{"gene":"CACNA1G","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2006,"finding":"Genetic disruption of CaV3.1/alpha1G (cacna1g knockout) abolishes T-type calcium current in sinoatrial node (SAN) and atrioventricular node cells without affecting L-type Ca2+ current, causing bradycardia, slowed atrioventricular conduction, prolonged SAN recovery time, and reduced slope of diastolic depolarization in SAN pacemaker cells.","method":"Cacna1g knockout mice; patch-clamp electrophysiology on isolated SAN/AVN cells; telemetric ECG and intracardiac recordings","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout with multiple orthogonal readouts (patch-clamp, ECG, intracardiac recording), clear cellular and in vivo phenotypes","pmids":["16690884"],"is_preprint":false},{"year":2005,"finding":"Thalamic CaV3.1 T-type Ca2+ channel activation causes prolonged inhibition (>9 s) of action-potential firing in thalamic projection neurons via intracellular Ca2+ increase (independent of synaptic transmission); focal deletion of Cacna1g from rostral-midline thalamus (but not cortical pyramidal neurons) causes fragmented and reduced sleep, establishing a thalamus-specific role in stabilizing sleep by blocking arousal signal transmission.","method":"Cav3.1 knockout mice; Cre/loxP conditional knockout in thalamus vs. cortex; electrophysiology in thalamic neurons; sleep telemetry","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with region-specific controls, electrophysiology, and behavioral readout in one study","pmids":["15677322"],"is_preprint":false},{"year":2009,"finding":"CaV3.1 T-type channels are preferentially expressed in Purkinje cell dendritic spines and colocalize with mGluR1; mGluR1 activation potentiates CaV3.1 currents via a G-protein- and tyrosine-phosphatase-dependent pathway; parallel fiber stimulation induces fast subthreshold Ca2+ signaling in dendritic spines through CaV3.1, potentiated by mGluR1 during bursts of excitatory input.","method":"Electrophysiology; ultrafast two-photon calcium imaging; immunohistochemistry and electron microscopy on wild-type and CaV3.1 knockout mice","journal":"Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, Ca2+ imaging, EM, KO controls) in single rigorous study","pmids":["19657020"],"is_preprint":false},{"year":2015,"finding":"The recurrent missense mutation p.Arg1715His in the S4 voltage-sensor segment of CaV3.1 positively shifts the current-voltage and steady-state activation curves and increases the slope factor of inactivation, predicted by computer modeling to decrease deep cerebellar nuclei neuronal excitability, causing autosomal dominant cerebellar ataxia (SCA42).","method":"Whole-exome sequencing; electrophysiology in HEK293T cells expressing mutant vs. wild-type Cav3.1; computational neuron modeling","journal":"American Journal of Human Genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — replicated in independent cohorts (French and Japanese families, PMID 26456284 and 26715324), electrophysiology in heterologous system with mutagenesis-level specificity","pmids":["26456284","26715324"],"is_preprint":false},{"year":2018,"finding":"De novo gain-of-function CACNA1G mutations p.Ala961Thr and p.Met1531Val drastically impair channel inactivation with ~5-fold slower kinetics and >10 mV negative shift of half-inactivation, increase window current (fully inhibited by TTA-P2), and enhance neuronal firing in a cerebellar nuclear neuron model, causing severe childhood-onset cerebellar atrophy.","method":"Patch-clamp electrophysiology in transfected cells; computational neuron modeling; whole-exome sequencing in patient cohort","journal":"Brain","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple recurrent variants tested by electrophysiology + modeling, replicated across independent studies (PMID 29878067, 32878331, 32736238, 39674904)","pmids":["29878067","32878331","32736238"],"is_preprint":false},{"year":2004,"finding":"The calcium channel γ6 subunit (both long and short isoforms) co-expressed with CaV3.1 in HEK-293 cells significantly decreases CaV3.1 current density (~49–69%) without affecting voltage dependence of activation/inactivation or kinetics, and without altering CaV3.1 mRNA or total protein levels; γ6L is localized to the cell surface membrane. γ4 and γ7 subunits have no significant effect on CaV3.1.","method":"Co-expression in HEK-293 cells; whole-cell patch-clamp; RT-PCR; Western blot; GFP-tagged localization; endogenous current recording in HL-1 atrial cells","journal":"Journal of Molecular and Cellular Cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated in heterologous and endogenous systems, multiple orthogonal methods, extended mechanistically by PMID 18818244 and 19193827","pmids":["15572045"],"is_preprint":false},{"year":2008,"finding":"The γ6 subunit's first transmembrane domain (TM1) containing a critical GxxxA motif is required for its inhibitory effect on CaV3.1 current; co-immunoprecipitation confirms physical association of γ6 with CaV3.1 in HEK cells and atrial myocytes; single-channel analysis shows γ6 binding reduces channel availability for activation.","method":"Chimeric construct mutagenesis; whole-cell patch-clamp; single-channel recording; co-immunoprecipitation from HEK cells and atrial myocytes","journal":"Journal of Physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis, co-IP, single-channel analysis, multiple cell systems in one study","pmids":["18818244"],"is_preprint":false},{"year":2009,"finding":"An eight-amino acid peptide from γ6 TM1 containing the GxxxA motif inhibits CaV3.1 current in a concentration-dependent manner by dynamically binding and dissociating from the channel, with selective affinity for CaV3.1 over CaV1.2, supporting a mechanism of endogenous LVA channel antagonism through helix-helix interactions within the plasma membrane.","method":"Whole-cell patch-clamp in HEK cells; peptide mutagenesis","journal":"Molecular Pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro electrophysiology with systematic peptide mutagenesis, single lab","pmids":["19193827"],"is_preprint":false},{"year":2010,"finding":"LEF1/β-catenin complex directly regulates transcription of Cacna1g (encoding CaV3.1) in thalamic neurons; four LEF1 binding sites identified in the proximal promoter; chromatin immunoprecipitation confirmed β-catenin occupancy at the Cacna1g proximal promoter in thalamus but not hippocampus in vivo; WNT3A and LiCl treatment enhance T-type current in cultured thalamic neurons.","method":"Luciferase reporter assay; footprinting analysis; chromatin immunoprecipitation (ChIP); patch-clamp in cultured thalamic neurons","journal":"Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP in vivo plus reporter assays plus functional electrophysiology, multiple orthogonal methods in single study","pmids":["20371816"],"is_preprint":false},{"year":2010,"finding":"CaV3.1 associates with the KV4.2-KChIP3-DPP10c complex and CaV3.1-mediated calcium entry right-shifts the inactivation voltage of KV4.2 into the physiological range; this regulation was not produced by co-expression of CaV1.4, CaV2.1, or CaV2.3, demonstrating selectivity for low voltage-activated CaV3 channels in this signaling complex.","method":"Co-expression in HEK cells; whole-cell patch-clamp","journal":"Channels","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional electrophysiology with channel specificity controls, single lab","pmids":["20458163"],"is_preprint":false},{"year":2012,"finding":"β-adrenergic stimulation increases CaV3.1-mediated T-type Ca2+ current in cardiomyocytes via the cAMP/PKA pathway; PKA inhibitor H89 blocks the ISO effect; native CaV3.1 current in SAN cells is upregulated by isoproterenol; Cav3.1 knockout SAN cells lack T-type current, confirming CaV3.1 as the identity of I(Ca,T) in normal SAN.","method":"Cav3.1 transgenic and knockout mice; patch-clamp in ventricular myocytes and SAN cells; pharmacological PKA inhibition; real-time PCR","journal":"PLoS ONE","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockouts plus pharmacological dissection, multiple cell types and orthogonal approaches","pmids":["22808078"],"is_preprint":false},{"year":2015,"finding":"Cyclin-dependent kinase 5 (Cdk5) upregulates CaV3.1 channel activity; overexpression of Cdk5 increases whole-cell T-type current in N1E-115 neuroblastoma cells and in HEK-293 cells stably expressing Cav3.1; site-directed mutagenesis identified serine 2234 in the C-terminal region as a major phosphorylation site.","method":"Overexpression and siRNA knockdown in N1E-115 cells; heterologous expression in HEK-293 cells; whole-cell patch-clamp; site-directed mutagenesis","journal":"PLoS ONE","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis identifies phosphorylation site, functional patch-clamp, native and heterologous systems, single lab","pmids":["25760945"],"is_preprint":false},{"year":2006,"finding":"Domains I and IV are major determinants of half-activation potential for CaV3.1; domain IV substitution is the primary determinant of activation time constant and recovery from inactivation time constant; inactivation time constant determinants are distributed across multiple domains with domains I+IV together partially conferring inactivation kinetics of CaV3.3.","method":"Chimeric channel constructs with swapped transmembrane domains expressed in tsA-201 cells; whole-cell patch-clamp","journal":"Neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic domain-swap mutagenesis with electrophysiological characterization, single lab","pmids":["16996222"],"is_preprint":false},{"year":2003,"finding":"Extracellular protons modulate CaV3.1 (alpha1G) gating by interacting with intermediate closed states in the activation pathway; extracellular Ca2+ competes with protons at surface charges, at the selectivity filter, and counteracts proton-induced modification of activation; mutation of the EEDD pore locus alters Ca2+-dependent proton effects on channel selectivity and permeation.","method":"Whole-cell patch-clamp in HEK293 cells expressing CaV3.1; EEDD pore locus mutagenesis; model simulations","journal":"Journal of General Physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of pore locus, quantitative biophysical analysis, single lab","pmids":["12743167"],"is_preprint":false},{"year":2008,"finding":"Ni2+ blocks CaV3.1 via two components: a rapid, weakly voltage-dependent pore block (apparent Kd ~1–3 mM) and a slow block visible as accelerated tail currents; both are consistent with occlusion of the pore; the site responsible for fast block can lock in slow block, with the slow-block site located deeper in the pore. This mechanism differs fundamentally from Ni2+ inhibition of CaV3.2, which is voltage-independent and outside the pore.","method":"Whole-cell patch-clamp in HEK293 cells stably expressing CaV3.1 or CaV3.2; varied permeant ion concentration and identity","journal":"Journal of General Physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous biophysical dissection with ion substitution, voltage dependence analysis, comparative channel controls","pmids":["18663132"],"is_preprint":false},{"year":2008,"finding":"CaV3.1 permeation follows a two-site/three-barrier model; apparent Kd for Ca2+ and Ba2+ block of Na+ currents are similar (~3–4 µM) but Kd for permeation shows Ca2+ and Ba2+ differ; Ba2+ accelerates inactivation ~35% faster than Ca2+, correlating with Ba2+ occupancy of the pore; reversal potential analysis gives P(Ca)/P(Na) = 87.","method":"Whole-cell patch-clamp with instantaneous I-V relationships; Ca2+/Ba2+/Na+ substitution over wide concentration range in HEK293 cells stably expressing CaV3.1","journal":"Journal of General Physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous quantitative biophysical analysis, multiple ion conditions, single lab","pmids":["18663131"],"is_preprint":false},{"year":2012,"finding":"Fe2+ blocks CaV3.1 in a voltage-dependent manner (Kd = 2.5 mM at 0 mV) competing with Ca2+, and can permeate through CaV3.1 channels carrying inward current at millimolar concentrations; estimated Fe2+ transport rate ~20 ions/s per open channel at -60 mV with 1 µM extracellular Fe2+; window current (~1% open probability at -60 mV) makes CaV3.1 a candidate pathway for non-transferrin-mediated Fe2+ influx.","method":"Whole-cell patch-clamp with instantaneous I-V; Eyring permeation modeling; ascorbate Fe2+ stabilization in HEK293 cells stably expressing CaV3.1","journal":"Molecular Pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — quantitative permeation modeling with biophysical controls, single lab","pmids":["22973060"],"is_preprint":false},{"year":2012,"finding":"Cd2+ blocks CaV3.1 in a voltage-dependent manner consistent with permeation through the selectivity filter; Cd2+ carries sizable inward currents through CaV3.1 in absence of Ca2+ and Na+; radiolabeled 109Cd2+ uptake confirmed Cd2+ entry into cells expressing CaV3.1.","method":"Whole-cell patch-clamp; radiotracer 109Cd2+ uptake assay in HEK293 cells stably expressing CaV3.1","journal":"Molecular Pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — electrophysiology plus orthogonal radiotracer uptake confirming Cd2+ permeation, single lab","pmids":["22973059"],"is_preprint":false},{"year":2016,"finding":"CaV3.1 mediates a substantial calcium current at resting membrane potentials in T helper cells; CaV3.1 deficiency had no effect on TCR-initiated store-operated calcium entry; CaV3.1-deficient mice show reduced GM-CSF production by CNS-infiltrating Th1 and Th17 cells, reduced NFAT nuclear translocation in T cells, and resistance to experimental autoimmune encephalomyelitis.","method":"Cav3.1 knockout mice; patch-clamp in T cells; intracellular Ca2+ measurement; in vitro T cell polarization; EAE induction","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse with electrophysiology, NFAT translocation, cytokine assays, and disease model, multiple orthogonal methods","pmids":["27037192"],"is_preprint":false},{"year":2006,"finding":"CaV3.1 subunit is present in pulmonary microvascular endothelial cells (PMVECs) but not pulmonary artery endothelial cells; thrombin-induced VWF secretion (Weibel-Palade body exocytosis) in PMVECs is abolished by T-type channel blocker mibefradil and by CaV3.1 shRNA gene silencing; recombinant CaV3.1 expression in PAECs reconstitutes thrombin-stimulated Ca2+ entry sensitive to mibefradil.","method":"Live-cell imaging of VWF-GFP vesicles; shRNA knockdown; recombinant CaV3.1 overexpression; Ca2+ measurement; pharmacological blockade","journal":"American Journal of Physiology – Lung Cellular and Molecular Physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reconstitution by overexpression plus loss-of-function (shRNA), multiple readouts, single lab","pmids":["17172292"],"is_preprint":false},{"year":2010,"finding":"CaV3.1 is the dominant T-type voltage-gated Ca2+ channel in mouse preadipocytes; siRNA knockdown of alpha1G markedly inhibits Ca2+ current; CaV3.1 expression decreases upon differentiation to adipocytes; pharmacological blockade and siRNA knockdown prevent cell cycle entry/progression and serum-stimulated proliferation.","method":"Patch-clamp; siRNA knockdown; Western blot; immunohistochemistry; cell cycle analysis","journal":"American Journal of Physiology – Cell Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus pharmacology with cell cycle readout, multiple orthogonal methods, single lab","pmids":["20457833"],"is_preprint":false},{"year":2010,"finding":"IGF-I upregulates CaV3.1 mRNA in proliferating pulmonary artery smooth muscle cells (PASMCs) via PI3K/Akt signaling; CaV3.1 knockdown by RNAi blocks IGF-I-induced cyclin D expression/activation and cell cycle progression/proliferation.","method":"siRNA knockdown; RT-PCR; cell cycle analysis; pharmacological PI3K/Akt inhibition in PASMCs","journal":"American Journal of Physiology – Cell Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with pathway dissection, single lab","pmids":["21148410"],"is_preprint":false},{"year":2016,"finding":"Transgenic elevation of Cacna1g expression in Scn2aQ54 mice increases spontaneous seizure frequency, while transgenic reduction decreases seizure frequency, establishing Cacna1g as a genetic modifier of sodium channel–based epilepsy; in the Scn1a+/- Dravet model, decreased Cacna1g expression partially ameliorates disease phenotypes (improved survival, reduced spontaneous seizures) but does not alter hyperthermia-induced seizures.","method":"Transgenic overexpression and underexpression of Cacna1g in Scn2aQ54 and Scn1a+/- mouse models; seizure frequency monitoring; survival analysis","journal":"Epilepsia","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation in two independent epilepsy models, replicated across PMID 27112236 and 28556246","pmids":["27112236","28556246"],"is_preprint":false},{"year":2008,"finding":"Alpha1G (CaV3.1) T-type Ca2+ channel knockout mice show reduced spontaneous neuropathic pain responses, increased mechanical threshold, and attenuated thermal hyperalgesia after L5 spinal nerve ligation, demonstrating CaV3.1 is required for neuropathic pain development.","method":"CaV3.1 knockout mice; behavioral pain assays (paw withdrawal, thermal hyperalgesia) after spinal nerve ligation","journal":"Molecules and Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout model with specific pain behavioral readouts, single lab","pmids":["18414012"],"is_preprint":false},{"year":2011,"finding":"Roscovitine blocks CaV3.1 channels (EC50 ~10 µM at depolarized potentials) primarily by stabilizing the closed-inactivated state: it accelerates closed-state inactivation and slows recovery from inactivation, producing a negative shift in voltage dependence of closed-state inactivation.","method":"Transient expression in HEK293 cells; whole-cell patch-clamp; voltage-clamp protocols dissecting inactivation states","journal":"Journal of Pharmacology and Experimental Therapeutics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous biophysical dissection but single lab, single method","pmids":["22088954"],"is_preprint":false},{"year":2012,"finding":"Overexpression of full-length CaV3.1 in MCF-7 breast cancer cells suppresses proliferation and promotes apoptosis; knockdown by siRNA or pharmacological inhibition with ProTx-I promotes proliferation; CaV3.1 is specifically visualized on plasma membranes of apoptotic cells; CaV3.1 knockdown blocks cyclophosphamide-induced apoptosis. Parallel manipulation of CaV3.2 had no effect on proliferation.","method":"CaV3.1 overexpression; siRNA knockdown; immunocytochemistry with Annexin V/TUNEL; apoptosis assay; cell proliferation assay","journal":"International Journal of Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (OE and KD) with multiple orthogonal readouts and isoform specificity controls, single lab","pmids":["22469755"],"is_preprint":false},{"year":2008,"finding":"Dexamethasone increases CaV3.1 T-type Ca2+ current and mRNA in neonatal rat ventricular myocytes; a minimal Dex-responsive region in the Cacna1g promoter contains glucocorticoid receptor (GR) and NFκB targets; the GR antagonist RU38486 abolishes promoter activity, and the NFκB inhibitor PDTC completely abolishes Dex-induced mRNA increase, indicating both GR and NFκB are required for glucocorticoid-driven Cacna1g transcription.","method":"Primary cultured neonatal cardiomyocytes; patch-clamp; luciferase reporter assay; RT-PCR; pharmacological inhibition","journal":"Molecular and Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus pharmacological dissection plus electrophysiology, single lab","pmids":["18820838"],"is_preprint":false},{"year":2009,"finding":"Functional GREs (glucocorticoid response elements) in the Cacna1g promoter were mapped by punctual mutagenesis: GRE-1 mediates aldosterone-induced promoter activity; GRE-4 and GRE-5 mediate dexamethasone-induced activity; GRE-2 and GRE-3 mediate basal promoter activity in neonatal cardiomyocytes.","method":"Site-directed mutagenesis of GREs; luciferase reporter assay in neonatal cardiac myocytes","journal":"Molecular and Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis-based functional dissection of promoter elements, single lab","pmids":["19705257"],"is_preprint":false},{"year":2006,"finding":"Human CACNA1G undergoes extensive alternative splicing at 11 sites within the open reading frame plus 2 alternative 5'-UTR promoters; 30 distinct transcripts identified; splice isoforms shift from nearly independent splicing in fetal transcripts to strongly concerted 'programs' in adult brain; patch-clamp of 9 selected variants reveals combinatorial interactions between variable domains that modify T-channel gating parameters.","method":"Full-length cDNA survey of 1580 human brain cDNAs; statistical linkage analysis; patch-clamp of expressed variants","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic electrophysiological characterization of multiple splice variants with developmental population analysis, single lab","pmids":["16671074"],"is_preprint":false},{"year":2003,"finding":"Differentiation of Y79 retinoblastoma cells reduces alpha1G mRNA and T-type current; two promoters (A and B) with different transcription start sites drive distinct 5'-UTR transcripts; promoter A is favored in undifferentiated cells and promoter B in differentiated cells; enhancer sequences upstream of promoter A and repressor sequences upstream of promoter B identified; downregulation is mediated primarily by decreased promoter A activity.","method":"RT-PCR; 5' RACE; luciferase reporter assays with deletion analysis; patch-clamp","journal":"European Journal of Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays plus 5' RACE plus electrophysiology in differentiation model, single lab","pmids":["12752779"],"is_preprint":false},{"year":2014,"finding":"Pharmacological inhibition of T-type calcium channels with NNC-55-0396 increases amyloid beta production via reductions in non-amyloidogenic processing in N2a cells and the 3xTg-AD mouse model; genetic overexpression of CaV3.1 in HEK cells expressing amyloid precursor protein produces complementary (anti-amyloidogenic) effects.","method":"Pharmacological inhibition in N2a cells and 3xTg-AD mice; CaV3.1 overexpression in HEK cells with APP; amyloid beta ELISA","journal":"Neurobiology of Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (inhibition and overexpression) with complementary readouts, single lab","pmids":["24268883"],"is_preprint":false},{"year":2012,"finding":"Insulin-induced upregulation of T-type current in GH3 pituitary cells does not change CaV3.1 transcript or total protein levels; the effect requires endosomal recycling—disruption by Brefeldin A or dominant-negative Rab11a mutant prevents insulin's stimulatory effect on CaV3.1 current in HEK-293 cells—indicating insulin increases surface CaV3.1 channel density via enhanced recycling rather than transcription.","method":"Real-time RT-PCR; Western blot; luciferase reporter; patch-clamp; dominant-negative Rab11a; Brefeldin A treatment in GH3 and HEK-293 cells","journal":"Cell Calcium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches dissecting transcriptional vs. post-transcriptional regulation, single lab","pmids":["22770883"],"is_preprint":false},{"year":2005,"finding":"T-type Ca2+ channel subtype switches from CaV3.2 to CaV3.1 during differentiation of mouse embryonic stem cells to cardiac cell lineage; Cav3.2 transcript/current predominates at early stage while Cav3.1 and Cav1.2 are upregulated at late stage, with channel expression largely determined at the transcriptional level.","method":"Real-time RT-PCR; whole-cell patch-clamp at early and late differentiation stages of Nkx2.5+ cells","journal":"Circulation Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — parallel transcript and current density measurements across developmental stages, single lab","pmids":["16195632"],"is_preprint":false},{"year":2014,"finding":"BMP4 induces upregulation of CaV3.1 mRNA and T-type Ca2+ current in HL-1 atrial myocytes; this is mediated through NOX4 upregulation, increased ROS, and activation of JNK and p38 MAPK pathways; inhibitors of NADPH oxidase, ROS, JNK, or p38 prevent BMP4-induced CaV3.1 upregulation.","method":"Patch-clamp; real-time PCR; pharmacological inhibition of NOX4, ROS, JNK, p38 in HL-1 cells","journal":"Pflügers Archiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic pharmacological pathway dissection with electrophysiological readout, single lab","pmids":["24510064"],"is_preprint":false},{"year":2022,"finding":"CaV3.1-driven burst firing in ventromedial hypothalamus (VMH) neurons mediates anxiety-like behavior, shifts respiratory exchange ratio toward fat oxidation, and decreases food intake; knockdown of CaV3.1 in dmVMH has opposite effects; optogenetically evoked burst firing recapitulates these phenotypes; fluoxetine blocks increased CaV3.1 expression to inhibit burst firing and rescue anxiety and metabolic changes.","method":"CaV3.1 knockdown in dmVMH; optogenetic burst stimulation; behavioral tests; respiratory exchange ratio measurement; in vivo electrophysiology","journal":"Molecular Psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function plus optogenetic gain-of-function with mechanistic pathway link, single lab","pmids":["35318460"],"is_preprint":false},{"year":2024,"finding":"In human thalamocortical assembloids, the M1531V CACNA1G gain-of-function variant leads to changes in T-type currents in thalamic neurons and correlated hyperactivity of thalamic and cortical neurons; CACNA1G loss results in abnormal thalamocortical connectivity via both increased spontaneous thalamic activity and aberrant axonal projections.","method":"Human iPSC-derived thalamocortical assembloids with CACNA1G variants; patch-clamp; calcium imaging; axonal projection analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — human-specific cellular model with reciprocal GOF/LOF manipulations and circuit-level readouts, novel platform","pmids":["39419023"],"is_preprint":false},{"year":2024,"finding":"De novo missense variants in the intracellular gate region (S5 and S6 segments) of CaV3.1 cause slow inactivation and deactivation kinetics and increased window current (gain-of-function); the p.Met197Arg variant (IS4-S5 loop) results in loss of channel activity; gain-of-function variants associated with more severe SCA42ND phenotypes.","method":"Patch-clamp in transfected cells; structural analysis; neuronal modeling","journal":"Genetics in Medicine","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — systematic electrophysiology of multiple variants with structural localization and modeling, single lab","pmids":["39674904"],"is_preprint":false},{"year":2025,"finding":"Leucine directly binds a hydrophobic pocket in the voltage-sensing segment of CaV3.1 and lowers its threshold for voltage-dependent activation; pharmacological inhibition of CaV3.1 blunts leucine-induced POMC neuron activation; conditional knockout of Cacna1g in POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding; pharmacological activation of hypothalamic CaV3.1 promotes weight loss in diet-induced obese mice.","method":"Binding assays; patch-clamp in cultured neurons and brain slices; conditional knockout in POMC neurons; in vivo pharmacology; food intake and weight measurements","journal":"Cell Metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding evidence plus conditional KO plus pharmacological activation/inhibition with in vivo and ex vivo readouts","pmids":["42025169"],"is_preprint":false},{"year":2025,"finding":"In zebrafish, cacna1g loss-of-function (homozygous mutants) causes prolonged fin regenerative outgrowth beyond original size; live GCaMP imaging shows CaV3.1/Cacna1g enables Ca2+ dynamics specifically in distal fibroblast-lineage blastemal mesenchyme during the outgrowth phase, establishing a role for this T-type channel in restraining regenerative growth.","method":"cacna1g homozygous mutant zebrafish; fin regeneration assay; live GCaMP Ca2+ imaging in regenerating fins","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with live Ca2+ imaging, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2022,"finding":"CaV3.1 (but not CaV3.2) is required for stimulated ERK1/2 phosphorylation in mouse mesangial cells in response to serum, PDGF, and TGF-β1; CRISPR-Cas9 knockout of CaV3.1 abolishes these phospho-ERK1/2 responses while CaV3.2 SKO retains them.","method":"CRISPR-Cas9 single and double knockout of CaV3.1/CaV3.2 in mouse mesangial cells; ERK1/2 phosphorylation assays; proliferation assays","journal":"BMC Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific CRISPR knockout with pathway-specific readout, single lab","pmids":["35710406"],"is_preprint":false},{"year":2021,"finding":"CaV3.1 is predominantly localized in neuronal progenitor cells of the mouse hippocampal dentate gyrus; CaV3.1 knockout mice show decreased proliferation and survival of newly generated cells, impaired differentiation of doublecortin-positive cells, reduced CaMKII and Akt phosphorylation, decreased BDNF expression, and decreased social interaction.","method":"CaV3.1 knockout mice; BrdU labeling; doublecortin immunostaining; Western blot for signaling molecules; behavioral testing; gene ontology analysis","journal":"Acta Physiologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout with multiple cellular and molecular readouts, single lab","pmids":["33393208"],"is_preprint":false},{"year":2018,"finding":"PIP2 modulates CaV3.1 channel gating properties without affecting maximum current density; both short- and long-term PIP2 potentiation shift the activation and steady-state inactivation curves of CaV3.1 toward hyperpolarization; long-term but not short-term PIP2 blunts the voltage-dependency of current decay.","method":"Whole-cell patch-clamp of recombinant CaV3.1 expressed in mammalian cells with PIP2 application","journal":"Pathophysiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method, limited mechanistic follow-up","pmids":["30528337"],"is_preprint":false},{"year":2025,"finding":"CACNA1G/Cacna1g knockdown in Xenopus tropicalis disrupts left-right patterning with abnormal pitx2c and dand5 expression; crispant LR organizers contain reduced cilia quantity, establishing a role for CaV3.1 in ciliogenesis and LR patterning during early embryonic development.","method":"CRISPR knockdown in Xenopus tropicalis; LR patterning marker analysis; cilia counting in LR organizer","journal":"Genesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR loss-of-function with molecular marker and morphological readouts in vivo, single lab","pmids":["40008628"],"is_preprint":false}],"current_model":"CaV3.1 (CACNA1G) is a low-voltage-activated T-type calcium channel whose pore-forming α1G subunit mediates calcium entry near resting membrane potential; it contributes to sinoatrial node pacemaker activity and AV conduction, thalamic sleep stabilization (by suppressing arousal signal transmission via prolonged post-activation inhibition), cerebellar Purkinje cell synaptic Ca2+ signaling in partnership with mGluR1, hypothalamic leucine sensing in POMC neurons (leucine binds the voltage-sensing domain to lower activation threshold), and immune T-cell cytokine production via NFAT; its activity is positively regulated by PKA (β-adrenergic/cAMP pathway), Cdk5 (phosphorylating Ser2234 in the C-terminus), and the LEF1/β-catenin transcriptional complex, while the γ6 calcium channel subunit physically associates with CaV3.1 and negatively modulates current density through a GxxxA-motif-dependent helix-helix interaction; disease-causing gain-of-function mutations (notably p.Ala961Thr, p.Met1531Val) slow inactivation kinetics and increase window current leading to cerebellar atrophy and neurodevelopmental encephalopathy, whereas the p.Arg1715His voltage-sensor mutation shifts activation positively to cause adult-onset spinocerebellar ataxia (SCA42)."},"narrative":{"mechanistic_narrative":"CACNA1G encodes CaV3.1 (α1G), the pore-forming subunit of a low-voltage-activated T-type calcium channel that opens near resting membrane potential to provide depolarizing Ca2+ entry, and through this single biophysical role it shapes pacemaking, neuronal firing, and proliferative signaling across many tissues [PMID:16690884, PMID:19657020]. Its permeation pathway follows a two-site/three-barrier mechanism with high Ca2+ selectivity (P_Ca/P_Na ≈ 87), is gated by extracellular protons competing with Ca2+ at the pore, and conducts divalent cations including Cd2+ and Fe2+, making it a candidate route for non-transferrin metal influx [PMID:12743167, PMID:18663131, PMID:22973059, PMID:22973060]; activation and inactivation kinetics are set by domains I and IV [PMID:16996222]. In the heart, CaV3.1 is the sole T-type current of sinoatrial and atrioventricular node cells, and its loss causes bradycardia and slowed conduction with intact L-type current [PMID:16690884]. In the CNS it stabilizes sleep by driving prolonged post-activation inhibition in thalamic relay neurons [PMID:15677322], supports mGluR1-coupled subthreshold dendritic Ca2+ signaling in Purkinje cell spines [PMID:19657020], and in hypothalamic POMC neurons senses leucine, which directly binds the voltage-sensing segment to lower the activation threshold and mediate appetite suppression by high-protein feeding [PMID:42025169]. CaV3.1 also drives resting Ca2+ entry that promotes NFAT-dependent cytokine production in T helper cells [PMID:27037192]. Channel output is tuned by physical and signaling partners: the calcium channel γ6 subunit associates via a GxxxA motif in its first transmembrane domain to reduce current density and channel availability [PMID:15572045, PMID:18818244], while PKA (β-adrenergic/cAMP), Cdk5 (phosphorylating Ser2234), and PIP2 positively modulate the current [PMID:22808078, PMID:25760945]; surface density is also controlled by Rab11-dependent endosomal recycling [PMID:22770883] and by LEF1/β-catenin and glucocorticoid/NF-κB transcriptional inputs at the Cacna1g promoter [PMID:20371816, PMID:18820838]. Gain-of-function mutations that slow inactivation and enlarge window current (p.Ala961Thr, p.Met1531Val, and intracellular-gate S5/S6 variants) cause childhood-onset cerebellar atrophy and neurodevelopmental encephalopathy, whereas the S4 voltage-sensor mutation p.Arg1715His positively shifts activation to cause adult-onset spinocerebellar ataxia SCA42 [PMID:26456284, PMID:26715324, PMID:29878067, PMID:32878331, PMID:32736238, PMID:39674904].","teleology":[{"year":2003,"claim":"Establishing the biophysical permeation and gating rules of CaV3.1 was needed before its physiological roles could be interpreted, and ion-substitution and pore mutagenesis defined how the channel selects and conducts Ca2+ and is modulated by protons.","evidence":"Whole-cell patch-clamp with ion substitution and EEDD pore-locus mutagenesis in HEK293 cells","pmids":["12743167","18663131","18663132"],"confidence":"High","gaps":["No atomic structure of the pore in the timeline","Physiological relevance of proton modulation not tested in native cells"]},{"year":2004,"claim":"Whether CaV3.1 has an endogenous modulatory subunit was unknown; co-expression showed the γ6 calcium channel subunit selectively suppresses CaV3.1 current density without changing voltage dependence or protein levels.","evidence":"Co-expression in HEK-293 and HL-1 cells with patch-clamp, RT-PCR, Western blot, and GFP localization","pmids":["15572045"],"confidence":"High","gaps":["Mechanism of current-density reduction not yet resolved at this stage","In vivo significance untested"]},{"year":2005,"claim":"The cellular basis of T-type channel control of sleep was unknown; region-specific deletion showed thalamic CaV3.1 produces prolonged firing inhibition that stabilizes sleep architecture.","evidence":"Conditional Cav3.1 knockout in thalamus vs cortex with thalamic electrophysiology and sleep telemetry","pmids":["15677322"],"confidence":"High","gaps":["Downstream circuit targets of the prolonged inhibition not mapped","Molecular trigger of the >9 s inhibition not defined"]},{"year":2006,"claim":"The molecular identity of nodal T-type current and the structural determinants of CaV3.1 gating were addressed, identifying CaV3.1 as the SAN/AVN pacemaker T-current and domains I and IV as gating determinants.","evidence":"Cacna1g knockout mice with patch-clamp/ECG plus chimeric domain-swap constructs in tsA-201 cells","pmids":["16690884","16996222"],"confidence":"High","gaps":["Quantitative contribution of T-current to pacemaking vs other currents not isolated","Domain swaps do not resolve single-residue gating determinants"]},{"year":2008,"claim":"How γ6 suppresses CaV3.1 was unresolved; mutagenesis, co-IP, and single-channel analysis showed a GxxxA-motif TM1 helix mediates physical association and reduces channel availability.","evidence":"Chimeric mutagenesis, co-immunoprecipitation, and single-channel recording in HEK cells and atrial myocytes","pmids":["18818244"],"confidence":"High","gaps":["Structural model of the γ6–CaV3.1 helix interface absent","Stoichiometry of the interaction unknown"]},{"year":2009,"claim":"The narrowest molecular unit of γ6 inhibition and a synaptic signaling role were defined: an eight-residue GxxxA peptide selectively inhibits CaV3.1, and CaV3.1 couples to mGluR1 in Purkinje dendritic spines.","evidence":"Peptide mutagenesis patch-clamp in HEK cells; electrophysiology, two-photon Ca2+ imaging, and EM in CaV3.1 knockout mice","pmids":["19193827","19657020"],"confidence":"High","gaps":["mGluR1-to-CaV3.1 signaling intermediates only partly defined (G-protein/tyrosine phosphatase)","Peptide work is in vitro only"]},{"year":2010,"claim":"Transcriptional and complex-level control of CaV3.1 was addressed, identifying LEF1/β-catenin as a direct thalamic transcriptional regulator and a KV4.2-KChIP3-DPP10c signaling partnership.","evidence":"Luciferase reporters, in vivo ChIP, and thalamic patch-clamp; co-expression electrophysiology with channel-specificity controls","pmids":["20371816","20458163"],"confidence":"High","gaps":["Physiological output of KV4.2 right-shift not tested in native neurons","Wnt regulation shown in thalamus but not other CaV3.1-expressing tissues"]},{"year":2012,"claim":"Post-translational and signaling regulation of channel output was established, defining the β-adrenergic/PKA pathway as a positive modulator of nodal CaV3.1 current.","evidence":"Cav3.1 transgenic/knockout mice with patch-clamp and pharmacological PKA inhibition in SAN and ventricular myocytes","pmids":["22808078"],"confidence":"High","gaps":["PKA phosphosite on CaV3.1 not mapped in this study","Quantitative impact on heart rate in vivo not isolated"]},{"year":2012,"claim":"Whether CaV3.1 can conduct non-Ca2+ divalents was tested, showing Cd2+ and Fe2+ permeate the channel, positioning CaV3.1 as a candidate metal-influx pathway.","evidence":"Whole-cell patch-clamp, Eyring permeation modeling, and 109Cd2+ radiotracer uptake in HEK293 cells","pmids":["22973059","22973060"],"confidence":"High","gaps":["Physiological metal transport through CaV3.1 not demonstrated in vivo","Fe2+ permeation evidence is medium-confidence modeling"]},{"year":2015,"claim":"The first disease link and a kinase regulator were established: the S4 voltage-sensor mutation p.Arg1715His shifts activation to cause SCA42, and Cdk5 phosphorylates Ser2234 to upregulate the channel.","evidence":"Exome sequencing with HEK293T electrophysiology and neuron modeling (SCA42); overexpression/siRNA with mutagenesis-mapped phosphosite (Cdk5)","pmids":["26456284","26715324","25760945"],"confidence":"High","gaps":["How a single biophysical shift produces selective cerebellar degeneration not fully explained","Cdk5 regulation not shown in disease context"]},{"year":2016,"claim":"A non-excitable immune role was defined: resting-potential Ca2+ entry through CaV3.1 drives NFAT translocation and pathogenic cytokine production in T cells, conferring susceptibility to autoimmune neuroinflammation.","evidence":"Cav3.1 knockout mice with T-cell patch-clamp, NFAT translocation, cytokine assays, and EAE","pmids":["27037192"],"confidence":"High","gaps":["Link between Ca2+ entry and NFAT in T cells not mechanistically dissected","Store-operated entry shown unaffected but interplay not explored"]},{"year":2018,"claim":"Encephalopathy-causing variants were characterized, showing de novo p.Ala961Thr and p.Met1531Val are gain-of-function via impaired inactivation and enlarged window current that enhances neuronal firing.","evidence":"Patch-clamp of transfected cells, TTA-P2 block, and computational cerebellar neuron modeling with patient exomes","pmids":["29878067","32878331","32736238"],"confidence":"High","gaps":["No in vivo model of these specific variants in this study","Threshold of window current driving pathology not quantified"]},{"year":2024,"claim":"Variant–phenotype relationships and human circuit consequences were refined: intracellular-gate S5/S6 GOF variants cause SCA42ND while a loss-of-activity variant maps to IS4-S5, and human assembloids show GOF/LOF perturb thalamocortical activity and connectivity.","evidence":"Patch-clamp/structural analysis of multiple variants; human iPSC thalamocortical assembloids with calcium imaging and axonal analysis","pmids":["39674904","39419023"],"confidence":"High","gaps":["Genotype–severity correlation rests on heterologous electrophysiology","Assembloid phenotypes not yet linked to in vivo human pathology"]},{"year":2025,"claim":"A direct ligand-sensing mechanism was identified: leucine binds the CaV3.1 voltage-sensing domain to lower activation threshold and mediate high-protein appetite suppression through POMC neurons.","evidence":"Binding assays, slice/cultured-neuron patch-clamp, POMC-specific conditional knockout, and in vivo pharmacology in obese mice","pmids":["42025169"],"confidence":"High","gaps":["Atomic structure of the leucine-bound voltage sensor not provided","Whether other amino acids share the binding pocket untested"]},{"year":null,"claim":"It remains unresolved how the channel's single low-threshold Ca2+-entry function is decoded into such divergent tissue outcomes—pacemaking, sleep, T-cell cytokines, proliferation, regeneration, and ciliogenesis—and what molecular machinery couples CaV3.1 Ca2+ to each effector.","evidence":"No timeline study unifies the downstream effector pathways across tissues","pmids":[],"confidence":"Low","gaps":["Tissue-specific Ca2+ effectors downstream of CaV3.1 not defined","No structural basis for variant-specific phenotype severity","Relationship between window current and degeneration mechanistically open"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,13,15,17]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[37,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,25,6]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,2,37]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,36]}],"complexes":[],"partners":["CACNG6","GRM1","KCND2","KCNIP3","DPP10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43497","full_name":"Voltage-dependent T-type calcium channel subunit alpha-1G","aliases":["Cav3.1c","NBR13","Voltage-gated calcium channel subunit alpha Cav3.1"],"length_aa":2377,"mass_kda":262.5,"function":"Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the 'low-voltage activated (LVA)' group and are strongly blocked by mibefradil. A particularity of this type of channel is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents","subcellular_location":"Cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O43497/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CACNA1G","classification":"Not Classified","n_dependent_lines":50,"n_total_lines":1208,"dependency_fraction":0.041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CACNA1G","total_profiled":1310},"omim":[{"mim_id":"620144","title":"CACHE DOMAIN-CONTAINING PROTEIN 1; CACHD1","url":"https://www.omim.org/entry/620144"},{"mim_id":"619863","title":"JUNCTOPHILIN 4; JPH4","url":"https://www.omim.org/entry/619863"},{"mim_id":"618087","title":"SPINOCEREBELLAR ATAXIA 42, EARLY-ONSET, SEVERE, WITH NEURODEVELOPMENTAL DEFICITS; SCA42ND","url":"https://www.omim.org/entry/618087"},{"mim_id":"616795","title":"SPINOCEREBELLAR ATAXIA 42; SCA42","url":"https://www.omim.org/entry/616795"},{"mim_id":"613514","title":"ZONA PELLUCIDA GLYCOPROTEIN 4; ZP4","url":"https://www.omim.org/entry/613514"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Acrosome","reliability":"Approved"},{"location":"Equatorial segment","reliability":"Approved"},{"location":"Perinuclear theca","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":19.3},{"tissue":"cervix","ntpm":8.2},{"tissue":"retina","ntpm":8.0}],"url":"https://www.proteinatlas.org/search/CACNA1G"},"hgnc":{"alias_symbol":["Cav3.1","NBR13"],"prev_symbol":[]},"alphafold":{"accession":"O43497","domains":[{"cath_id":"1.20.120.350","chopping":"60-194","consensus_level":"high","plddt":84.4601,"start":60,"end":194},{"cath_id":"1.20.120.350","chopping":"743-848","consensus_level":"high","plddt":82.2658,"start":743,"end":848},{"cath_id":"1.10.287.70","chopping":"851-982","consensus_level":"medium","plddt":78.5605,"start":851,"end":982},{"cath_id":"1.20.120.350","chopping":"1276-1392","consensus_level":"medium","plddt":83.3891,"start":1276,"end":1392},{"cath_id":"1.10.287.70","chopping":"1396-1570","consensus_level":"medium","plddt":81.8961,"start":1396,"end":1570},{"cath_id":"1.20.120.350","chopping":"1594-1726","consensus_level":"high","plddt":84.761,"start":1594,"end":1726},{"cath_id":"1.10.287.70","chopping":"1727-1870","consensus_level":"medium","plddt":80.102,"start":1727,"end":1870}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43497","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43497-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43497-F1-predicted_aligned_error_v6.png","plddt_mean":58.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CACNA1G","jax_strain_url":"https://www.jax.org/strain/search?query=CACNA1G"},"sequence":{"accession":"O43497","fasta_url":"https://rest.uniprot.org/uniprotkb/O43497.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43497/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43497"}},"corpus_meta":[{"pmid":"16690884","id":"PMC_16690884","title":"Bradycardia 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parallel fiber-induced fast calcium signaling within Purkinje cell dendritic spines.","date":"2009","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19657020","citation_count":86,"is_preprint":false},{"pmid":"26456284","id":"PMC_26456284","title":"A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia.","date":"2015","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26456284","citation_count":85,"is_preprint":false},{"pmid":"26715324","id":"PMC_26715324","title":"A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia.","date":"2015","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/26715324","citation_count":82,"is_preprint":false},{"pmid":"29878067","id":"PMC_29878067","title":"De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene.","date":"2018","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29878067","citation_count":80,"is_preprint":false},{"pmid":"12614673","id":"PMC_12614673","title":"Immunological characterization of T-type voltage-dependent calcium channel CaV3.1 (alpha 1G) and CaV3.3 (alpha 1I) isoforms reveal differences in their localization, expression, and neural development.","date":"2003","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12614673","citation_count":72,"is_preprint":false},{"pmid":"22469755","id":"PMC_22469755","title":"T-type voltage-activated calcium channel Cav3.1, but not Cav3.2, is involved in the inhibition of proliferation and apoptosis in MCF-7 human breast cancer cells.","date":"2012","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22469755","citation_count":68,"is_preprint":false},{"pmid":"17397049","id":"PMC_17397049","title":"Mutational analysis of CACNA1G in idiopathic generalized epilepsy. Mutation in brief #962. Online.","date":"2007","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/17397049","citation_count":65,"is_preprint":false},{"pmid":"20371816","id":"PMC_20371816","title":"LEF1/beta-catenin complex regulates transcription of the Cav3.1 calcium channel gene (Cacna1g) in thalamic neurons of the adult brain.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20371816","citation_count":58,"is_preprint":false},{"pmid":"16671074","id":"PMC_16671074","title":"Profiling the array of Ca(v)3.1 variants from the human T-type calcium channel gene CACNA1G: alternative structures, developmental expression, and biophysical variations.","date":"2006","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/16671074","citation_count":53,"is_preprint":false},{"pmid":"19455149","id":"PMC_19455149","title":"High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene.","date":"2009","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/19455149","citation_count":52,"is_preprint":false},{"pmid":"24268883","id":"PMC_24268883","title":"Age-related downregulation of the CaV3.1 T-type calcium channel as a mediator of amyloid beta production.","date":"2013","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/24268883","citation_count":46,"is_preprint":false},{"pmid":"28556246","id":"PMC_28556246","title":"Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome.","date":"2017","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/28556246","citation_count":45,"is_preprint":false},{"pmid":"18414012","id":"PMC_18414012","title":"Attenuated neuropathic pain in Cav3.1 null mice.","date":"2008","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/18414012","citation_count":40,"is_preprint":false},{"pmid":"37304234","id":"PMC_37304234","title":"LncRNA CACNA1G-AS1 up-regulates FTH1 to inhibit ferroptosis and promote malignant phenotypes in ovarian cancer cells.","date":"2023","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/37304234","citation_count":39,"is_preprint":false},{"pmid":"27616982","id":"PMC_27616982","title":"Ontogenic Changes and Differential Localization of T-type Ca(2+) Channel Subunits Cav3.1 and Cav3.2 in Mouse Hippocampus and Cerebellum.","date":"2016","source":"Frontiers in neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/27616982","citation_count":39,"is_preprint":false},{"pmid":"27112236","id":"PMC_27112236","title":"Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel 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CaV3.1/alpha1G (cacna1g knockout) abolishes T-type calcium current in sinoatrial node (SAN) and atrioventricular node cells without affecting L-type Ca2+ current, causing bradycardia, slowed atrioventricular conduction, prolonged SAN recovery time, and reduced slope of diastolic depolarization in SAN pacemaker cells.\",\n      \"method\": \"Cacna1g knockout mice; patch-clamp electrophysiology on isolated SAN/AVN cells; telemetric ECG and intracardiac recordings\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout with multiple orthogonal readouts (patch-clamp, ECG, intracardiac recording), clear cellular and in vivo phenotypes\",\n      \"pmids\": [\"16690884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Thalamic CaV3.1 T-type Ca2+ channel activation causes prolonged inhibition (>9 s) of action-potential firing in thalamic projection neurons via intracellular Ca2+ increase (independent of synaptic transmission); focal deletion of Cacna1g from rostral-midline thalamus (but not cortical pyramidal neurons) causes fragmented and reduced sleep, establishing a thalamus-specific role in stabilizing sleep by blocking arousal signal transmission.\",\n      \"method\": \"Cav3.1 knockout mice; Cre/loxP conditional knockout in thalamus vs. cortex; electrophysiology in thalamic neurons; sleep telemetry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with region-specific controls, electrophysiology, and behavioral readout in one study\",\n      \"pmids\": [\"15677322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CaV3.1 T-type channels are preferentially expressed in Purkinje cell dendritic spines and colocalize with mGluR1; mGluR1 activation potentiates CaV3.1 currents via a G-protein- and tyrosine-phosphatase-dependent pathway; parallel fiber stimulation induces fast subthreshold Ca2+ signaling in dendritic spines through CaV3.1, potentiated by mGluR1 during bursts of excitatory input.\",\n      \"method\": \"Electrophysiology; ultrafast two-photon calcium imaging; immunohistochemistry and electron microscopy on wild-type and CaV3.1 knockout mice\",\n      \"journal\": \"Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, Ca2+ imaging, EM, KO controls) in single rigorous study\",\n      \"pmids\": [\"19657020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The recurrent missense mutation p.Arg1715His in the S4 voltage-sensor segment of CaV3.1 positively shifts the current-voltage and steady-state activation curves and increases the slope factor of inactivation, predicted by computer modeling to decrease deep cerebellar nuclei neuronal excitability, causing autosomal dominant cerebellar ataxia (SCA42).\",\n      \"method\": \"Whole-exome sequencing; electrophysiology in HEK293T cells expressing mutant vs. wild-type Cav3.1; computational neuron modeling\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — replicated in independent cohorts (French and Japanese families, PMID 26456284 and 26715324), electrophysiology in heterologous system with mutagenesis-level specificity\",\n      \"pmids\": [\"26456284\", \"26715324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"De novo gain-of-function CACNA1G mutations p.Ala961Thr and p.Met1531Val drastically impair channel inactivation with ~5-fold slower kinetics and >10 mV negative shift of half-inactivation, increase window current (fully inhibited by TTA-P2), and enhance neuronal firing in a cerebellar nuclear neuron model, causing severe childhood-onset cerebellar atrophy.\",\n      \"method\": \"Patch-clamp electrophysiology in transfected cells; computational neuron modeling; whole-exome sequencing in patient cohort\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple recurrent variants tested by electrophysiology + modeling, replicated across independent studies (PMID 29878067, 32878331, 32736238, 39674904)\",\n      \"pmids\": [\"29878067\", \"32878331\", \"32736238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The calcium channel γ6 subunit (both long and short isoforms) co-expressed with CaV3.1 in HEK-293 cells significantly decreases CaV3.1 current density (~49–69%) without affecting voltage dependence of activation/inactivation or kinetics, and without altering CaV3.1 mRNA or total protein levels; γ6L is localized to the cell surface membrane. γ4 and γ7 subunits have no significant effect on CaV3.1.\",\n      \"method\": \"Co-expression in HEK-293 cells; whole-cell patch-clamp; RT-PCR; Western blot; GFP-tagged localization; endogenous current recording in HL-1 atrial cells\",\n      \"journal\": \"Journal of Molecular and Cellular Cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated in heterologous and endogenous systems, multiple orthogonal methods, extended mechanistically by PMID 18818244 and 19193827\",\n      \"pmids\": [\"15572045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The γ6 subunit's first transmembrane domain (TM1) containing a critical GxxxA motif is required for its inhibitory effect on CaV3.1 current; co-immunoprecipitation confirms physical association of γ6 with CaV3.1 in HEK cells and atrial myocytes; single-channel analysis shows γ6 binding reduces channel availability for activation.\",\n      \"method\": \"Chimeric construct mutagenesis; whole-cell patch-clamp; single-channel recording; co-immunoprecipitation from HEK cells and atrial myocytes\",\n      \"journal\": \"Journal of Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis, co-IP, single-channel analysis, multiple cell systems in one study\",\n      \"pmids\": [\"18818244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"An eight-amino acid peptide from γ6 TM1 containing the GxxxA motif inhibits CaV3.1 current in a concentration-dependent manner by dynamically binding and dissociating from the channel, with selective affinity for CaV3.1 over CaV1.2, supporting a mechanism of endogenous LVA channel antagonism through helix-helix interactions within the plasma membrane.\",\n      \"method\": \"Whole-cell patch-clamp in HEK cells; peptide mutagenesis\",\n      \"journal\": \"Molecular Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro electrophysiology with systematic peptide mutagenesis, single lab\",\n      \"pmids\": [\"19193827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LEF1/β-catenin complex directly regulates transcription of Cacna1g (encoding CaV3.1) in thalamic neurons; four LEF1 binding sites identified in the proximal promoter; chromatin immunoprecipitation confirmed β-catenin occupancy at the Cacna1g proximal promoter in thalamus but not hippocampus in vivo; WNT3A and LiCl treatment enhance T-type current in cultured thalamic neurons.\",\n      \"method\": \"Luciferase reporter assay; footprinting analysis; chromatin immunoprecipitation (ChIP); patch-clamp in cultured thalamic neurons\",\n      \"journal\": \"Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP in vivo plus reporter assays plus functional electrophysiology, multiple orthogonal methods in single study\",\n      \"pmids\": [\"20371816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CaV3.1 associates with the KV4.2-KChIP3-DPP10c complex and CaV3.1-mediated calcium entry right-shifts the inactivation voltage of KV4.2 into the physiological range; this regulation was not produced by co-expression of CaV1.4, CaV2.1, or CaV2.3, demonstrating selectivity for low voltage-activated CaV3 channels in this signaling complex.\",\n      \"method\": \"Co-expression in HEK cells; whole-cell patch-clamp\",\n      \"journal\": \"Channels\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional electrophysiology with channel specificity controls, single lab\",\n      \"pmids\": [\"20458163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"β-adrenergic stimulation increases CaV3.1-mediated T-type Ca2+ current in cardiomyocytes via the cAMP/PKA pathway; PKA inhibitor H89 blocks the ISO effect; native CaV3.1 current in SAN cells is upregulated by isoproterenol; Cav3.1 knockout SAN cells lack T-type current, confirming CaV3.1 as the identity of I(Ca,T) in normal SAN.\",\n      \"method\": \"Cav3.1 transgenic and knockout mice; patch-clamp in ventricular myocytes and SAN cells; pharmacological PKA inhibition; real-time PCR\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockouts plus pharmacological dissection, multiple cell types and orthogonal approaches\",\n      \"pmids\": [\"22808078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cyclin-dependent kinase 5 (Cdk5) upregulates CaV3.1 channel activity; overexpression of Cdk5 increases whole-cell T-type current in N1E-115 neuroblastoma cells and in HEK-293 cells stably expressing Cav3.1; site-directed mutagenesis identified serine 2234 in the C-terminal region as a major phosphorylation site.\",\n      \"method\": \"Overexpression and siRNA knockdown in N1E-115 cells; heterologous expression in HEK-293 cells; whole-cell patch-clamp; site-directed mutagenesis\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis identifies phosphorylation site, functional patch-clamp, native and heterologous systems, single lab\",\n      \"pmids\": [\"25760945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Domains I and IV are major determinants of half-activation potential for CaV3.1; domain IV substitution is the primary determinant of activation time constant and recovery from inactivation time constant; inactivation time constant determinants are distributed across multiple domains with domains I+IV together partially conferring inactivation kinetics of CaV3.3.\",\n      \"method\": \"Chimeric channel constructs with swapped transmembrane domains expressed in tsA-201 cells; whole-cell patch-clamp\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic domain-swap mutagenesis with electrophysiological characterization, single lab\",\n      \"pmids\": [\"16996222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Extracellular protons modulate CaV3.1 (alpha1G) gating by interacting with intermediate closed states in the activation pathway; extracellular Ca2+ competes with protons at surface charges, at the selectivity filter, and counteracts proton-induced modification of activation; mutation of the EEDD pore locus alters Ca2+-dependent proton effects on channel selectivity and permeation.\",\n      \"method\": \"Whole-cell patch-clamp in HEK293 cells expressing CaV3.1; EEDD pore locus mutagenesis; model simulations\",\n      \"journal\": \"Journal of General Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of pore locus, quantitative biophysical analysis, single lab\",\n      \"pmids\": [\"12743167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ni2+ blocks CaV3.1 via two components: a rapid, weakly voltage-dependent pore block (apparent Kd ~1–3 mM) and a slow block visible as accelerated tail currents; both are consistent with occlusion of the pore; the site responsible for fast block can lock in slow block, with the slow-block site located deeper in the pore. This mechanism differs fundamentally from Ni2+ inhibition of CaV3.2, which is voltage-independent and outside the pore.\",\n      \"method\": \"Whole-cell patch-clamp in HEK293 cells stably expressing CaV3.1 or CaV3.2; varied permeant ion concentration and identity\",\n      \"journal\": \"Journal of General Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous biophysical dissection with ion substitution, voltage dependence analysis, comparative channel controls\",\n      \"pmids\": [\"18663132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CaV3.1 permeation follows a two-site/three-barrier model; apparent Kd for Ca2+ and Ba2+ block of Na+ currents are similar (~3–4 µM) but Kd for permeation shows Ca2+ and Ba2+ differ; Ba2+ accelerates inactivation ~35% faster than Ca2+, correlating with Ba2+ occupancy of the pore; reversal potential analysis gives P(Ca)/P(Na) = 87.\",\n      \"method\": \"Whole-cell patch-clamp with instantaneous I-V relationships; Ca2+/Ba2+/Na+ substitution over wide concentration range in HEK293 cells stably expressing CaV3.1\",\n      \"journal\": \"Journal of General Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous quantitative biophysical analysis, multiple ion conditions, single lab\",\n      \"pmids\": [\"18663131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Fe2+ blocks CaV3.1 in a voltage-dependent manner (Kd = 2.5 mM at 0 mV) competing with Ca2+, and can permeate through CaV3.1 channels carrying inward current at millimolar concentrations; estimated Fe2+ transport rate ~20 ions/s per open channel at -60 mV with 1 µM extracellular Fe2+; window current (~1% open probability at -60 mV) makes CaV3.1 a candidate pathway for non-transferrin-mediated Fe2+ influx.\",\n      \"method\": \"Whole-cell patch-clamp with instantaneous I-V; Eyring permeation modeling; ascorbate Fe2+ stabilization in HEK293 cells stably expressing CaV3.1\",\n      \"journal\": \"Molecular Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative permeation modeling with biophysical controls, single lab\",\n      \"pmids\": [\"22973060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cd2+ blocks CaV3.1 in a voltage-dependent manner consistent with permeation through the selectivity filter; Cd2+ carries sizable inward currents through CaV3.1 in absence of Ca2+ and Na+; radiolabeled 109Cd2+ uptake confirmed Cd2+ entry into cells expressing CaV3.1.\",\n      \"method\": \"Whole-cell patch-clamp; radiotracer 109Cd2+ uptake assay in HEK293 cells stably expressing CaV3.1\",\n      \"journal\": \"Molecular Pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology plus orthogonal radiotracer uptake confirming Cd2+ permeation, single lab\",\n      \"pmids\": [\"22973059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CaV3.1 mediates a substantial calcium current at resting membrane potentials in T helper cells; CaV3.1 deficiency had no effect on TCR-initiated store-operated calcium entry; CaV3.1-deficient mice show reduced GM-CSF production by CNS-infiltrating Th1 and Th17 cells, reduced NFAT nuclear translocation in T cells, and resistance to experimental autoimmune encephalomyelitis.\",\n      \"method\": \"Cav3.1 knockout mice; patch-clamp in T cells; intracellular Ca2+ measurement; in vitro T cell polarization; EAE induction\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse with electrophysiology, NFAT translocation, cytokine assays, and disease model, multiple orthogonal methods\",\n      \"pmids\": [\"27037192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CaV3.1 subunit is present in pulmonary microvascular endothelial cells (PMVECs) but not pulmonary artery endothelial cells; thrombin-induced VWF secretion (Weibel-Palade body exocytosis) in PMVECs is abolished by T-type channel blocker mibefradil and by CaV3.1 shRNA gene silencing; recombinant CaV3.1 expression in PAECs reconstitutes thrombin-stimulated Ca2+ entry sensitive to mibefradil.\",\n      \"method\": \"Live-cell imaging of VWF-GFP vesicles; shRNA knockdown; recombinant CaV3.1 overexpression; Ca2+ measurement; pharmacological blockade\",\n      \"journal\": \"American Journal of Physiology – Lung Cellular and Molecular Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstitution by overexpression plus loss-of-function (shRNA), multiple readouts, single lab\",\n      \"pmids\": [\"17172292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CaV3.1 is the dominant T-type voltage-gated Ca2+ channel in mouse preadipocytes; siRNA knockdown of alpha1G markedly inhibits Ca2+ current; CaV3.1 expression decreases upon differentiation to adipocytes; pharmacological blockade and siRNA knockdown prevent cell cycle entry/progression and serum-stimulated proliferation.\",\n      \"method\": \"Patch-clamp; siRNA knockdown; Western blot; immunohistochemistry; cell cycle analysis\",\n      \"journal\": \"American Journal of Physiology – Cell Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus pharmacology with cell cycle readout, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"20457833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IGF-I upregulates CaV3.1 mRNA in proliferating pulmonary artery smooth muscle cells (PASMCs) via PI3K/Akt signaling; CaV3.1 knockdown by RNAi blocks IGF-I-induced cyclin D expression/activation and cell cycle progression/proliferation.\",\n      \"method\": \"siRNA knockdown; RT-PCR; cell cycle analysis; pharmacological PI3K/Akt inhibition in PASMCs\",\n      \"journal\": \"American Journal of Physiology – Cell Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with pathway dissection, single lab\",\n      \"pmids\": [\"21148410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Transgenic elevation of Cacna1g expression in Scn2aQ54 mice increases spontaneous seizure frequency, while transgenic reduction decreases seizure frequency, establishing Cacna1g as a genetic modifier of sodium channel–based epilepsy; in the Scn1a+/- Dravet model, decreased Cacna1g expression partially ameliorates disease phenotypes (improved survival, reduced spontaneous seizures) but does not alter hyperthermia-induced seizures.\",\n      \"method\": \"Transgenic overexpression and underexpression of Cacna1g in Scn2aQ54 and Scn1a+/- mouse models; seizure frequency monitoring; survival analysis\",\n      \"journal\": \"Epilepsia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation in two independent epilepsy models, replicated across PMID 27112236 and 28556246\",\n      \"pmids\": [\"27112236\", \"28556246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Alpha1G (CaV3.1) T-type Ca2+ channel knockout mice show reduced spontaneous neuropathic pain responses, increased mechanical threshold, and attenuated thermal hyperalgesia after L5 spinal nerve ligation, demonstrating CaV3.1 is required for neuropathic pain development.\",\n      \"method\": \"CaV3.1 knockout mice; behavioral pain assays (paw withdrawal, thermal hyperalgesia) after spinal nerve ligation\",\n      \"journal\": \"Molecules and Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout model with specific pain behavioral readouts, single lab\",\n      \"pmids\": [\"18414012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Roscovitine blocks CaV3.1 channels (EC50 ~10 µM at depolarized potentials) primarily by stabilizing the closed-inactivated state: it accelerates closed-state inactivation and slows recovery from inactivation, producing a negative shift in voltage dependence of closed-state inactivation.\",\n      \"method\": \"Transient expression in HEK293 cells; whole-cell patch-clamp; voltage-clamp protocols dissecting inactivation states\",\n      \"journal\": \"Journal of Pharmacology and Experimental Therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous biophysical dissection but single lab, single method\",\n      \"pmids\": [\"22088954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Overexpression of full-length CaV3.1 in MCF-7 breast cancer cells suppresses proliferation and promotes apoptosis; knockdown by siRNA or pharmacological inhibition with ProTx-I promotes proliferation; CaV3.1 is specifically visualized on plasma membranes of apoptotic cells; CaV3.1 knockdown blocks cyclophosphamide-induced apoptosis. Parallel manipulation of CaV3.2 had no effect on proliferation.\",\n      \"method\": \"CaV3.1 overexpression; siRNA knockdown; immunocytochemistry with Annexin V/TUNEL; apoptosis assay; cell proliferation assay\",\n      \"journal\": \"International Journal of Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (OE and KD) with multiple orthogonal readouts and isoform specificity controls, single lab\",\n      \"pmids\": [\"22469755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Dexamethasone increases CaV3.1 T-type Ca2+ current and mRNA in neonatal rat ventricular myocytes; a minimal Dex-responsive region in the Cacna1g promoter contains glucocorticoid receptor (GR) and NFκB targets; the GR antagonist RU38486 abolishes promoter activity, and the NFκB inhibitor PDTC completely abolishes Dex-induced mRNA increase, indicating both GR and NFκB are required for glucocorticoid-driven Cacna1g transcription.\",\n      \"method\": \"Primary cultured neonatal cardiomyocytes; patch-clamp; luciferase reporter assay; RT-PCR; pharmacological inhibition\",\n      \"journal\": \"Molecular and Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus pharmacological dissection plus electrophysiology, single lab\",\n      \"pmids\": [\"18820838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Functional GREs (glucocorticoid response elements) in the Cacna1g promoter were mapped by punctual mutagenesis: GRE-1 mediates aldosterone-induced promoter activity; GRE-4 and GRE-5 mediate dexamethasone-induced activity; GRE-2 and GRE-3 mediate basal promoter activity in neonatal cardiomyocytes.\",\n      \"method\": \"Site-directed mutagenesis of GREs; luciferase reporter assay in neonatal cardiac myocytes\",\n      \"journal\": \"Molecular and Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis-based functional dissection of promoter elements, single lab\",\n      \"pmids\": [\"19705257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human CACNA1G undergoes extensive alternative splicing at 11 sites within the open reading frame plus 2 alternative 5'-UTR promoters; 30 distinct transcripts identified; splice isoforms shift from nearly independent splicing in fetal transcripts to strongly concerted 'programs' in adult brain; patch-clamp of 9 selected variants reveals combinatorial interactions between variable domains that modify T-channel gating parameters.\",\n      \"method\": \"Full-length cDNA survey of 1580 human brain cDNAs; statistical linkage analysis; patch-clamp of expressed variants\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic electrophysiological characterization of multiple splice variants with developmental population analysis, single lab\",\n      \"pmids\": [\"16671074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Differentiation of Y79 retinoblastoma cells reduces alpha1G mRNA and T-type current; two promoters (A and B) with different transcription start sites drive distinct 5'-UTR transcripts; promoter A is favored in undifferentiated cells and promoter B in differentiated cells; enhancer sequences upstream of promoter A and repressor sequences upstream of promoter B identified; downregulation is mediated primarily by decreased promoter A activity.\",\n      \"method\": \"RT-PCR; 5' RACE; luciferase reporter assays with deletion analysis; patch-clamp\",\n      \"journal\": \"European Journal of Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays plus 5' RACE plus electrophysiology in differentiation model, single lab\",\n      \"pmids\": [\"12752779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Pharmacological inhibition of T-type calcium channels with NNC-55-0396 increases amyloid beta production via reductions in non-amyloidogenic processing in N2a cells and the 3xTg-AD mouse model; genetic overexpression of CaV3.1 in HEK cells expressing amyloid precursor protein produces complementary (anti-amyloidogenic) effects.\",\n      \"method\": \"Pharmacological inhibition in N2a cells and 3xTg-AD mice; CaV3.1 overexpression in HEK cells with APP; amyloid beta ELISA\",\n      \"journal\": \"Neurobiology of Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (inhibition and overexpression) with complementary readouts, single lab\",\n      \"pmids\": [\"24268883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Insulin-induced upregulation of T-type current in GH3 pituitary cells does not change CaV3.1 transcript or total protein levels; the effect requires endosomal recycling—disruption by Brefeldin A or dominant-negative Rab11a mutant prevents insulin's stimulatory effect on CaV3.1 current in HEK-293 cells—indicating insulin increases surface CaV3.1 channel density via enhanced recycling rather than transcription.\",\n      \"method\": \"Real-time RT-PCR; Western blot; luciferase reporter; patch-clamp; dominant-negative Rab11a; Brefeldin A treatment in GH3 and HEK-293 cells\",\n      \"journal\": \"Cell Calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches dissecting transcriptional vs. post-transcriptional regulation, single lab\",\n      \"pmids\": [\"22770883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"T-type Ca2+ channel subtype switches from CaV3.2 to CaV3.1 during differentiation of mouse embryonic stem cells to cardiac cell lineage; Cav3.2 transcript/current predominates at early stage while Cav3.1 and Cav1.2 are upregulated at late stage, with channel expression largely determined at the transcriptional level.\",\n      \"method\": \"Real-time RT-PCR; whole-cell patch-clamp at early and late differentiation stages of Nkx2.5+ cells\",\n      \"journal\": \"Circulation Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — parallel transcript and current density measurements across developmental stages, single lab\",\n      \"pmids\": [\"16195632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BMP4 induces upregulation of CaV3.1 mRNA and T-type Ca2+ current in HL-1 atrial myocytes; this is mediated through NOX4 upregulation, increased ROS, and activation of JNK and p38 MAPK pathways; inhibitors of NADPH oxidase, ROS, JNK, or p38 prevent BMP4-induced CaV3.1 upregulation.\",\n      \"method\": \"Patch-clamp; real-time PCR; pharmacological inhibition of NOX4, ROS, JNK, p38 in HL-1 cells\",\n      \"journal\": \"Pflügers Archiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic pharmacological pathway dissection with electrophysiological readout, single lab\",\n      \"pmids\": [\"24510064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CaV3.1-driven burst firing in ventromedial hypothalamus (VMH) neurons mediates anxiety-like behavior, shifts respiratory exchange ratio toward fat oxidation, and decreases food intake; knockdown of CaV3.1 in dmVMH has opposite effects; optogenetically evoked burst firing recapitulates these phenotypes; fluoxetine blocks increased CaV3.1 expression to inhibit burst firing and rescue anxiety and metabolic changes.\",\n      \"method\": \"CaV3.1 knockdown in dmVMH; optogenetic burst stimulation; behavioral tests; respiratory exchange ratio measurement; in vivo electrophysiology\",\n      \"journal\": \"Molecular Psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function plus optogenetic gain-of-function with mechanistic pathway link, single lab\",\n      \"pmids\": [\"35318460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In human thalamocortical assembloids, the M1531V CACNA1G gain-of-function variant leads to changes in T-type currents in thalamic neurons and correlated hyperactivity of thalamic and cortical neurons; CACNA1G loss results in abnormal thalamocortical connectivity via both increased spontaneous thalamic activity and aberrant axonal projections.\",\n      \"method\": \"Human iPSC-derived thalamocortical assembloids with CACNA1G variants; patch-clamp; calcium imaging; axonal projection analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human-specific cellular model with reciprocal GOF/LOF manipulations and circuit-level readouts, novel platform\",\n      \"pmids\": [\"39419023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"De novo missense variants in the intracellular gate region (S5 and S6 segments) of CaV3.1 cause slow inactivation and deactivation kinetics and increased window current (gain-of-function); the p.Met197Arg variant (IS4-S5 loop) results in loss of channel activity; gain-of-function variants associated with more severe SCA42ND phenotypes.\",\n      \"method\": \"Patch-clamp in transfected cells; structural analysis; neuronal modeling\",\n      \"journal\": \"Genetics in Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — systematic electrophysiology of multiple variants with structural localization and modeling, single lab\",\n      \"pmids\": [\"39674904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Leucine directly binds a hydrophobic pocket in the voltage-sensing segment of CaV3.1 and lowers its threshold for voltage-dependent activation; pharmacological inhibition of CaV3.1 blunts leucine-induced POMC neuron activation; conditional knockout of Cacna1g in POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding; pharmacological activation of hypothalamic CaV3.1 promotes weight loss in diet-induced obese mice.\",\n      \"method\": \"Binding assays; patch-clamp in cultured neurons and brain slices; conditional knockout in POMC neurons; in vivo pharmacology; food intake and weight measurements\",\n      \"journal\": \"Cell Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding evidence plus conditional KO plus pharmacological activation/inhibition with in vivo and ex vivo readouts\",\n      \"pmids\": [\"42025169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, cacna1g loss-of-function (homozygous mutants) causes prolonged fin regenerative outgrowth beyond original size; live GCaMP imaging shows CaV3.1/Cacna1g enables Ca2+ dynamics specifically in distal fibroblast-lineage blastemal mesenchyme during the outgrowth phase, establishing a role for this T-type channel in restraining regenerative growth.\",\n      \"method\": \"cacna1g homozygous mutant zebrafish; fin regeneration assay; live GCaMP Ca2+ imaging in regenerating fins\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with live Ca2+ imaging, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CaV3.1 (but not CaV3.2) is required for stimulated ERK1/2 phosphorylation in mouse mesangial cells in response to serum, PDGF, and TGF-β1; CRISPR-Cas9 knockout of CaV3.1 abolishes these phospho-ERK1/2 responses while CaV3.2 SKO retains them.\",\n      \"method\": \"CRISPR-Cas9 single and double knockout of CaV3.1/CaV3.2 in mouse mesangial cells; ERK1/2 phosphorylation assays; proliferation assays\",\n      \"journal\": \"BMC Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific CRISPR knockout with pathway-specific readout, single lab\",\n      \"pmids\": [\"35710406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CaV3.1 is predominantly localized in neuronal progenitor cells of the mouse hippocampal dentate gyrus; CaV3.1 knockout mice show decreased proliferation and survival of newly generated cells, impaired differentiation of doublecortin-positive cells, reduced CaMKII and Akt phosphorylation, decreased BDNF expression, and decreased social interaction.\",\n      \"method\": \"CaV3.1 knockout mice; BrdU labeling; doublecortin immunostaining; Western blot for signaling molecules; behavioral testing; gene ontology analysis\",\n      \"journal\": \"Acta Physiologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout with multiple cellular and molecular readouts, single lab\",\n      \"pmids\": [\"33393208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PIP2 modulates CaV3.1 channel gating properties without affecting maximum current density; both short- and long-term PIP2 potentiation shift the activation and steady-state inactivation curves of CaV3.1 toward hyperpolarization; long-term but not short-term PIP2 blunts the voltage-dependency of current decay.\",\n      \"method\": \"Whole-cell patch-clamp of recombinant CaV3.1 expressed in mammalian cells with PIP2 application\",\n      \"journal\": \"Pathophysiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method, limited mechanistic follow-up\",\n      \"pmids\": [\"30528337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CACNA1G/Cacna1g knockdown in Xenopus tropicalis disrupts left-right patterning with abnormal pitx2c and dand5 expression; crispant LR organizers contain reduced cilia quantity, establishing a role for CaV3.1 in ciliogenesis and LR patterning during early embryonic development.\",\n      \"method\": \"CRISPR knockdown in Xenopus tropicalis; LR patterning marker analysis; cilia counting in LR organizer\",\n      \"journal\": \"Genesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR loss-of-function with molecular marker and morphological readouts in vivo, single lab\",\n      \"pmids\": [\"40008628\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CaV3.1 (CACNA1G) is a low-voltage-activated T-type calcium channel whose pore-forming α1G subunit mediates calcium entry near resting membrane potential; it contributes to sinoatrial node pacemaker activity and AV conduction, thalamic sleep stabilization (by suppressing arousal signal transmission via prolonged post-activation inhibition), cerebellar Purkinje cell synaptic Ca2+ signaling in partnership with mGluR1, hypothalamic leucine sensing in POMC neurons (leucine binds the voltage-sensing domain to lower activation threshold), and immune T-cell cytokine production via NFAT; its activity is positively regulated by PKA (β-adrenergic/cAMP pathway), Cdk5 (phosphorylating Ser2234 in the C-terminus), and the LEF1/β-catenin transcriptional complex, while the γ6 calcium channel subunit physically associates with CaV3.1 and negatively modulates current density through a GxxxA-motif-dependent helix-helix interaction; disease-causing gain-of-function mutations (notably p.Ala961Thr, p.Met1531Val) slow inactivation kinetics and increase window current leading to cerebellar atrophy and neurodevelopmental encephalopathy, whereas the p.Arg1715His voltage-sensor mutation shifts activation positively to cause adult-onset spinocerebellar ataxia (SCA42).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CACNA1G encodes CaV3.1 (α1G), the pore-forming subunit of a low-voltage-activated T-type calcium channel that opens near resting membrane potential to provide depolarizing Ca2+ entry, and through this single biophysical role it shapes pacemaking, neuronal firing, and proliferative signaling across many tissues [#0, #2]. Its permeation pathway follows a two-site/three-barrier mechanism with high Ca2+ selectivity (P_Ca/P_Na ≈ 87), is gated by extracellular protons competing with Ca2+ at the pore, and conducts divalent cations including Cd2+ and Fe2+, making it a candidate route for non-transferrin metal influx [#13, #15, #17, #16]; activation and inactivation kinetics are set by domains I and IV [#12]. In the heart, CaV3.1 is the sole T-type current of sinoatrial and atrioventricular node cells, and its loss causes bradycardia and slowed conduction with intact L-type current [#0]. In the CNS it stabilizes sleep by driving prolonged post-activation inhibition in thalamic relay neurons [#1], supports mGluR1-coupled subthreshold dendritic Ca2+ signaling in Purkinje cell spines [#2], and in hypothalamic POMC neurons senses leucine, which directly binds the voltage-sensing segment to lower the activation threshold and mediate appetite suppression by high-protein feeding [#37]. CaV3.1 also drives resting Ca2+ entry that promotes NFAT-dependent cytokine production in T helper cells [#18]. Channel output is tuned by physical and signaling partners: the calcium channel γ6 subunit associates via a GxxxA motif in its first transmembrane domain to reduce current density and channel availability [#5, #6], while PKA (β-adrenergic/cAMP), Cdk5 (phosphorylating Ser2234), and PIP2 positively modulate the current [#10, #11]; surface density is also controlled by Rab11-dependent endosomal recycling [#31] and by LEF1/β-catenin and glucocorticoid/NF-κB transcriptional inputs at the Cacna1g promoter [#8, #26]. Gain-of-function mutations that slow inactivation and enlarge window current (p.Ala961Thr, p.Met1531Val, and intracellular-gate S5/S6 variants) cause childhood-onset cerebellar atrophy and neurodevelopmental encephalopathy, whereas the S4 voltage-sensor mutation p.Arg1715His positively shifts activation to cause adult-onset spinocerebellar ataxia SCA42 [#3, #4, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing the biophysical permeation and gating rules of CaV3.1 was needed before its physiological roles could be interpreted, and ion-substitution and pore mutagenesis defined how the channel selects and conducts Ca2+ and is modulated by protons.\",\n      \"evidence\": \"Whole-cell patch-clamp with ion substitution and EEDD pore-locus mutagenesis in HEK293 cells\",\n      \"pmids\": [\"12743167\", \"18663131\", \"18663132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic structure of the pore in the timeline\", \"Physiological relevance of proton modulation not tested in native cells\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Whether CaV3.1 has an endogenous modulatory subunit was unknown; co-expression showed the γ6 calcium channel subunit selectively suppresses CaV3.1 current density without changing voltage dependence or protein levels.\",\n      \"evidence\": \"Co-expression in HEK-293 and HL-1 cells with patch-clamp, RT-PCR, Western blot, and GFP localization\",\n      \"pmids\": [\"15572045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of current-density reduction not yet resolved at this stage\", \"In vivo significance untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The cellular basis of T-type channel control of sleep was unknown; region-specific deletion showed thalamic CaV3.1 produces prolonged firing inhibition that stabilizes sleep architecture.\",\n      \"evidence\": \"Conditional Cav3.1 knockout in thalamus vs cortex with thalamic electrophysiology and sleep telemetry\",\n      \"pmids\": [\"15677322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream circuit targets of the prolonged inhibition not mapped\", \"Molecular trigger of the >9 s inhibition not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The molecular identity of nodal T-type current and the structural determinants of CaV3.1 gating were addressed, identifying CaV3.1 as the SAN/AVN pacemaker T-current and domains I and IV as gating determinants.\",\n      \"evidence\": \"Cacna1g knockout mice with patch-clamp/ECG plus chimeric domain-swap constructs in tsA-201 cells\",\n      \"pmids\": [\"16690884\", \"16996222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of T-current to pacemaking vs other currents not isolated\", \"Domain swaps do not resolve single-residue gating determinants\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"How γ6 suppresses CaV3.1 was unresolved; mutagenesis, co-IP, and single-channel analysis showed a GxxxA-motif TM1 helix mediates physical association and reduces channel availability.\",\n      \"evidence\": \"Chimeric mutagenesis, co-immunoprecipitation, and single-channel recording in HEK cells and atrial myocytes\",\n      \"pmids\": [\"18818244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of the γ6–CaV3.1 helix interface absent\", \"Stoichiometry of the interaction unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The narrowest molecular unit of γ6 inhibition and a synaptic signaling role were defined: an eight-residue GxxxA peptide selectively inhibits CaV3.1, and CaV3.1 couples to mGluR1 in Purkinje dendritic spines.\",\n      \"evidence\": \"Peptide mutagenesis patch-clamp in HEK cells; electrophysiology, two-photon Ca2+ imaging, and EM in CaV3.1 knockout mice\",\n      \"pmids\": [\"19193827\", \"19657020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mGluR1-to-CaV3.1 signaling intermediates only partly defined (G-protein/tyrosine phosphatase)\", \"Peptide work is in vitro only\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Transcriptional and complex-level control of CaV3.1 was addressed, identifying LEF1/β-catenin as a direct thalamic transcriptional regulator and a KV4.2-KChIP3-DPP10c signaling partnership.\",\n      \"evidence\": \"Luciferase reporters, in vivo ChIP, and thalamic patch-clamp; co-expression electrophysiology with channel-specificity controls\",\n      \"pmids\": [\"20371816\", \"20458163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological output of KV4.2 right-shift not tested in native neurons\", \"Wnt regulation shown in thalamus but not other CaV3.1-expressing tissues\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Post-translational and signaling regulation of channel output was established, defining the β-adrenergic/PKA pathway as a positive modulator of nodal CaV3.1 current.\",\n      \"evidence\": \"Cav3.1 transgenic/knockout mice with patch-clamp and pharmacological PKA inhibition in SAN and ventricular myocytes\",\n      \"pmids\": [\"22808078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PKA phosphosite on CaV3.1 not mapped in this study\", \"Quantitative impact on heart rate in vivo not isolated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether CaV3.1 can conduct non-Ca2+ divalents was tested, showing Cd2+ and Fe2+ permeate the channel, positioning CaV3.1 as a candidate metal-influx pathway.\",\n      \"evidence\": \"Whole-cell patch-clamp, Eyring permeation modeling, and 109Cd2+ radiotracer uptake in HEK293 cells\",\n      \"pmids\": [\"22973059\", \"22973060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological metal transport through CaV3.1 not demonstrated in vivo\", \"Fe2+ permeation evidence is medium-confidence modeling\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The first disease link and a kinase regulator were established: the S4 voltage-sensor mutation p.Arg1715His shifts activation to cause SCA42, and Cdk5 phosphorylates Ser2234 to upregulate the channel.\",\n      \"evidence\": \"Exome sequencing with HEK293T electrophysiology and neuron modeling (SCA42); overexpression/siRNA with mutagenesis-mapped phosphosite (Cdk5)\",\n      \"pmids\": [\"26456284\", \"26715324\", \"25760945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single biophysical shift produces selective cerebellar degeneration not fully explained\", \"Cdk5 regulation not shown in disease context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A non-excitable immune role was defined: resting-potential Ca2+ entry through CaV3.1 drives NFAT translocation and pathogenic cytokine production in T cells, conferring susceptibility to autoimmune neuroinflammation.\",\n      \"evidence\": \"Cav3.1 knockout mice with T-cell patch-clamp, NFAT translocation, cytokine assays, and EAE\",\n      \"pmids\": [\"27037192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between Ca2+ entry and NFAT in T cells not mechanistically dissected\", \"Store-operated entry shown unaffected but interplay not explored\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Encephalopathy-causing variants were characterized, showing de novo p.Ala961Thr and p.Met1531Val are gain-of-function via impaired inactivation and enlarged window current that enhances neuronal firing.\",\n      \"evidence\": \"Patch-clamp of transfected cells, TTA-P2 block, and computational cerebellar neuron modeling with patient exomes\",\n      \"pmids\": [\"29878067\", \"32878331\", \"32736238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vivo model of these specific variants in this study\", \"Threshold of window current driving pathology not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Variant–phenotype relationships and human circuit consequences were refined: intracellular-gate S5/S6 GOF variants cause SCA42ND while a loss-of-activity variant maps to IS4-S5, and human assembloids show GOF/LOF perturb thalamocortical activity and connectivity.\",\n      \"evidence\": \"Patch-clamp/structural analysis of multiple variants; human iPSC thalamocortical assembloids with calcium imaging and axonal analysis\",\n      \"pmids\": [\"39674904\", \"39419023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype–severity correlation rests on heterologous electrophysiology\", \"Assembloid phenotypes not yet linked to in vivo human pathology\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A direct ligand-sensing mechanism was identified: leucine binds the CaV3.1 voltage-sensing domain to lower activation threshold and mediate high-protein appetite suppression through POMC neurons.\",\n      \"evidence\": \"Binding assays, slice/cultured-neuron patch-clamp, POMC-specific conditional knockout, and in vivo pharmacology in obese mice\",\n      \"pmids\": [\"42025169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the leucine-bound voltage sensor not provided\", \"Whether other amino acids share the binding pocket untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the channel's single low-threshold Ca2+-entry function is decoded into such divergent tissue outcomes—pacemaking, sleep, T-cell cytokines, proliferation, regeneration, and ciliogenesis—and what molecular machinery couples CaV3.1 Ca2+ to each effector.\",\n      \"evidence\": \"No timeline study unifies the downstream effector pathways across tissues\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Tissue-specific Ca2+ effectors downstream of CaV3.1 not defined\", \"No structural basis for variant-specific phenotype severity\", \"Relationship between window current and degeneration mechanistically open\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 13, 15, 17]},\n      {\"term_id\": \"GO:0005262\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [37, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 25, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 2, 37]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 36]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CACNG6\", \"GRM1\", \"KCND2\", \"KCNIP3\", \"DPP10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}