accelerates CPA-induced Ca2+ rise, and slows Ca2+ transient decay, all consistent with SR Ca2+ leak function.","method":"TRPC1-YFP overexpression in adult mouse muscle fibers, immunostaining, Ca2+ measurements (Fluo-4), CPA-induced contracture assay, voltage-clamp Ca2+ transients","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional Ca2+ assays; single lab, contradicts prior plasma membrane models","pmids":["19875453"],"is_preprint":false},{"year":2010,"finding":"TRPC1 is required for angiogenesis in zebrafish: morpholino knockdown of trpc1 severely disrupts intersegmental vessel sprouting in an endothelial-cell-autonomous manner, impairing filopodial extension, tip-cell migration and proliferation. TRPC1 acts downstream of Vegf-a and is required for Vegf-a-induced ERK phosphorylation.","method":"Antisense morpholino knockdown, rescue with morpholino-resistant trpc1 mRNA, cell transplantation, in vivo time-lapse imaging, Vegf-a interaction experiments, ERK phosphorylation assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — morpholino KD with mRNA rescue, cell-autonomy test, and downstream signaling readout; multiple orthogonal approaches","pmids":["20185799"],"is_preprint":false},{"year":2011,"finding":"Recombinant TRPC1 subunits do not form functional homomeric channels; instead they form functional heteromeric receptor-operated channels with all other TRPC subfamily members (TRPC3, 4, 5, 6, 7). In all TRPC1-containing heteromers, TRPC1 significantly reduces calcium permeability. Pore-region amino acid substitutions in TRPC1 further reduce Ca2+ permeability, confirming TRPC1 contributes to the channel pore.","method":"Electrophysiology of heterologously expressed TRPC1 homomers and heteromers, pore-region mutagenesis, Ca2+ permeability measurements, TRPC1 siRNA in GnRH neurons","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — electrophysiology with mutagenesis of pore region plus native cell siRNA knockdown; single lab with multiple orthogonal approaches","pmids":["22157757"],"is_preprint":false},{"year":2011,"finding":"In vascular smooth muscle cells (VSMCs), store depletion activates native heteromeric TRPC1/TRPC5 channels (~2 pS conductance, activated by PKC, PIP2, and PIP3). In TRPC1−/− VSMCs, TRPC5 homomeric channels (with multiple subconductance states 14/32/53 pS) form instead and show opposite regulation (inhibited by PKC, PIP2, PIP3; activated by elevated [Ca2+]i). TRPC1 determines unitary conductance and confers PKC/phosphoinositide activation.","method":"Single-channel patch-clamp in acutely isolated mesenteric artery VSMCs from WT and TRPC1−/− mice, co-immunoprecipitation, anti-TRPC antibody blocking, PKC activator/inhibitor pharmacology, PIP2/PIP3 application","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct single-channel electrophysiology with genetic KO comparison, biochemical interaction confirmation, and pharmacological characterization; single lab but rigorous","pmids":["21968068"],"is_preprint":false},{"year":2012,"finding":"TRPC1 depletion in non-small cell lung carcinoma cells causes G0/G1 arrest, reduces cyclin D1/D3, and decreases EGFR phosphorylation with disruption of PI3K/Akt and MAPK signaling. EGF stimulation triggers Ca2+ release and Ca2+ entry through TRPC1, and this Ca2+ entry reciprocally activates EGFR, forming a Ca2+-dependent amplification loop for EGF-dependent proliferation.","method":"siRNA knockdown of TRPC1, cell cycle analysis, Western blot for cyclins and phospho-EGFR, EGF stimulation with Ca2+ imaging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with cell cycle and signaling readouts plus receptor-channel feedback loop validation; single lab","pmids":["22451676"],"is_preprint":false},{"year":2012,"finding":"Trpc1−/− mice show impaired PI3K/Akt/mTOR/p70S6K signaling during muscle regeneration. Trpc1 KO primary myoblasts and regenerating muscles have reduced Akt phosphorylation, decreased MyoD/Myf5/myogenin expression, smaller fiber size, and delayed regeneration after cardiotoxin injury. Ca2+ entry through Trpc1 enhances PI3K activity, placing Trpc1 upstream of the PI3K/Akt pathway in myogenesis.","method":"Trpc1−/− mouse, cardiotoxin muscle injury model, primary myoblast culture, Western blot for PI3K/Akt/p70S6K/myogenic factors, EGTA-AM and wortmannin pharmacology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO validated in both in vitro primary cells and in vivo injury model with multiple pathway readouts; extends PMID:19001499","pmids":["22399301"],"is_preprint":false},{"year":2013,"finding":"TRPC1 and I-mfa (inhibitor of MyoD family) antagonistically regulate osteoclastogenesis. A new splice variant TRPC1ε uniquely amplifies CRAC channel activity and physically interacts with Orai1 (pore-forming CRAC subunit). I-mfa is recruited to the TRPC1ε–Orai1 complex through TRPC1ε and suppresses CRAC activity, revealing a positive/negative modulation axis.","method":"TRPC1−/− and I-mfa−/− double-KO mice, in vitro osteoclast differentiation, bone resorption assays, whole-cell electrophysiology, co-immunoprecipitation of TRPC1ε–Orai1 complex, heterologous expression of TRPC1ε in HEK293","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic double-KO epistasis plus Co-IP of TRPC1ε–Orai1 plus electrophysiology; multiple orthogonal methods","pmids":["23770672"],"is_preprint":false},{"year":2014,"finding":"Caspase-11 cleaves/degrades TRPC1 as a substrate. TRPC1 deficiency increases IL-1β secretion without altering caspase-1 cleavage or cell death in macrophages, and trpc1−/− mice show higher IL-1β in a sepsis model, indicating TRPC1 negatively regulates unconventional IL-1β secretion downstream of caspase-11 independently of caspase-1.","method":"Identification of TRPC1 as caspase-11 substrate, trpc1−/− macrophages and mice, LPS-induced sepsis model, IL-1β ELISA, caspase-1 cleavage assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — substrate identification combined with in vitro cell and in vivo mouse KO experiments with mechanistically specific readouts","pmids":["24630989"],"is_preprint":false},{"year":2016,"finding":"SARAF (SOCE-associated regulatory factor) interacts with TRPC1 independently of STIM1 and negatively regulates TRPC1-mediated Ca2+ entry. This interaction is enhanced by agonist (ATP) stimulation. In contrast, SARAF–TRPC6 interaction is constitutive and SARAF does not regulate TRPC6-mediated Ca2+ entry.","method":"Co-immunoprecipitation in STIM1-deficient NG115-401L cells and STIM1-expressing SH-SY5Y cells, SARAF siRNA, Ca2+ entry measurements, TRPC6 overexpression cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in two cell systems including STIM1-deficient cells plus functional Ca2+ assays; single lab","pmids":["27506849"],"is_preprint":false},{"year":2016,"finding":"Store-operated STIM1–TRPC1 interactions in VSMCs stimulate PLCβ1 activity and PKC phosphorylation of TRPC1 to induce channel gating. Store depletion causes STIM1 translocation to the plasma membrane where it forms complexes with TRPC1, Gαq, and PLCβ1. TRPC1-based SOC activity and store-operated PLCβ1 activity are absent in TRPC1−/− VSMCs.","method":"Patch-clamp, GFP-PLCδ1-PH imaging for PLCβ1 activity, co-immunoprecipitation, proximity ligation assays, STIM1 shRNA, TRPC1−/− VSMCs, immunocytochemistry","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, live-cell PIP2 imaging, PLA, Co-IP, genetic KO) establishing a new activation mechanism; single lab","pmids":["27753095"],"is_preprint":false},{"year":2017,"finding":"TRPC1, TRPC4, and TRPC5 assemble exclusively into heteromultimers with each other (not other TRP family members) in mouse brain and hippocampus, as determined by quantitative mass spectrometry. In Trpc1/4/5 triple-KO hippocampal neurons, action potential-triggered EPSCs are reduced while miniature EPSC frequency/amplitude are unchanged, and spatial working memory and flexible relearning are impaired in vivo.","method":"Quantitative high-resolution mass spectrometry of native complexes, Trpc1/4/5 triple-KO mice, whole-cell patch-clamp of hippocampal neurons, hippocampal slice recordings, in vivo behavioral testing","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — native complex composition determined by mass spectrometry plus genetic triple-KO with electrophysiology and in vivo behavior; highly rigorous","pmids":["28790178"],"is_preprint":false},{"year":2017,"finding":"TRPC1 and TRPC4 functionally interact preferentially with STIM1L (muscle-specific long isoform) compared to canonical STIM1 in human myotubes. Knockdown of TRPC1 or TRPC4 reduces SOCE by ~50%, delays Ca2+ entry onset, and impairs myotube formation—effects similar to STIM1L invalidation.","method":"siRNA knockdown of TRPC1, TRPC4, and STIM1L in human myotubes, Co-immunoprecipitation on store depletion, Ca2+ imaging (Fluo-4), myotube size quantification","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing preferential STIM1L interaction plus siRNA functional assays; single lab","pmids":["28185894"],"is_preprint":false},{"year":2017,"finding":"Heteromeric TRPV4–TRPC1 channels mediate calcium-sensing receptor (CaSR)-induced NO production and vasorelaxation in rabbit mesenteric artery endothelial cells. TRPV4 and TRPC1 co-localize and are in proximity at the plasma membrane of endothelial cells. A TRPV4 agonist activates 6 pS cation channels blocked by both TRPV4 antagonists and TRPC1 extracellular antibody.","method":"Proximity ligation assay, immunocytochemistry, wire myography, DAF-FM NO fluorescence, perforated-patch electrophysiology, pharmacological antagonists (RN1734, HC067047) and TRPC1 antibody (T1E3)","journal":"Vascular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity ligation plus single-channel electrophysiology and functional vascular assays; single lab","pmids":["28867591"],"is_preprint":false},{"year":2018,"finding":"Gαq protein directly interacts with TRPC4 or TRPC5 subunits (not TRPC1) in TRPC1/4 and TRPC1/5 heterotetramers to permit activation by the Gαq-PLCβ pathway. Simultaneously, PLCβ-driven PI(4,5)P2 depletion inhibits TRPC1/4 and TRPC1/5 channel activity, creating a self-limited dual regulatory mechanism.","method":"Co-immunoprecipitation of Gαq with TRPC subunits, patch-clamp electrophysiology of heteromeric channels, DrVSP-based PI(4,5)P2 depletion, pharmacological activation of Gαq","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of Gαq with channel subunits plus electrophysiology; single lab","pmids":["30108272"],"is_preprint":false},{"year":2018,"finding":"mGluR5 activation specifically activates TRPC1-containing channels in hippocampal CA1-3 neurons. Trpc1−/− mice show impaired mGluR-induced synaptic excitability, defective LTP maintenance, impaired mGluR-LTD, and altered spatial working memory. Acute inhibition with Pico145 mimics genetic TRPC1 depletion, excluding developmental compensation.","method":"Trpc1−/− mice, whole-cell patch-clamp, LTP and LTD recordings in hippocampal slices, mGluR5 activation, Pico145 pharmacology, behavioral testing (Morris water maze, fear conditioning)","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus acute pharmacological inhibition with multiple electrophysiological and behavioral readouts","pmids":["30271326"],"is_preprint":false},{"year":2020,"finding":"HSV-1 glycoprotein D interacts with the third ectodomain of TRPC1, facilitating viral entry into cells. TRPC1 knockout attenuates HSV-1-induced Ca2+ entry, viral infection, and ocular pathology in vivo. HSV-1 infection correlates with plasma membrane localization of TRPC1 in oral lesion epithelial cells.","method":"Co-immunoprecipitation of gD with TRPC1 ectodomain, TRPC1 knockdown/knockout, Ca2+ imaging, viral entry/infection assays, TRPC1−/− mouse ocular model, human biopsy immunostaining","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct protein–protein interaction identified plus functional viral entry assays in vitro and in vivo KO mouse; multiple orthogonal methods","pmids":["32206724"],"is_preprint":false},{"year":2021,"finding":"TRPC1 directly binds calmodulin (CaM) and enhances the interaction between CaM and the PI3K p85 subunit, thereby activating the PI3K/AKT and downstream signaling pathways involved in cell cycle progression and EMT in colorectal cancer cells. Silencing of CaM abolishes the oncogenic effects of TRPC1.","method":"Co-immunoprecipitation of TRPC1-CaM and CaM-PI3K p85, siRNA knockdown of TRPC1 and CaM, TRPC1 overexpression, proliferation/invasion/migration assays, Trpc1−/− mouse CRC model","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing TRPC1–CaM–PI3K p85 interaction plus genetic KO mouse and siRNA functional assays; single lab","pmids":["34642309"],"is_preprint":false},{"year":2016,"finding":"TRPC1 interaction domains for heteromerization with TRPC4 and TRPC5 were mapped: TRPC1's N-terminal coiled-coil domain (CCD) and C-terminal 725–745 region interact with TRPC4's N-terminal CCD and C-terminal 700–728 region; TRPC1's N-terminal CCD and C-terminal 673–725 region interact with TRPC5's N-terminal CCD and C-terminal 707–735 region. TRPC1 only reaches the plasma membrane when co-expressed with TRPC4 or TRPC5.","method":"FRET, patch-clamp electrophysiology, truncation/deletion mutants of TRPC1, TRPC4, and TRPC5","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET-based interaction mapping with functional electrophysiology confirmation; single lab","pmids":["27131740"],"is_preprint":false},{"year":2019,"finding":"TRPC1 acts as a negative regulator of TRPC4 and TRPC5 channel activity: incorporation of TRPC1 into TRPC1/4 or TRPC1/5 heterotetramers reduces PI(4,5)P2 sensitivity compared to TRPC4 or TRPC5 homotetramers. PI(4,5)P2 binding sites were mapped to specific basic residues (K419, K664/R511, K518, H630) in TRPC4; TRPC1 equalizes PI(4,5)P2 affinity across heteromers.","method":"DrVSP-based PI(4,5)P2 dephosphorylation combined with patch-clamp, FRET to PI(4,5)P2 sensor, neutralizing mutagenesis of PI(4,5)P2 binding residues","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of PI(4,5)P2 binding sites with FRET and electrophysiology; single lab","pmids":["30755645"],"is_preprint":false},{"year":2014,"finding":"Induced TRPC1 expression in intestinal epithelial cells increases protein phosphatase 2A (PP2A) activity through Ca2+ influx. Elevated PP2A reduces nuclear NF-κB levels and transcriptional activity, sensitizing cells to TNF-α/cycloheximide-induced apoptosis. Inhibition of PP2A or Ca2+ removal reverses these effects, placing TRPC1-mediated Ca2+ entry upstream of PP2A and NF-κB.","method":"Stable TRPC1 transfection in IEC-6 cells, PP2A activity assay, PP2A siRNA, okadaic acid, NF-κB reporter assay, apoptosis assay, Ca2+-free medium","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods establishing TRPC1→Ca2+→PP2A→NF-κB pathway; single lab","pmids":["18322138"],"is_preprint":false},{"year":2014,"finding":"PKG phosphorylates TRPC1 directly at Ser172 and Thr313. NO–cGMP–PKG pathway inhibits 11,12-EET-induced smooth muscle hyperpolarization and vascular relaxation via PKG-mediated phosphorylation of TRPC1. TRPV4, TRPC1, and KCa1.1 physically associate with each other in smooth muscle cells and TRPC1 inhibition abolishes EET responses.","method":"In vitro PKG phosphorylation assay of TRPC1 peptides, TAT-linked phosphorylation-site peptides (competitive inhibition), co-immunoprecipitation of TRPV4–TRPC1–KCa1.1 complex, membrane potential and arterial tension measurements","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct in vitro phosphorylation assay identifying specific residues plus Co-IP of native complex and functional vascular assays; single lab with multiple orthogonal methods","pmids":["25139746"],"is_preprint":false},{"year":2015,"finding":"TRPC1-mediated Ca2+ entry regulates hypoxia- and nutrient-depletion-induced autophagy to prevent cell death. Hypoxia increases TRPC1 expression and Ca2+ entry through TRPC1. Silencing of TRPC1 reduces Ca2+ influx, decreases autophagic markers, and increases apoptosis. Notably, this effect is specific to TRPC1 and not TRPC3.","method":"TRPC1 siRNA, TRPC1 overexpression, Ca2+ imaging, autophagy markers (LC3B), apoptosis assays, primary salivary gland cells under hypoxia","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD and OE with multiple Ca2+ and autophagy/apoptosis readouts; primary cell validation; single lab","pmids":["25741599"],"is_preprint":false}],"current_model":"TRPC1 is a non-selective, Ca2+-permeable cation channel subunit that cannot form functional homomeric channels and instead obligately assembles as heterotetramers with other TRPC members (TRPC3–7, with preference for TRPC4/5) or with TRPP2, where it reduces Ca2+ permeability and modulates PI(4,5)P2 sensitivity; it is activated downstream of ER Ca2+ store depletion via a STIM1-dependent mechanism requiring STIM1's ERM domain for selective binding and a polybasic domain for gating, with Orai1-mediated Ca2+ entry required to recruit TRPC1 to the plasma membrane; PKCα (phosphorylating TRPC1 in a STIM1-facilitated Gαq/PLCβ1 pathway) and PKG (phosphorylating Ser172/Thr313) modulate its activity; TRPC1 interacts with caveolin-1/3, IP3R3, calmodulin, and HSV-1 glycoprotein D, and is cleaved by caspase-11; functionally, it regulates store-operated Ca2+ entry, myoblast migration/differentiation (via calpain and PI3K/Akt), cardiac hypertrophy (via calcineurin/NFAT/mTOR), neuronal synaptic plasticity via mGluR5, angiogenesis downstream of VEGF-A, and IL-1β secretion in macrophages."},"narrative":{"mechanistic_narrative":"TRPC1 is the founding mammalian member of the canonical transient receptor potential (TRPC) family, a non-voltage-gated, Ca2+-permeable cation channel subunit that functions as a regulator of store-operated and receptor-operated Ca2+ entry across many cell types [PMID:7568191]. Its membrane topology positions hydrophobic region 7 as a re-entrant pore loop anchored by the cytosolic C-terminus [PMID:14707123]. TRPC1 cannot form functional homomeric channels; instead it obligately heteromerizes with other TRPC subunits—TRPC3-7, with selective assembly into TRPC1/4/5 multimers in brain—via its N-terminal coiled-coil and defined C-terminal interaction regions, and only reaches the plasma membrane when co-expressed with TRPC4 or TRPC5 [PMID:22157757, PMID:28790178, PMID:27131740]. Within these heteromers TRPC1 contributes to the channel pore, reduces Ca2+ permeability, and lowers PI(4,5)P2 sensitivity, thereby tuning channel gating [PMID:22157757, PMID:30755645]. TRPC1 is converted from a receptor-operated to a store-operated channel by STIM1, which binds TRPC1 selectively through its ERM domain and gates it via a lysine-rich polybasic region, promoting TRPC1 insertion into lipid rafts at ER-PM junctions [PMID:16906149, PMID:18420269]; in vascular smooth muscle this STIM1-TRPC1 association nucleates a Gαq/PLCβ1 complex whose PKC-mediated phosphorylation gates the channel [PMID:27753095]. Channel activity is further modulated by PKCα phosphorylation downstream of thrombin [PMID:15016832], by direct PKG phosphorylation at Ser172/Thr313 [PMID:25139746], and by negative regulators including SARAF and the inhibitor I-mfa acting at a TRPC1ε–Orai1 complex [PMID:27506849, PMID:23770672]. TRPC1 also assembles into distinct functional complexes with TRPP2 at the primary cilium, with TRPV4 (and KCa1.1) in endothelium and smooth muscle, and with caveolin-1/3 and IP3R3 for plasma-membrane targeting and store-release coupling [PMID:18323855, PMID:28867591, PMID:25139746, PMID:18544631, PMID:19052258]. Through these channels, TRPC1-mediated Ca2+ entry drives diverse processes: myoblast migration, differentiation and regeneration via calpain and PI3K/Akt/mTOR signaling [PMID:19001499, PMID:22399301], maladaptive cardiac hypertrophy via calcineurin/NFAT/mTOR/Akt [PMID:19797170], VEGF-A-dependent angiogenesis through ERK [PMID:20185799], mGluR5-dependent hippocampal synaptic plasticity and spatial memory [PMID:30271326, PMID:28790178], and cancer cell proliferation through EGFR and CaM-PI3K amplification loops [PMID:22451676, PMID:34642309]. TRPC1 is cleaved by caspase-11 and negatively regulates unconventional IL-1β secretion in macrophages [PMID:24630989], and is exploited by HSV-1 glycoprotein D, which binds its third ectodomain to facilitate viral entry [PMID:32206724].","teleology":[{"year":1995,"claim":"Established the existence and identity of a mammalian TRP homolog, defining TRPC1 as a candidate non-voltage-gated plasma membrane Ca2+ channel and founding the TRPC family.","evidence":"Molecular cloning, sequence analysis, and expression profiling of the human TRP homolog","pmids":["7568191"],"confidence":"Medium","gaps":["No direct electrophysiology demonstrating channel activity","Activation mechanism and partners unknown"]},{"year":2004,"claim":"Resolved how the polypeptide threads the membrane, defining the re-entrant pore loop and the C-terminal anchor required to form the conduction pathway.","evidence":"Truncation mutants plus N-glycosylation topology reporters in HEK-293T cells","pmids":["14707123"],"confidence":"High","gaps":["No high-resolution structure","Topology in native heteromeric channels not addressed"]},{"year":2004,"claim":"Identified PKCα phosphorylation as a required gating input linking GPCR/store-depletion stimuli to TRPC1-dependent Ca2+ entry and endothelial permeability.","evidence":"Patch clamp, Ca2+ imaging, kinase-defective PKCα mutants, phosphorylation assays in endothelial cells","pmids":["15016832"],"confidence":"High","gaps":["Phosphorylation sites not mapped","Direct vs indirect phosphorylation not resolved"]},{"year":2005,"claim":"Proposed TRPC1 as a constituent of the vertebrate mechanosensitive cation channel gated by bilayer tension.","evidence":"Liposome reconstitution + patch-clamp, heterologous overexpression and antisense knockdown in oocytes and CHO cells","pmids":["15665854"],"confidence":"Medium","gaps":["Subsequently not replicated in COS/CHO cells (#5)","Whether TRPC1 alone confers mechanosensitivity disputed"]},{"year":2006,"claim":"Defined STIM1 as the store-sensor that activates TRPC1, mapping selective binding to the ERM domain and gating to a lysine-rich region.","evidence":"Reciprocal Co-IP, STIM1 siRNA, constitutively active and dominant-negative STIM1 mutants, electrophysiology in HEK293","pmids":["16906149"],"confidence":"High","gaps":["Stoichiometry of STIM1-TRPC1 coupling unresolved","Role of Orai not addressed in this study"]},{"year":2007,"claim":"Directly challenged the simple TRPC1-as-MscCa model by showing overexpression does not augment mechanosensitive currents.","evidence":"Fast pressure-clamp patch-clamp of TRPC1/TRPC6-transfected COS/CHO cells with protein verification","pmids":["17957383"],"confidence":"Medium","gaps":["Negative result; cell-type or partner dependence not excluded","Does not exclude TRPC1 in native mechanosensory complexes"]},{"year":2008,"claim":"Showed STIM1 converts TRPC1 from a receptor-operated to a store-operated channel by driving its insertion into lipid rafts, and defined caveolin-1/IP3R3 C-terminal interactions required for store-release coupling and PM targeting.","evidence":"TIRFM-FRET, lipid raft fractionation, domain-mapping mutagenesis, Co-IP and Ca2+ imaging in endothelial and Cav-1 KO cells","pmids":["18420269","19052258"],"confidence":"High","gaps":["Dynamics of raft recruitment in vivo unclear","Interplay of STIM1 vs caveolin targeting not fully integrated"]},{"year":2008,"claim":"Demonstrated that TRPC1 forms functionally distinct heteromeric channels beyond the TRPC family, assembling with TRPP2 at the primary cilium with unique conductance and permeability.","evidence":"Heterologous electrophysiology, Co-IP from kidney membranes, gain/loss-of-function and ciliary immunolocalization","pmids":["18323855"],"confidence":"High","gaps":["Physiological stimulus gating the ciliary complex unknown","Stoichiometry undetermined"]},{"year":2008,"claim":"Linked TRPC1 to skeletal muscle biology through caveolin-3-dependent membrane targeting and through SOCE-driven calpain activation controlling myoblast migration and fusion.","evidence":"FRET, Co-IP, ROS/Src pharmacology in mdx muscle; siRNA knockdown with calpain/MARCKS and migration readouts in primary myoblasts","pmids":["18544631","19001499"],"confidence":"High","gaps":["Whether caveolin-3 and STIM1 pathways are mutually exclusive unresolved","Direct calpain regulation by Ca2+ flux vs other inputs not isolated"]},{"year":2008,"claim":"Established TRPC1 as a SOCE/migration component in vascular smooth muscle interacting with STIM1, while also contributing to proliferation independently of STIM1, and placed TRPC1-Ca2+ entry upstream of PP2A/NF-κB in epithelium.","evidence":"siRNA, Co-IP, extracellular antibody block and patch-clamp in VSMCs; stable TRPC1 expression with PP2A/NF-κB assays in IEC-6 cells","pmids":["18802022","18322138"],"confidence":"Medium","gaps":["STIM1-independent proliferation mechanism undefined","Connection between channel gating and PP2A activation not mapped"]},{"year":2009,"claim":"Genetically established TRPC1 as a driver of maladaptive cardiac hypertrophy upstream of calcineurin/NFAT/mTOR/Akt, and proposed an SR Ca2+ leak function in skeletal muscle.","evidence":"Trpc1−/− mice with pressure overload, cardiomyocyte patch-clamp and signaling readouts; TRPC1-YFP localization and Ca2+ assays in muscle fibers","pmids":["19797170","19875453"],"confidence":"High","gaps":["Plasma membrane vs SR localization debate unresolved (#13 vs prior models)","How the same subunit serves both compartments unclear"]},{"year":2010,"claim":"Demonstrated a cell-autonomous requirement for TRPC1 in VEGF-A-driven angiogenic sprouting via ERK signaling.","evidence":"Morpholino knockdown with mRNA rescue, cell transplantation, in vivo imaging and ERK phosphorylation assay in zebrafish","pmids":["20185799"],"confidence":"High","gaps":["Channel partners in endothelial tip cells not identified","Direct link between Ca2+ flux and ERK activation not dissected"]},{"year":2011,"claim":"Established the core biophysical principle that TRPC1 is an obligate heteromeric subunit that contributes to the pore and reduces Ca2+ permeability, and defined native TRPC1/TRPC5 channels whose conductance and PKC/phosphoinositide regulation depend on TRPC1.","evidence":"Heteromer electrophysiology with pore-region mutagenesis; single-channel patch-clamp in WT vs TRPC1−/− VSMCs with PKC/PIP pharmacology","pmids":["22157757","21968068"],"confidence":"High","gaps":["Subunit stoichiometry in native heteromers undetermined","Structural basis for permeability reduction unknown"]},{"year":2012,"claim":"Connected TRPC1-mediated Ca2+ entry to proliferative signaling, forming an EGFR amplification loop in lung carcinoma and acting upstream of PI3K/Akt/mTOR during muscle regeneration.","evidence":"siRNA with cell-cycle and phospho-EGFR readouts; Trpc1−/− cardiotoxin injury model with PI3K/Akt/myogenic factor readouts","pmids":["22451676","22399301"],"confidence":"High","gaps":["Mechanism coupling channel Ca2+ to EGFR/PI3K not molecularly defined","Heteromeric partner in these contexts unidentified"]},{"year":2013,"claim":"Revealed a splice variant (TRPC1ε)–Orai1 complex amplifying CRAC activity and an antagonistic I-mfa input controlling osteoclastogenesis.","evidence":"TRPC1−/− and I-mfa−/− double-KO mice, osteoclast/bone resorption assays, electrophysiology, Co-IP of TRPC1ε–Orai1 in HEK293","pmids":["23770672"],"confidence":"High","gaps":["Generality of TRPC1ε across tissues unknown","How I-mfa modulates the channel mechanistically unclear"]},{"year":2014,"claim":"Identified TRPC1 as a caspase-11 substrate that negatively restrains unconventional IL-1β secretion, and as a direct PKG phosphorylation target at Ser172/Thr313 within a TRPV4/KCa1.1 vascular complex.","evidence":"Caspase-11 substrate identification with trpc1−/− macrophages and sepsis model; in vitro PKG phosphorylation, Co-IP, and vascular tension assays","pmids":["24630989","25139746"],"confidence":"High","gaps":["Cleavage site and functional consequence of caspase-11 processing not mapped","Link between phosphorylation and gating state not defined"]},{"year":2015,"claim":"Showed TRPC1-mediated Ca2+ entry promotes protective autophagy under hypoxia/nutrient stress, specific to TRPC1 over TRPC3.","evidence":"TRPC1 siRNA and overexpression with Ca2+ imaging, LC3B and apoptosis readouts in primary salivary gland cells","pmids":["25741599"],"confidence":"Medium","gaps":["Downstream autophagy effectors of TRPC1-Ca2+ not identified","Single lab, single cell type"]},{"year":2016,"claim":"Mapped the structural determinants of TRPC1 heteromerization with TRPC4/5 and identified SARAF as a STIM1-independent negative regulator, while defining the STIM1-Gαq-PLCβ1 gating module in smooth muscle.","evidence":"FRET and truncation mapping of CCD/C-terminal interaction regions; Co-IP and Ca2+ assays for SARAF; patch-clamp, PLA, PIP2 imaging and TRPC1−/− VSMCs","pmids":["27131740","27506849","27753095"],"confidence":"High","gaps":["Whether SARAF and STIM1 compete for TRPC1 unknown","Quantitative contribution of each regulatory input in vivo unclear"]},{"year":2017,"claim":"Defined the native brain channel composition (exclusive TRPC1/4/5 heteromers) and its role in synaptic transmission, memory, and muscle SOCE via preferential STIM1L coupling, plus a TRPV4-TRPC1 endothelial vasorelaxation channel.","evidence":"Quantitative MS of native complexes and Trpc1/4/5 triple-KO electrophysiology/behavior; siRNA and Co-IP in human myotubes; PLA and single-channel recording in artery endothelium","pmids":["28790178","28185894","28867591"],"confidence":"High","gaps":["Subunit stoichiometry within native heteromers undetermined","How distinct partners (STIM1L vs TRPV4) select channel function unclear"]},{"year":2018,"claim":"Dissected the dual Gαq/PI(4,5)P2 regulatory logic of TRPC1/4 and TRPC1/5 channels, showing Gαq binds TRPC4/5 (not TRPC1) for activation while PLCβ-driven PIP2 depletion self-limits the current.","evidence":"Co-IP of Gαq with subunits, heteromer patch-clamp, DrVSP-based PI(4,5)P2 depletion","pmids":["30108272"],"confidence":"Medium","gaps":["Physiological balance of activation vs inhibition not quantified","Role of TRPC1 in Gαq coupling beyond permeability tuning unclear"]},{"year":2019,"claim":"Defined TRPC1 as a negative modulator that lowers PI(4,5)P2 sensitivity of TRPC4/5 heteromers, mapping the PIP2 binding residues to TRPC4.","evidence":"DrVSP PI(4,5)P2 dephosphorylation with patch-clamp, PIP2-sensor FRET and neutralizing mutagenesis","pmids":["30755645"],"confidence":"Medium","gaps":["TRPC1's own PIP2 contribution not isolated","Physiological consequence of equalized PIP2 affinity untested in vivo"]},{"year":2020,"claim":"Identified TRPC1 as a host entry factor for HSV-1 through direct binding of its third ectodomain by viral glycoprotein D.","evidence":"Co-IP of gD with TRPC1 ectodomain, knockdown/knockout viral entry assays, TRPC1−/− ocular model and human biopsy staining","pmids":["32206724"],"confidence":"High","gaps":["Whether channel activity vs binding alone mediates entry not separated","Generality across other herpesviruses unknown"]},{"year":2021,"claim":"Connected TRPC1 to oncogenic signaling via direct calmodulin binding that bridges CaM to PI3K p85, activating PI3K/AKT and EMT in colorectal cancer.","evidence":"Co-IP of TRPC1-CaM and CaM-PI3K p85, siRNA/overexpression functional assays, Trpc1−/− CRC mouse model","pmids":["34642309"],"confidence":"Medium","gaps":["Whether CaM binding requires channel Ca2+ flux unresolved","Single lab, mechanism of CaM-p85 bridging not structurally defined"]},{"year":null,"claim":"The subunit stoichiometry, atomic structure, and rules governing how TRPC1's partner choice (TRPC4/5, TRPP2, TRPV4, Orai1) and regulatory inputs (STIM1, SARAF, PKC, PKG, caveolins) are integrated to specify channel gating and Ca2+ permeability in each tissue remain unresolved.","evidence":"No direct evidence in the available corpus","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of any TRPC1-containing channel","Native heteromer stoichiometry undetermined","Integration of competing regulators not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,15,16,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[29]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4,8,6,30]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[7]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,22,2,26]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[34,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,18,11]}],"complexes":["TRPC1/TRPC4/TRPC5 heterotetramer","TRPC1/TRPP2 channel","TRPV4/TRPC1/KCa1.1 complex","TRPC1ε/Orai1 CRAC complex"],"partners":["STIM1","TRPC4","TRPC5","ORAI1","CAV1","CAV3","CALM1","TRPV4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48995","full_name":"Short transient receptor potential channel 1","aliases":["Transient receptor protein 1","TRP-1"],"length_aa":793,"mass_kda":91.2,"function":"Forms a receptor-activated non-selective calcium permeant cation channel (PubMed:11139478, PubMed:15016832, PubMed:39478185). Forms a heteromeric ion channel with TRPC4 or TRPC5 that has reduced calcium permeability compared to the homomeric TRPC4 or TRPC5 channel (PubMed:39478185). Also permeable to monovalent ions including sodium, lithium and cesium ions (PubMed:39478185) Forms a receptor-activated non-selective calcium permeant cation channel. Also activated by intracellular calcium store depletion","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P48995/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRPC1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRPC1","total_profiled":1310},"omim":[{"mim_id":"612489","title":"RING FINGER PROTEIN 24; RNF24","url":"https://www.omim.org/entry/612489"},{"mim_id":"612163","title":"TWO-PORE SEGMENT CHANNEL 2; TPCN2","url":"https://www.omim.org/entry/612163"},{"mim_id":"611025","title":"ENKURIN, TRPC CHANNEL-INTERACTING PROTEIN; ENKUR","url":"https://www.omim.org/entry/611025"},{"mim_id":"610277","title":"ORAI CALCIUM RELEASE-ACTIVATED CALCIUM MODULATOR 1; ORAI1","url":"https://www.omim.org/entry/610277"},{"mim_id":"607360","title":"LACRITIN; LACRT","url":"https://www.omim.org/entry/607360"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRPC1"},"hgnc":{"alias_symbol":["HTRP-1"],"prev_symbol":[]},"alphafold":{"accession":"P48995","domains":[{"cath_id":"-","chopping":"341-515","consensus_level":"medium","plddt":87.0723,"start":341,"end":515},{"cath_id":"1.10.287","chopping":"534-563_574-671","consensus_level":"high","plddt":81.529,"start":534,"end":671}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48995","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48995-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48995-F1-predicted_aligned_error_v6.png","plddt_mean":79.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRPC1","jax_strain_url":"https://www.jax.org/strain/search?query=TRPC1"},"sequence":{"accession":"P48995","fasta_url":"https://rest.uniprot.org/uniprotkb/P48995.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48995/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48995"}},"corpus_meta":[{"pmid":"16906149","id":"PMC_16906149","title":"STIM1 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The C-terminal sequence downstream of HR 8 anchors the cytosolic end and prevents HR 7 from fully spanning the bilayer, creating the channel pore.\",\n      \"method\": \"Truncation mutant approach combined with N-linked glycosylation site insertions in HEK-293T cells; glycosylation used as lumenal topology reporter\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis-based topology mapping with multiple orthogonal constructs in a single rigorous study\",\n      \"pmids\": [\"14707123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PKCα phosphorylates TRPC1 in human endothelial cells downstream of thrombin or thapsigargin stimulation, and this phosphorylation is required for store-operated Ca2+ entry and the resulting increase in endothelial permeability. Genetic or pharmacological inhibition of PKCα blocked IP3-induced cationic current and Ca2+ entry, and thrombin failed to phosphorylate TRPC1 when PKCα was inactive.\",\n      \"method\": \"Whole-cell patch clamp, Fura-2 Ca2+ imaging, kinase-defective PKCα mutants, pharmacological inhibition (Gö6976), TRPC1-specific extracellular antibody block, phosphorylation assays, transendothelial resistance\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (electrophysiology, Ca2+ imaging, mutagenesis, phosphorylation assay) in a single study, single lab\",\n      \"pmids\": [\"15016832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRPC1 protein was identified as a component of the vertebrate mechanosensitive cation channel (MscCa): purification of frog oocyte membrane proteins followed by liposome reconstitution and patch-clamp identified an ~80 kDa protein as TRPC1 by immunological methods. Heterologous expression of human TRPC1 in oocytes increased MscCa patch density >1000%, and TRPC1-specific antisense RNA abolished endogenous MscCa activity. Transfection into CHO-K1 cells also increased MscCa expression. The channel is gated by tension in the lipid bilayer.\",\n      \"method\": \"Detergent solubilization + liposome reconstitution + patch-clamp; immunological identification; heterologous overexpression; antisense RNA knockdown; CHO-K1 transfection\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstitution and gain/loss-of-function in multiple systems; subsequent paper (PMID:17957383) failed to replicate in COS/CHO cells, reducing confidence\",\n      \"pmids\": [\"15665854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The cytosolic C-terminus of STIM1 is sufficient to activate TRPC1 channels. STIM1 binds TRPC1, TRPC2, and TRPC4 selectively (not TRPC3, 6, or 7) via its ERM domain, and gates TRPC1 through a cationic lysine-rich region. Deletion of either domain in constitutively active STIM1(D76A) produces dominant-negative mutants that block native SOC and TRPC1 channel activity.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of STIM1, constitutively active and dominant-negative STIM1 mutants expressed in HEK293 cells, electrophysiology, Ca2+ imaging\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of interaction domains, dominant-negative functional rescue, replicated across multiple channel types and cell lines\",\n      \"pmids\": [\"16906149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Overexpression of TRPC1 or TRPC6 in COS or CHO cells did not significantly alter the amplitude of mechanosensitive currents measured with a fast pressure clamp, contradicting a simple model in which TRPC1 alone forms the vertebrate MscCa.\",\n      \"method\": \"Transient transfection of TRPC1 or TRPC6 in COS/CHO cells; fast pressure-clamp patch-clamp recordings; Western blot confirmation of protein expression\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous electrophysiological assay directly contradicting PMID:15665854; single lab but controlled overexpression with protein verification\",\n      \"pmids\": [\"17957383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRPC1 and caveolin-3 co-localize and co-immunoprecipitate in muscle cells; direct binding was confirmed by FRET between TRPC1-CFP and caveolin-3-YFP in C2 myoblasts. Caveolin-3 targeted TRPC1 to the plasma membrane. ROS increased Src kinase activity and enhanced Ca2+ influx only in cells co-expressing TRPC1 and caveolin-3, revealing a ROS–Src–TRPC1/caveolin-3 pathway in Duchenne muscular dystrophy pathogenesis.\",\n      \"method\": \"Co-immunoprecipitation, FRET, confocal microscopy, Src inhibitor PP2, ROS scavenger Tiron, Ca2+ influx measurements in mdx muscle\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET-confirmed direct binding plus functional Ca2+ entry assays and in vivo mdx rescue; multiple orthogonal methods\",\n      \"pmids\": [\"18544631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRPP2 and TRPC1 assemble into a heteromeric receptor-operated channel with unique properties distinct from either subunit alone: different single-channel conductance, amiloride sensitivity, and ion permeability. Native TRPP2/TRPC1 channel activity was demonstrated in kidney cells by gain- and loss-of-function experiments; the complex co-localizes at the primary cilium and co-immunoprecipitates from kidney membranes.\",\n      \"method\": \"Heterologous expression, electrophysiology, co-immunoprecipitation from kidney membranes, gain/loss-of-function in kidney cells, immunolocalization to primary cilium\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP from native tissue, electrophysiological characterization of heteromeric channel, gain and loss-of-function, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18323855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"STIM1 association converts TRPC1 from a receptor-operated channel (ROC) to a store-operated channel (SOC) by promoting insertion of TRPC1 into lipid rafts. In the absence of STIM1, TRPC1 associates with other TRPC members to form ROCs. TIRFM-FRET demonstrated the dynamic association between STIM1 and TRPC1 at ER-PM junctions and lipid rafts.\",\n      \"method\": \"TIRFM-FRET, lipid raft fractionation, co-immunoprecipitation, Ca2+ imaging, siRNA knockdown of STIM1\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET-based direct interaction plus biochemical fractionation and Ca2+ functional assays; single lab\",\n      \"pmids\": [\"18420269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Caveolin-1 scaffold domain (CSD, residues 82–101) directly interacts with TRPC1 C-terminal residues 781–789 and also with IP3R3. The TRPC1-CΔ781-789 mutant abolishes Ca2+ store release-induced Ca2+ influx and disrupts binding to both IP3R3 and caveolin-1. Caveolin-1ΔCSD shows gain-of-function Ca2+ entry. WT caveolin-1 but not ΔCSD interacts with IP3R3 and TRPC1.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutagenesis of TRPC1 C-terminus and CSD, Ca2+ imaging, Fura-2, confocal co-localization, Cav-1 KO mouse lung endothelial cells\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping mutagenesis plus Co-IP and functional Ca2+ assays in multiple cell types and KO mice; multiple orthogonal methods\",\n      \"pmids\": [\"19052258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"STIM1 and TRPC1 interact in vascular smooth muscle cells (VSMCs); TRPC1 contributes to a component of store-operated cation current and cell migration. Extracellular STIM1 N-terminus was detected, and extracellular STIM1 antibody rapidly inhibited store-depletion-evoked current. TRPC1-containing channels also contributed to cell proliferation independently of STIM1.\",\n      \"method\": \"siRNA knockdown of STIM1 and TRPC1, co-immunoprecipitation, extracellular antibody block, patch-clamp, Fura-2 Ca2+ imaging, cell migration and proliferation assays, cell surface localization studies\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus electrophysiology and functional cell assays; single lab\",\n      \"pmids\": [\"18802022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRPC1 depletion in skeletal myoblasts reduces store-operated Ca2+ entry and abolishes the transient calpain activity peak at the onset of differentiation. This leads to accumulation of the calpain substrate MARCKS, slowed cell migration, and impaired myotube fusion. IGF-1-stimulated migration and calpain activation were also dependent on TRPC1 expression.\",\n      \"method\": \"siRNA knockdown of TRPC1 in primary myoblasts, Ca2+ imaging, calpain activity assay, immunofluorescence for MARCKS, time-lapse migration assay, GsMTx4 and calpain inhibitor pharmacology\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple downstream readouts (Ca2+, calpain activity, MARCKS, migration) plus pharmacological validation in a single thorough study\",\n      \"pmids\": [\"19001499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRPC1 knockout mice lack the TRPC-associated non-selective cation current observed after pressure overload and are protected from maladaptive cardiac hypertrophy. Mechanosensitive signaling through calcineurin/NFAT, mTOR, and Akt is altered in Trpc1−/− mice subjected to hemodynamic stress, placing TRPC1 upstream of these hypertrophic pathways.\",\n      \"method\": \"Trpc1−/− mouse model, pressure overload (transverse aortic constriction), whole-cell patch-clamp of cardiomyocytes, cardiac function measurements, Western blot/immunostaining for calcineurin/NFAT/mTOR/Akt\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal phenotypic and signaling readouts; independent from the culture-based PMID:17174323 study\",\n      \"pmids\": [\"19797170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRPC1 operates as a Ca2+ leak channel in the sarcoplasmic reticulum (SR) of skeletal muscle fibers, not at the sarcolemma as previously proposed. Immunostaining colocalizes TRPC1-YFP with SR Ca2+ pump markers in a striated pattern. Overexpression increases resting SR Ca2+, accelerates CPA-induced Ca2+ rise, and slows Ca2+ transient decay, all consistent with SR Ca2+ leak function.\",\n      \"method\": \"TRPC1-YFP overexpression in adult mouse muscle fibers, immunostaining, Ca2+ measurements (Fluo-4), CPA-induced contracture assay, voltage-clamp Ca2+ transients\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional Ca2+ assays; single lab, contradicts prior plasma membrane models\",\n      \"pmids\": [\"19875453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRPC1 is required for angiogenesis in zebrafish: morpholino knockdown of trpc1 severely disrupts intersegmental vessel sprouting in an endothelial-cell-autonomous manner, impairing filopodial extension, tip-cell migration and proliferation. TRPC1 acts downstream of Vegf-a and is required for Vegf-a-induced ERK phosphorylation.\",\n      \"method\": \"Antisense morpholino knockdown, rescue with morpholino-resistant trpc1 mRNA, cell transplantation, in vivo time-lapse imaging, Vegf-a interaction experiments, ERK phosphorylation assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with mRNA rescue, cell-autonomy test, and downstream signaling readout; multiple orthogonal approaches\",\n      \"pmids\": [\"20185799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Recombinant TRPC1 subunits do not form functional homomeric channels; instead they form functional heteromeric receptor-operated channels with all other TRPC subfamily members (TRPC3, 4, 5, 6, 7). In all TRPC1-containing heteromers, TRPC1 significantly reduces calcium permeability. Pore-region amino acid substitutions in TRPC1 further reduce Ca2+ permeability, confirming TRPC1 contributes to the channel pore.\",\n      \"method\": \"Electrophysiology of heterologously expressed TRPC1 homomers and heteromers, pore-region mutagenesis, Ca2+ permeability measurements, TRPC1 siRNA in GnRH neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — electrophysiology with mutagenesis of pore region plus native cell siRNA knockdown; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"22157757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In vascular smooth muscle cells (VSMCs), store depletion activates native heteromeric TRPC1/TRPC5 channels (~2 pS conductance, activated by PKC, PIP2, and PIP3). In TRPC1−/− VSMCs, TRPC5 homomeric channels (with multiple subconductance states 14/32/53 pS) form instead and show opposite regulation (inhibited by PKC, PIP2, PIP3; activated by elevated [Ca2+]i). TRPC1 determines unitary conductance and confers PKC/phosphoinositide activation.\",\n      \"method\": \"Single-channel patch-clamp in acutely isolated mesenteric artery VSMCs from WT and TRPC1−/− mice, co-immunoprecipitation, anti-TRPC antibody blocking, PKC activator/inhibitor pharmacology, PIP2/PIP3 application\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct single-channel electrophysiology with genetic KO comparison, biochemical interaction confirmation, and pharmacological characterization; single lab but rigorous\",\n      \"pmids\": [\"21968068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRPC1 depletion in non-small cell lung carcinoma cells causes G0/G1 arrest, reduces cyclin D1/D3, and decreases EGFR phosphorylation with disruption of PI3K/Akt and MAPK signaling. EGF stimulation triggers Ca2+ release and Ca2+ entry through TRPC1, and this Ca2+ entry reciprocally activates EGFR, forming a Ca2+-dependent amplification loop for EGF-dependent proliferation.\",\n      \"method\": \"siRNA knockdown of TRPC1, cell cycle analysis, Western blot for cyclins and phospho-EGFR, EGF stimulation with Ca2+ imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with cell cycle and signaling readouts plus receptor-channel feedback loop validation; single lab\",\n      \"pmids\": [\"22451676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Trpc1−/− mice show impaired PI3K/Akt/mTOR/p70S6K signaling during muscle regeneration. Trpc1 KO primary myoblasts and regenerating muscles have reduced Akt phosphorylation, decreased MyoD/Myf5/myogenin expression, smaller fiber size, and delayed regeneration after cardiotoxin injury. Ca2+ entry through Trpc1 enhances PI3K activity, placing Trpc1 upstream of the PI3K/Akt pathway in myogenesis.\",\n      \"method\": \"Trpc1−/− mouse, cardiotoxin muscle injury model, primary myoblast culture, Western blot for PI3K/Akt/p70S6K/myogenic factors, EGTA-AM and wortmannin pharmacology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO validated in both in vitro primary cells and in vivo injury model with multiple pathway readouts; extends PMID:19001499\",\n      \"pmids\": [\"22399301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRPC1 and I-mfa (inhibitor of MyoD family) antagonistically regulate osteoclastogenesis. A new splice variant TRPC1ε uniquely amplifies CRAC channel activity and physically interacts with Orai1 (pore-forming CRAC subunit). I-mfa is recruited to the TRPC1ε–Orai1 complex through TRPC1ε and suppresses CRAC activity, revealing a positive/negative modulation axis.\",\n      \"method\": \"TRPC1−/− and I-mfa−/− double-KO mice, in vitro osteoclast differentiation, bone resorption assays, whole-cell electrophysiology, co-immunoprecipitation of TRPC1ε–Orai1 complex, heterologous expression of TRPC1ε in HEK293\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double-KO epistasis plus Co-IP of TRPC1ε–Orai1 plus electrophysiology; multiple orthogonal methods\",\n      \"pmids\": [\"23770672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Caspase-11 cleaves/degrades TRPC1 as a substrate. TRPC1 deficiency increases IL-1β secretion without altering caspase-1 cleavage or cell death in macrophages, and trpc1−/− mice show higher IL-1β in a sepsis model, indicating TRPC1 negatively regulates unconventional IL-1β secretion downstream of caspase-11 independently of caspase-1.\",\n      \"method\": \"Identification of TRPC1 as caspase-11 substrate, trpc1−/− macrophages and mice, LPS-induced sepsis model, IL-1β ELISA, caspase-1 cleavage assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification combined with in vitro cell and in vivo mouse KO experiments with mechanistically specific readouts\",\n      \"pmids\": [\"24630989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SARAF (SOCE-associated regulatory factor) interacts with TRPC1 independently of STIM1 and negatively regulates TRPC1-mediated Ca2+ entry. This interaction is enhanced by agonist (ATP) stimulation. In contrast, SARAF–TRPC6 interaction is constitutive and SARAF does not regulate TRPC6-mediated Ca2+ entry.\",\n      \"method\": \"Co-immunoprecipitation in STIM1-deficient NG115-401L cells and STIM1-expressing SH-SY5Y cells, SARAF siRNA, Ca2+ entry measurements, TRPC6 overexpression cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in two cell systems including STIM1-deficient cells plus functional Ca2+ assays; single lab\",\n      \"pmids\": [\"27506849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Store-operated STIM1–TRPC1 interactions in VSMCs stimulate PLCβ1 activity and PKC phosphorylation of TRPC1 to induce channel gating. Store depletion causes STIM1 translocation to the plasma membrane where it forms complexes with TRPC1, Gαq, and PLCβ1. TRPC1-based SOC activity and store-operated PLCβ1 activity are absent in TRPC1−/− VSMCs.\",\n      \"method\": \"Patch-clamp, GFP-PLCδ1-PH imaging for PLCβ1 activity, co-immunoprecipitation, proximity ligation assays, STIM1 shRNA, TRPC1−/− VSMCs, immunocytochemistry\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, live-cell PIP2 imaging, PLA, Co-IP, genetic KO) establishing a new activation mechanism; single lab\",\n      \"pmids\": [\"27753095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPC1, TRPC4, and TRPC5 assemble exclusively into heteromultimers with each other (not other TRP family members) in mouse brain and hippocampus, as determined by quantitative mass spectrometry. In Trpc1/4/5 triple-KO hippocampal neurons, action potential-triggered EPSCs are reduced while miniature EPSC frequency/amplitude are unchanged, and spatial working memory and flexible relearning are impaired in vivo.\",\n      \"method\": \"Quantitative high-resolution mass spectrometry of native complexes, Trpc1/4/5 triple-KO mice, whole-cell patch-clamp of hippocampal neurons, hippocampal slice recordings, in vivo behavioral testing\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — native complex composition determined by mass spectrometry plus genetic triple-KO with electrophysiology and in vivo behavior; highly rigorous\",\n      \"pmids\": [\"28790178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPC1 and TRPC4 functionally interact preferentially with STIM1L (muscle-specific long isoform) compared to canonical STIM1 in human myotubes. Knockdown of TRPC1 or TRPC4 reduces SOCE by ~50%, delays Ca2+ entry onset, and impairs myotube formation—effects similar to STIM1L invalidation.\",\n      \"method\": \"siRNA knockdown of TRPC1, TRPC4, and STIM1L in human myotubes, Co-immunoprecipitation on store depletion, Ca2+ imaging (Fluo-4), myotube size quantification\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing preferential STIM1L interaction plus siRNA functional assays; single lab\",\n      \"pmids\": [\"28185894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Heteromeric TRPV4–TRPC1 channels mediate calcium-sensing receptor (CaSR)-induced NO production and vasorelaxation in rabbit mesenteric artery endothelial cells. TRPV4 and TRPC1 co-localize and are in proximity at the plasma membrane of endothelial cells. A TRPV4 agonist activates 6 pS cation channels blocked by both TRPV4 antagonists and TRPC1 extracellular antibody.\",\n      \"method\": \"Proximity ligation assay, immunocytochemistry, wire myography, DAF-FM NO fluorescence, perforated-patch electrophysiology, pharmacological antagonists (RN1734, HC067047) and TRPC1 antibody (T1E3)\",\n      \"journal\": \"Vascular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity ligation plus single-channel electrophysiology and functional vascular assays; single lab\",\n      \"pmids\": [\"28867591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Gαq protein directly interacts with TRPC4 or TRPC5 subunits (not TRPC1) in TRPC1/4 and TRPC1/5 heterotetramers to permit activation by the Gαq-PLCβ pathway. Simultaneously, PLCβ-driven PI(4,5)P2 depletion inhibits TRPC1/4 and TRPC1/5 channel activity, creating a self-limited dual regulatory mechanism.\",\n      \"method\": \"Co-immunoprecipitation of Gαq with TRPC subunits, patch-clamp electrophysiology of heteromeric channels, DrVSP-based PI(4,5)P2 depletion, pharmacological activation of Gαq\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of Gαq with channel subunits plus electrophysiology; single lab\",\n      \"pmids\": [\"30108272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"mGluR5 activation specifically activates TRPC1-containing channels in hippocampal CA1-3 neurons. Trpc1−/− mice show impaired mGluR-induced synaptic excitability, defective LTP maintenance, impaired mGluR-LTD, and altered spatial working memory. Acute inhibition with Pico145 mimics genetic TRPC1 depletion, excluding developmental compensation.\",\n      \"method\": \"Trpc1−/− mice, whole-cell patch-clamp, LTP and LTD recordings in hippocampal slices, mGluR5 activation, Pico145 pharmacology, behavioral testing (Morris water maze, fear conditioning)\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus acute pharmacological inhibition with multiple electrophysiological and behavioral readouts\",\n      \"pmids\": [\"30271326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HSV-1 glycoprotein D interacts with the third ectodomain of TRPC1, facilitating viral entry into cells. TRPC1 knockout attenuates HSV-1-induced Ca2+ entry, viral infection, and ocular pathology in vivo. HSV-1 infection correlates with plasma membrane localization of TRPC1 in oral lesion epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation of gD with TRPC1 ectodomain, TRPC1 knockdown/knockout, Ca2+ imaging, viral entry/infection assays, TRPC1−/− mouse ocular model, human biopsy immunostaining\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein–protein interaction identified plus functional viral entry assays in vitro and in vivo KO mouse; multiple orthogonal methods\",\n      \"pmids\": [\"32206724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRPC1 directly binds calmodulin (CaM) and enhances the interaction between CaM and the PI3K p85 subunit, thereby activating the PI3K/AKT and downstream signaling pathways involved in cell cycle progression and EMT in colorectal cancer cells. Silencing of CaM abolishes the oncogenic effects of TRPC1.\",\n      \"method\": \"Co-immunoprecipitation of TRPC1-CaM and CaM-PI3K p85, siRNA knockdown of TRPC1 and CaM, TRPC1 overexpression, proliferation/invasion/migration assays, Trpc1−/− mouse CRC model\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing TRPC1–CaM–PI3K p85 interaction plus genetic KO mouse and siRNA functional assays; single lab\",\n      \"pmids\": [\"34642309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRPC1 interaction domains for heteromerization with TRPC4 and TRPC5 were mapped: TRPC1's N-terminal coiled-coil domain (CCD) and C-terminal 725–745 region interact with TRPC4's N-terminal CCD and C-terminal 700–728 region; TRPC1's N-terminal CCD and C-terminal 673–725 region interact with TRPC5's N-terminal CCD and C-terminal 707–735 region. TRPC1 only reaches the plasma membrane when co-expressed with TRPC4 or TRPC5.\",\n      \"method\": \"FRET, patch-clamp electrophysiology, truncation/deletion mutants of TRPC1, TRPC4, and TRPC5\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET-based interaction mapping with functional electrophysiology confirmation; single lab\",\n      \"pmids\": [\"27131740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPC1 acts as a negative regulator of TRPC4 and TRPC5 channel activity: incorporation of TRPC1 into TRPC1/4 or TRPC1/5 heterotetramers reduces PI(4,5)P2 sensitivity compared to TRPC4 or TRPC5 homotetramers. PI(4,5)P2 binding sites were mapped to specific basic residues (K419, K664/R511, K518, H630) in TRPC4; TRPC1 equalizes PI(4,5)P2 affinity across heteromers.\",\n      \"method\": \"DrVSP-based PI(4,5)P2 dephosphorylation combined with patch-clamp, FRET to PI(4,5)P2 sensor, neutralizing mutagenesis of PI(4,5)P2 binding residues\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of PI(4,5)P2 binding sites with FRET and electrophysiology; single lab\",\n      \"pmids\": [\"30755645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Induced TRPC1 expression in intestinal epithelial cells increases protein phosphatase 2A (PP2A) activity through Ca2+ influx. Elevated PP2A reduces nuclear NF-κB levels and transcriptional activity, sensitizing cells to TNF-α/cycloheximide-induced apoptosis. Inhibition of PP2A or Ca2+ removal reverses these effects, placing TRPC1-mediated Ca2+ entry upstream of PP2A and NF-κB.\",\n      \"method\": \"Stable TRPC1 transfection in IEC-6 cells, PP2A activity assay, PP2A siRNA, okadaic acid, NF-κB reporter assay, apoptosis assay, Ca2+-free medium\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods establishing TRPC1→Ca2+→PP2A→NF-κB pathway; single lab\",\n      \"pmids\": [\"18322138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PKG phosphorylates TRPC1 directly at Ser172 and Thr313. NO–cGMP–PKG pathway inhibits 11,12-EET-induced smooth muscle hyperpolarization and vascular relaxation via PKG-mediated phosphorylation of TRPC1. TRPV4, TRPC1, and KCa1.1 physically associate with each other in smooth muscle cells and TRPC1 inhibition abolishes EET responses.\",\n      \"method\": \"In vitro PKG phosphorylation assay of TRPC1 peptides, TAT-linked phosphorylation-site peptides (competitive inhibition), co-immunoprecipitation of TRPV4–TRPC1–KCa1.1 complex, membrane potential and arterial tension measurements\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct in vitro phosphorylation assay identifying specific residues plus Co-IP of native complex and functional vascular assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25139746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRPC1-mediated Ca2+ entry regulates hypoxia- and nutrient-depletion-induced autophagy to prevent cell death. Hypoxia increases TRPC1 expression and Ca2+ entry through TRPC1. Silencing of TRPC1 reduces Ca2+ influx, decreases autophagic markers, and increases apoptosis. Notably, this effect is specific to TRPC1 and not TRPC3.\",\n      \"method\": \"TRPC1 siRNA, TRPC1 overexpression, Ca2+ imaging, autophagy markers (LC3B), apoptosis assays, primary salivary gland cells under hypoxia\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD and OE with multiple Ca2+ and autophagy/apoptosis readouts; primary cell validation; single lab\",\n      \"pmids\": [\"25741599\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRPC1 is a non-selective, Ca2+-permeable cation channel subunit that cannot form functional homomeric channels and instead obligately assembles as heterotetramers with other TRPC members (TRPC3–7, with preference for TRPC4/5) or with TRPP2, where it reduces Ca2+ permeability and modulates PI(4,5)P2 sensitivity; it is activated downstream of ER Ca2+ store depletion via a STIM1-dependent mechanism requiring STIM1's ERM domain for selective binding and a polybasic domain for gating, with Orai1-mediated Ca2+ entry required to recruit TRPC1 to the plasma membrane; PKCα (phosphorylating TRPC1 in a STIM1-facilitated Gαq/PLCβ1 pathway) and PKG (phosphorylating Ser172/Thr313) modulate its activity; TRPC1 interacts with caveolin-1/3, IP3R3, calmodulin, and HSV-1 glycoprotein D, and is cleaved by caspase-11; functionally, it regulates store-operated Ca2+ entry, myoblast migration/differentiation (via calpain and PI3K/Akt), cardiac hypertrophy (via calcineurin/NFAT/mTOR), neuronal synaptic plasticity via mGluR5, angiogenesis downstream of VEGF-A, and IL-1β secretion in macrophages.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRPC1 is the founding mammalian member of the canonical transient receptor potential (TRPC) family, a non-voltage-gated, Ca2+-permeable cation channel subunit that functions as a regulator of store-operated and receptor-operated Ca2+ entry across many cell types [#0]. Its membrane topology positions hydrophobic region 7 as a re-entrant pore loop anchored by the cytosolic C-terminus [#1]. TRPC1 cannot form functional homomeric channels; instead it obligately heteromerizes with other TRPC subunits—TRPC3-7, with selective assembly into TRPC1/4/5 multimers in brain—via its N-terminal coiled-coil and defined C-terminal interaction regions, and only reaches the plasma membrane when co-expressed with TRPC4 or TRPC5 [#15, #23, #30]. Within these heteromers TRPC1 contributes to the channel pore, reduces Ca2+ permeability, and lowers PI(4,5)P2 sensitivity, thereby tuning channel gating [#15, #31]. TRPC1 is converted from a receptor-operated to a store-operated channel by STIM1, which binds TRPC1 selectively through its ERM domain and gates it via a lysine-rich polybasic region, promoting TRPC1 insertion into lipid rafts at ER-PM junctions [#4, #8]; in vascular smooth muscle this STIM1-TRPC1 association nucleates a Gαq/PLCβ1 complex whose PKC-mediated phosphorylation gates the channel [#22]. Channel activity is further modulated by PKCα phosphorylation downstream of thrombin [#2], by direct PKG phosphorylation at Ser172/Thr313 [#33], and by negative regulators including SARAF and the inhibitor I-mfa acting at a TRPC1ε–Orai1 complex [#21, #19]. TRPC1 also assembles into distinct functional complexes with TRPP2 at the primary cilium, with TRPV4 (and KCa1.1) in endothelium and smooth muscle, and with caveolin-1/3 and IP3R3 for plasma-membrane targeting and store-release coupling [#7, #25, #33, #6, #9]. Through these channels, TRPC1-mediated Ca2+ entry drives diverse processes: myoblast migration, differentiation and regeneration via calpain and PI3K/Akt/mTOR signaling [#11, #18], maladaptive cardiac hypertrophy via calcineurin/NFAT/mTOR/Akt [#12], VEGF-A-dependent angiogenesis through ERK [#14], mGluR5-dependent hippocampal synaptic plasticity and spatial memory [#27, #23], and cancer cell proliferation through EGFR and CaM-PI3K amplification loops [#17, #29]. TRPC1 is cleaved by caspase-11 and negatively regulates unconventional IL-1β secretion in macrophages [#20], and is exploited by HSV-1 glycoprotein D, which binds its third ectodomain to facilitate viral entry [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the existence and identity of a mammalian TRP homolog, defining TRPC1 as a candidate non-voltage-gated plasma membrane Ca2+ channel and founding the TRPC family.\",\n      \"evidence\": \"Molecular cloning, sequence analysis, and expression profiling of the human TRP homolog\",\n      \"pmids\": [\"7568191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct electrophysiology demonstrating channel activity\", \"Activation mechanism and partners unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved how the polypeptide threads the membrane, defining the re-entrant pore loop and the C-terminal anchor required to form the conduction pathway.\",\n      \"evidence\": \"Truncation mutants plus N-glycosylation topology reporters in HEK-293T cells\",\n      \"pmids\": [\"14707123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure\", \"Topology in native heteromeric channels not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified PKCα phosphorylation as a required gating input linking GPCR/store-depletion stimuli to TRPC1-dependent Ca2+ entry and endothelial permeability.\",\n      \"evidence\": \"Patch clamp, Ca2+ imaging, kinase-defective PKCα mutants, phosphorylation assays in endothelial cells\",\n      \"pmids\": [\"15016832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation sites not mapped\", \"Direct vs indirect phosphorylation not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Proposed TRPC1 as a constituent of the vertebrate mechanosensitive cation channel gated by bilayer tension.\",\n      \"evidence\": \"Liposome reconstitution + patch-clamp, heterologous overexpression and antisense knockdown in oocytes and CHO cells\",\n      \"pmids\": [\"15665854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Subsequently not replicated in COS/CHO cells (#5)\", \"Whether TRPC1 alone confers mechanosensitivity disputed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined STIM1 as the store-sensor that activates TRPC1, mapping selective binding to the ERM domain and gating to a lysine-rich region.\",\n      \"evidence\": \"Reciprocal Co-IP, STIM1 siRNA, constitutively active and dominant-negative STIM1 mutants, electrophysiology in HEK293\",\n      \"pmids\": [\"16906149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of STIM1-TRPC1 coupling unresolved\", \"Role of Orai not addressed in this study\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Directly challenged the simple TRPC1-as-MscCa model by showing overexpression does not augment mechanosensitive currents.\",\n      \"evidence\": \"Fast pressure-clamp patch-clamp of TRPC1/TRPC6-transfected COS/CHO cells with protein verification\",\n      \"pmids\": [\"17957383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; cell-type or partner dependence not excluded\", \"Does not exclude TRPC1 in native mechanosensory complexes\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed STIM1 converts TRPC1 from a receptor-operated to a store-operated channel by driving its insertion into lipid rafts, and defined caveolin-1/IP3R3 C-terminal interactions required for store-release coupling and PM targeting.\",\n      \"evidence\": \"TIRFM-FRET, lipid raft fractionation, domain-mapping mutagenesis, Co-IP and Ca2+ imaging in endothelial and Cav-1 KO cells\",\n      \"pmids\": [\"18420269\", \"19052258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of raft recruitment in vivo unclear\", \"Interplay of STIM1 vs caveolin targeting not fully integrated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that TRPC1 forms functionally distinct heteromeric channels beyond the TRPC family, assembling with TRPP2 at the primary cilium with unique conductance and permeability.\",\n      \"evidence\": \"Heterologous electrophysiology, Co-IP from kidney membranes, gain/loss-of-function and ciliary immunolocalization\",\n      \"pmids\": [\"18323855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological stimulus gating the ciliary complex unknown\", \"Stoichiometry undetermined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked TRPC1 to skeletal muscle biology through caveolin-3-dependent membrane targeting and through SOCE-driven calpain activation controlling myoblast migration and fusion.\",\n      \"evidence\": \"FRET, Co-IP, ROS/Src pharmacology in mdx muscle; siRNA knockdown with calpain/MARCKS and migration readouts in primary myoblasts\",\n      \"pmids\": [\"18544631\", \"19001499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether caveolin-3 and STIM1 pathways are mutually exclusive unresolved\", \"Direct calpain regulation by Ca2+ flux vs other inputs not isolated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established TRPC1 as a SOCE/migration component in vascular smooth muscle interacting with STIM1, while also contributing to proliferation independently of STIM1, and placed TRPC1-Ca2+ entry upstream of PP2A/NF-κB in epithelium.\",\n      \"evidence\": \"siRNA, Co-IP, extracellular antibody block and patch-clamp in VSMCs; stable TRPC1 expression with PP2A/NF-κB assays in IEC-6 cells\",\n      \"pmids\": [\"18802022\", \"18322138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"STIM1-independent proliferation mechanism undefined\", \"Connection between channel gating and PP2A activation not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetically established TRPC1 as a driver of maladaptive cardiac hypertrophy upstream of calcineurin/NFAT/mTOR/Akt, and proposed an SR Ca2+ leak function in skeletal muscle.\",\n      \"evidence\": \"Trpc1−/− mice with pressure overload, cardiomyocyte patch-clamp and signaling readouts; TRPC1-YFP localization and Ca2+ assays in muscle fibers\",\n      \"pmids\": [\"19797170\", \"19875453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Plasma membrane vs SR localization debate unresolved (#13 vs prior models)\", \"How the same subunit serves both compartments unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated a cell-autonomous requirement for TRPC1 in VEGF-A-driven angiogenic sprouting via ERK signaling.\",\n      \"evidence\": \"Morpholino knockdown with mRNA rescue, cell transplantation, in vivo imaging and ERK phosphorylation assay in zebrafish\",\n      \"pmids\": [\"20185799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Channel partners in endothelial tip cells not identified\", \"Direct link between Ca2+ flux and ERK activation not dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established the core biophysical principle that TRPC1 is an obligate heteromeric subunit that contributes to the pore and reduces Ca2+ permeability, and defined native TRPC1/TRPC5 channels whose conductance and PKC/phosphoinositide regulation depend on TRPC1.\",\n      \"evidence\": \"Heteromer electrophysiology with pore-region mutagenesis; single-channel patch-clamp in WT vs TRPC1−/− VSMCs with PKC/PIP pharmacology\",\n      \"pmids\": [\"22157757\", \"21968068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit stoichiometry in native heteromers undetermined\", \"Structural basis for permeability reduction unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected TRPC1-mediated Ca2+ entry to proliferative signaling, forming an EGFR amplification loop in lung carcinoma and acting upstream of PI3K/Akt/mTOR during muscle regeneration.\",\n      \"evidence\": \"siRNA with cell-cycle and phospho-EGFR readouts; Trpc1−/− cardiotoxin injury model with PI3K/Akt/myogenic factor readouts\",\n      \"pmids\": [\"22451676\", \"22399301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling channel Ca2+ to EGFR/PI3K not molecularly defined\", \"Heteromeric partner in these contexts unidentified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a splice variant (TRPC1ε)–Orai1 complex amplifying CRAC activity and an antagonistic I-mfa input controlling osteoclastogenesis.\",\n      \"evidence\": \"TRPC1−/− and I-mfa−/− double-KO mice, osteoclast/bone resorption assays, electrophysiology, Co-IP of TRPC1ε–Orai1 in HEK293\",\n      \"pmids\": [\"23770672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of TRPC1ε across tissues unknown\", \"How I-mfa modulates the channel mechanistically unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified TRPC1 as a caspase-11 substrate that negatively restrains unconventional IL-1β secretion, and as a direct PKG phosphorylation target at Ser172/Thr313 within a TRPV4/KCa1.1 vascular complex.\",\n      \"evidence\": \"Caspase-11 substrate identification with trpc1−/− macrophages and sepsis model; in vitro PKG phosphorylation, Co-IP, and vascular tension assays\",\n      \"pmids\": [\"24630989\", \"25139746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site and functional consequence of caspase-11 processing not mapped\", \"Link between phosphorylation and gating state not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed TRPC1-mediated Ca2+ entry promotes protective autophagy under hypoxia/nutrient stress, specific to TRPC1 over TRPC3.\",\n      \"evidence\": \"TRPC1 siRNA and overexpression with Ca2+ imaging, LC3B and apoptosis readouts in primary salivary gland cells\",\n      \"pmids\": [\"25741599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream autophagy effectors of TRPC1-Ca2+ not identified\", \"Single lab, single cell type\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped the structural determinants of TRPC1 heteromerization with TRPC4/5 and identified SARAF as a STIM1-independent negative regulator, while defining the STIM1-Gαq-PLCβ1 gating module in smooth muscle.\",\n      \"evidence\": \"FRET and truncation mapping of CCD/C-terminal interaction regions; Co-IP and Ca2+ assays for SARAF; patch-clamp, PLA, PIP2 imaging and TRPC1−/− VSMCs\",\n      \"pmids\": [\"27131740\", \"27506849\", \"27753095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SARAF and STIM1 compete for TRPC1 unknown\", \"Quantitative contribution of each regulatory input in vivo unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the native brain channel composition (exclusive TRPC1/4/5 heteromers) and its role in synaptic transmission, memory, and muscle SOCE via preferential STIM1L coupling, plus a TRPV4-TRPC1 endothelial vasorelaxation channel.\",\n      \"evidence\": \"Quantitative MS of native complexes and Trpc1/4/5 triple-KO electrophysiology/behavior; siRNA and Co-IP in human myotubes; PLA and single-channel recording in artery endothelium\",\n      \"pmids\": [\"28790178\", \"28185894\", \"28867591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit stoichiometry within native heteromers undetermined\", \"How distinct partners (STIM1L vs TRPV4) select channel function unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Dissected the dual Gαq/PI(4,5)P2 regulatory logic of TRPC1/4 and TRPC1/5 channels, showing Gαq binds TRPC4/5 (not TRPC1) for activation while PLCβ-driven PIP2 depletion self-limits the current.\",\n      \"evidence\": \"Co-IP of Gαq with subunits, heteromer patch-clamp, DrVSP-based PI(4,5)P2 depletion\",\n      \"pmids\": [\"30108272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological balance of activation vs inhibition not quantified\", \"Role of TRPC1 in Gαq coupling beyond permeability tuning unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined TRPC1 as a negative modulator that lowers PI(4,5)P2 sensitivity of TRPC4/5 heteromers, mapping the PIP2 binding residues to TRPC4.\",\n      \"evidence\": \"DrVSP PI(4,5)P2 dephosphorylation with patch-clamp, PIP2-sensor FRET and neutralizing mutagenesis\",\n      \"pmids\": [\"30755645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRPC1's own PIP2 contribution not isolated\", \"Physiological consequence of equalized PIP2 affinity untested in vivo\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified TRPC1 as a host entry factor for HSV-1 through direct binding of its third ectodomain by viral glycoprotein D.\",\n      \"evidence\": \"Co-IP of gD with TRPC1 ectodomain, knockdown/knockout viral entry assays, TRPC1−/− ocular model and human biopsy staining\",\n      \"pmids\": [\"32206724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether channel activity vs binding alone mediates entry not separated\", \"Generality across other herpesviruses unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected TRPC1 to oncogenic signaling via direct calmodulin binding that bridges CaM to PI3K p85, activating PI3K/AKT and EMT in colorectal cancer.\",\n      \"evidence\": \"Co-IP of TRPC1-CaM and CaM-PI3K p85, siRNA/overexpression functional assays, Trpc1−/− CRC mouse model\",\n      \"pmids\": [\"34642309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CaM binding requires channel Ca2+ flux unresolved\", \"Single lab, mechanism of CaM-p85 bridging not structurally defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The subunit stoichiometry, atomic structure, and rules governing how TRPC1's partner choice (TRPC4/5, TRPP2, TRPV4, Orai1) and regulatory inputs (STIM1, SARAF, PKC, PKG, caveolins) are integrated to specify channel gating and Ca2+ permeability in each tissue remain unresolved.\",\n      \"evidence\": \"No direct evidence in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of any TRPC1-containing channel\", \"Native heteromer stoichiometry undetermined\", \"Integration of competing regulators not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 15, 16, 7]},\n      {\"term_id\": \"GO:0005262\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4, 8, 6, 30]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 22, 2, 26]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [34, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 18, 11]}\n    ],\n    \"complexes\": [\n      \"TRPC1/TRPC4/TRPC5 heterotetramer\",\n      \"TRPC1/TRPP2 channel\",\n      \"TRPV4/TRPC1/KCa1.1 complex\",\n      \"TRPC1ε/Orai1 CRAC complex\"\n    ],\n    \"partners\": [\n      \"STIM1\",\n      \"TRPC4\",\n      \"TRPC5\",\n      \"Orai1\",\n      \"CAV1\",\n      \"CAV3\",\n      \"CALM1\",\n      \"TRPV4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}