Affinage

CACNA1G

Voltage-dependent T-type calcium channel subunit alpha-1G · UniProt O43497

Length
2377 aa
Mass
262.5 kDa
Annotated
2026-06-09
89 papers in source corpus 46 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 High

    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

    PMID:12743167 PMID:18663131 PMID:18663132

    Open questions at the time
    • No atomic structure of the pore in the timeline
    • Physiological relevance of proton modulation not tested in native cells
  2. 2004 High

    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

    PMID:15572045

    Open questions at the time
    • Mechanism of current-density reduction not yet resolved at this stage
    • In vivo significance untested
  3. 2005 High

    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

    PMID:15677322

    Open questions at the time
    • Downstream circuit targets of the prolonged inhibition not mapped
    • Molecular trigger of the >9 s inhibition not defined
  4. 2006 High

    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

    PMID:16690884 PMID:16996222

    Open questions at the time
    • Quantitative contribution of T-current to pacemaking vs other currents not isolated
    • Domain swaps do not resolve single-residue gating determinants
  5. 2008 High

    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

    PMID:18818244

    Open questions at the time
    • Structural model of the γ6–CaV3.1 helix interface absent
    • Stoichiometry of the interaction unknown
  6. 2009 High

    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

    PMID:19193827 PMID:19657020

    Open questions at the time
    • mGluR1-to-CaV3.1 signaling intermediates only partly defined (G-protein/tyrosine phosphatase)
    • Peptide work is in vitro only
  7. 2010 High

    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

    PMID:20371816 PMID:20458163

    Open questions at the time
    • Physiological output of KV4.2 right-shift not tested in native neurons
    • Wnt regulation shown in thalamus but not other CaV3.1-expressing tissues
  8. 2012 High

    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

    PMID:22808078

    Open questions at the time
    • PKA phosphosite on CaV3.1 not mapped in this study
    • Quantitative impact on heart rate in vivo not isolated
  9. 2012 High

    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

    PMID:22973059 PMID:22973060

    Open questions at the time
    • Physiological metal transport through CaV3.1 not demonstrated in vivo
    • Fe2+ permeation evidence is medium-confidence modeling
  10. 2015 High

    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)

    PMID:25760945 PMID:26456284 PMID:26715324

    Open questions at the time
    • How a single biophysical shift produces selective cerebellar degeneration not fully explained
    • Cdk5 regulation not shown in disease context
  11. 2016 High

    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

    PMID:27037192

    Open questions at the time
    • Link between Ca2+ entry and NFAT in T cells not mechanistically dissected
    • Store-operated entry shown unaffected but interplay not explored
  12. 2018 High

    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

    PMID:29878067 PMID:32736238 PMID:32878331

    Open questions at the time
    • No in vivo model of these specific variants in this study
    • Threshold of window current driving pathology not quantified
  13. 2024 High

    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

    PMID:39419023 PMID:39674904

    Open questions at the time
    • Genotype–severity correlation rests on heterologous electrophysiology
    • Assembloid phenotypes not yet linked to in vivo human pathology
  14. 2025 High

    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

    PMID:42025169

    Open questions at the time
    • Atomic structure of the leucine-bound voltage sensor not provided
    • Whether other amino acids share the binding pocket untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-397014 Muscle contraction 2 R-HSA-168256 Immune System 1
Partners
CACNG6DPP10GRM1KCND2KCNIP3

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. Cacna1g knockout mice; patch-clamp electrophysiology on isolated SAN/AVN cells; telemetric ECG and intracardiac recordings Circulation Research High 16690884
2005 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. Cav3.1 knockout mice; Cre/loxP conditional knockout in thalamus vs. cortex; electrophysiology in thalamic neurons; sleep telemetry Proceedings of the National Academy of Sciences High 15677322
2009 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. Electrophysiology; ultrafast two-photon calcium imaging; immunohistochemistry and electron microscopy on wild-type and CaV3.1 knockout mice Journal of Neuroscience High 19657020
2015 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). Whole-exome sequencing; electrophysiology in HEK293T cells expressing mutant vs. wild-type Cav3.1; computational neuron modeling American Journal of Human Genetics High 26456284 26715324
2018 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. Patch-clamp electrophysiology in transfected cells; computational neuron modeling; whole-exome sequencing in patient cohort Brain High 29878067 32736238 32878331
2004 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. 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 of Molecular and Cellular Cardiology High 15572045
2008 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. Chimeric construct mutagenesis; whole-cell patch-clamp; single-channel recording; co-immunoprecipitation from HEK cells and atrial myocytes Journal of Physiology High 18818244
2009 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. Whole-cell patch-clamp in HEK cells; peptide mutagenesis Molecular Pharmacology Medium 19193827
2010 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. Luciferase reporter assay; footprinting analysis; chromatin immunoprecipitation (ChIP); patch-clamp in cultured thalamic neurons Journal of Neuroscience High 20371816
2010 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. Co-expression in HEK cells; whole-cell patch-clamp Channels Medium 20458163
2012 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. Cav3.1 transgenic and knockout mice; patch-clamp in ventricular myocytes and SAN cells; pharmacological PKA inhibition; real-time PCR PLoS ONE High 22808078
2015 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. Overexpression and siRNA knockdown in N1E-115 cells; heterologous expression in HEK-293 cells; whole-cell patch-clamp; site-directed mutagenesis PLoS ONE High 25760945
2006 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. Chimeric channel constructs with swapped transmembrane domains expressed in tsA-201 cells; whole-cell patch-clamp Neuroscience High 16996222
2003 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. Whole-cell patch-clamp in HEK293 cells expressing CaV3.1; EEDD pore locus mutagenesis; model simulations Journal of General Physiology High 12743167
2008 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. Whole-cell patch-clamp in HEK293 cells stably expressing CaV3.1 or CaV3.2; varied permeant ion concentration and identity Journal of General Physiology High 18663132
2008 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. 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 of General Physiology High 18663131
2012 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. Whole-cell patch-clamp with instantaneous I-V; Eyring permeation modeling; ascorbate Fe2+ stabilization in HEK293 cells stably expressing CaV3.1 Molecular Pharmacology Medium 22973060
2012 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. Whole-cell patch-clamp; radiotracer 109Cd2+ uptake assay in HEK293 cells stably expressing CaV3.1 Molecular Pharmacology High 22973059
2016 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. Cav3.1 knockout mice; patch-clamp in T cells; intracellular Ca2+ measurement; in vitro T cell polarization; EAE induction Immunity High 27037192
2006 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. Live-cell imaging of VWF-GFP vesicles; shRNA knockdown; recombinant CaV3.1 overexpression; Ca2+ measurement; pharmacological blockade American Journal of Physiology – Lung Cellular and Molecular Physiology High 17172292
2010 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. Patch-clamp; siRNA knockdown; Western blot; immunohistochemistry; cell cycle analysis American Journal of Physiology – Cell Physiology Medium 20457833
2010 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. siRNA knockdown; RT-PCR; cell cycle analysis; pharmacological PI3K/Akt inhibition in PASMCs American Journal of Physiology – Cell Physiology Medium 21148410
2016 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. Transgenic overexpression and underexpression of Cacna1g in Scn2aQ54 and Scn1a+/- mouse models; seizure frequency monitoring; survival analysis Epilepsia High 27112236 28556246
2008 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. CaV3.1 knockout mice; behavioral pain assays (paw withdrawal, thermal hyperalgesia) after spinal nerve ligation Molecules and Cells Medium 18414012
2011 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. Transient expression in HEK293 cells; whole-cell patch-clamp; voltage-clamp protocols dissecting inactivation states Journal of Pharmacology and Experimental Therapeutics Medium 22088954
2012 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. CaV3.1 overexpression; siRNA knockdown; immunocytochemistry with Annexin V/TUNEL; apoptosis assay; cell proliferation assay International Journal of Oncology Medium 22469755
2008 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. Primary cultured neonatal cardiomyocytes; patch-clamp; luciferase reporter assay; RT-PCR; pharmacological inhibition Molecular and Cellular Biochemistry Medium 18820838
2009 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. Site-directed mutagenesis of GREs; luciferase reporter assay in neonatal cardiac myocytes Molecular and Cellular Biochemistry Medium 19705257
2006 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. Full-length cDNA survey of 1580 human brain cDNAs; statistical linkage analysis; patch-clamp of expressed variants Proteins Medium 16671074
2003 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. RT-PCR; 5' RACE; luciferase reporter assays with deletion analysis; patch-clamp European Journal of Neuroscience Medium 12752779
2014 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. Pharmacological inhibition in N2a cells and 3xTg-AD mice; CaV3.1 overexpression in HEK cells with APP; amyloid beta ELISA Neurobiology of Aging Medium 24268883
2012 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. Real-time RT-PCR; Western blot; luciferase reporter; patch-clamp; dominant-negative Rab11a; Brefeldin A treatment in GH3 and HEK-293 cells Cell Calcium Medium 22770883
2005 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. Real-time RT-PCR; whole-cell patch-clamp at early and late differentiation stages of Nkx2.5+ cells Circulation Journal Medium 16195632
2014 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. Patch-clamp; real-time PCR; pharmacological inhibition of NOX4, ROS, JNK, p38 in HL-1 cells Pflügers Archiv Medium 24510064
2022 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. CaV3.1 knockdown in dmVMH; optogenetic burst stimulation; behavioral tests; respiratory exchange ratio measurement; in vivo electrophysiology Molecular Psychiatry Medium 35318460
2024 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. Human iPSC-derived thalamocortical assembloids with CACNA1G variants; patch-clamp; calcium imaging; axonal projection analysis Neuron High 39419023
2024 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. Patch-clamp in transfected cells; structural analysis; neuronal modeling Genetics in Medicine Medium 39674904
2025 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. Binding assays; patch-clamp in cultured neurons and brain slices; conditional knockout in POMC neurons; in vivo pharmacology; food intake and weight measurements Cell Metabolism High 42025169
2025 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. cacna1g homozygous mutant zebrafish; fin regeneration assay; live GCaMP Ca2+ imaging in regenerating fins bioRxivpreprint Medium
2022 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. CRISPR-Cas9 single and double knockout of CaV3.1/CaV3.2 in mouse mesangial cells; ERK1/2 phosphorylation assays; proliferation assays BMC Nephrology Medium 35710406
2021 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. CaV3.1 knockout mice; BrdU labeling; doublecortin immunostaining; Western blot for signaling molecules; behavioral testing; gene ontology analysis Acta Physiologica Medium 33393208
2018 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. Whole-cell patch-clamp of recombinant CaV3.1 expressed in mammalian cells with PIP2 application Pathophysiology Low 30528337
2025 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. CRISPR knockdown in Xenopus tropicalis; LR patterning marker analysis; cilia counting in LR organizer Genesis Medium 40008628

Source papers

Stage 0 corpus · 89 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Bradycardia and slowing of the atrioventricular conduction in mice lacking CaV3.1/alpha1G T-type calcium channels. Circulation research 232 16690884
2005 Thalamic Cav3.1 T-type Ca2+ channel plays a crucial role in stabilizing sleep. Proceedings of the National Academy of Sciences of the United States of America 159 15677322
1999 Inactivation of CACNA1G, a T-type calcium channel gene, by aberrant methylation of its 5' CpG island in human tumors. Cancer research 132 10493502
2009 Functional coupling between mGluR1 and Cav3.1 T-type calcium channels contributes to parallel fiber-induced fast calcium signaling within Purkinje cell dendritic spines. The Journal of neuroscience : the official journal of the Society for Neuroscience 86 19657020
2015 A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia. American journal of human genetics 85 26456284
2015 A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. Molecular brain 82 26715324
2018 De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene. Brain : a journal of neurology 80 29878067
2003 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. Neuroscience 72 12614673
2012 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. International journal of oncology 68 22469755
2007 Mutational analysis of CACNA1G in idiopathic generalized epilepsy. Mutation in brief #962. Online. Human mutation 65 17397049
2010 LEF1/beta-catenin complex regulates transcription of the Cav3.1 calcium channel gene (Cacna1g) in thalamic neurons of the adult brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 58 20371816
2006 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. Proteins 53 16671074
2009 High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene. Molecular psychiatry 52 19455149
2013 Age-related downregulation of the CaV3.1 T-type calcium channel as a mediator of amyloid beta production. Neurobiology of aging 46 24268883
2017 Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome. Epilepsia 45 28556246
2008 Attenuated neuropathic pain in Cav3.1 null mice. Molecules and cells 40 18414012
2023 LncRNA CACNA1G-AS1 up-regulates FTH1 to inhibit ferroptosis and promote malignant phenotypes in ovarian cancer cells. Oncology research 39 37304234
2016 Ontogenic Changes and Differential Localization of T-type Ca(2+) Channel Subunits Cav3.1 and Cav3.2 in Mouse Hippocampus and Cerebellum. Frontiers in neuroanatomy 39 27616982
2016 Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a. Epilepsia 38 27112236
2024 Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway. Neuron 36 39419023
2010 Regulation of the KV4.2 complex by CaV3.1 calcium channels. Channels (Austin, Tex.) 36 20458163
2017 Transcriptome analysis of PDGFRα+ cells identifies T-type Ca2+ channel CACNA1G as a new pathological marker for PDGFRα+ cell hyperplasia. PloS one 34 28806761
2016 Low-Voltage-Activated CaV3.1 Calcium Channels Shape T Helper Cell Cytokine Profiles. Immunity 34 27037192
2022 Cav3.1-driven bursting firing in ventromedial hypothalamic neurons exerts dual control of anxiety-like behavior and energy expenditure. Molecular psychiatry 33 35318460
2005 Subtype switching of T-type Ca 2+ channels from Cav3.2 to Cav3.1 during differentiation of embryonic stem cells to cardiac cell lineage. Circulation journal : official journal of the Japanese Circulation Society 32 16195632
2004 Calcium channel gamma6 subunits are unique modulators of low voltage-activated (Cav3.1) calcium current. Journal of molecular and cellular cardiology 32 15572045
2012 Fe²⁺ block and permeation of CaV3.1 (α1G) T-type calcium channels: candidate mechanism for non-transferrin-mediated Fe²⁺ influx. Molecular pharmacology 31 22973060
2008 Ni2+ block of CaV3.1 (alpha1G) T-type calcium channels. The Journal of general physiology 29 18663132
2018 Long non-coding RNA CACNA1G-AS1 promotes cell migration, invasion and epithelial-mesenchymal transition by HNRNPA2B1 in non-small cell lung cancer. European review for medical and pharmacological sciences 27 29509247
2013 Bisphenol A differently inhibits CaV3.1, Ca V3.2 and Ca V3.3 calcium channels. Naunyn-Schmiedeberg's archives of pharmacology 27 24170242
2003 Extracellular Ca2+ modulates the effects of protons on gating and conduction properties of the T-type Ca2+ channel alpha1G (CaV3.1). The Journal of general physiology 26 12743167
2012 Cd²⁺ block and permeation of CaV3.1 (α1G) T-type calcium channels: candidate mechanism for Cd²⁺ influx. Molecular pharmacology 25 22973059
2010 Regulation and function of Cav3.1 T-type calcium channels in IGF-I-stimulated pulmonary artery smooth muscle cells. American journal of physiology. Cell physiology 25 21148410
2012 β-Adrenergic stimulation increases Cav3.1 activity in cardiac myocytes through protein kinase A. PloS one 24 22808078
2006 Cav3.1 (alpha1G) controls von Willebrand factor secretion in rat pulmonary microvascular endothelial cells. American journal of physiology. Lung cellular and molecular physiology 24 17172292
2010 Involvement of CaV3.1 T-type calcium channels in cell proliferation in mouse preadipocytes. American journal of physiology. Cell physiology 23 20457833
2006 Determinants of the differential gating properties of Cav3.1 and Cav3.3 T-type channels: a role of domain IV? Neuroscience 22 16996222
2003 Regulation of alpha1G T-type calcium channel gene (CACNA1G) expression during neuronal differentiation. The European journal of neuroscience 22 12752779
2020 Channelopathies of voltage-gated L-type Cav1.3/α1D and T-type Cav3.1/α1G Ca2+ channels in dysfunction of heart automaticity. Pflugers Archiv : European journal of physiology 21 32601767
2019 Infantile-Onset Syndromic Cerebellar Ataxia and CACNA1G Mutations. Pediatric neurology 21 31836334
2008 Permeation and gating in CaV3.1 (alpha1G) T-type calcium channels effects of Ca2+, Ba2+, Mg2+, and Na+. The Journal of general physiology 21 18663131
2015 Regulation of neuronal cav3.1 channels by cyclin-dependent kinase 5 (Cdk5). PloS one 19 25760945
2020 Long non-coding RNA CACNA1G-AS1 promotes proliferation and invasion and inhibits apoptosis by regulating expression of miR-205 in human keloid fibroblasts. Bioscience reports 18 32495824
2019 LncRNA CACNA1G-AS1 facilitates hepatocellular carcinoma progression through the miR-2392/C1orf61 pathway. Journal of cellular physiology 18 30908634
2018 A case of a novel CACNA1G mutation from a Chinese family with SCA42: A case report and literature review. Medicine 18 30200108
2020 Novel Missense CACNA1G Mutations Associated with Infantile-Onset Developmental and Epileptic Encephalopathy. International journal of molecular sciences 17 32878331
2015 CaV3.1 T-Type Ca2+ Channels Contribute to Myogenic Signaling in Rat Retinal Arterioles. Investigative ophthalmology & visual science 17 26241400
2008 A critical GxxxA motif in the gamma6 calcium channel subunit mediates its inhibitory effect on Cav3.1 calcium current. The Journal of physiology 17 18818244
2008 Regulation of T-type Cav3.1 channels expression by synthetic glucocorticoid dexamethasone in neonatal cardiac myocytes. Molecular and cellular biochemistry 17 18820838
2005 Inorganic mercury and methylmercury inhibit the Cav3.1 channel expressed in human embryonic kidney 293 cells by different mechanisms. The Journal of pharmacology and experimental therapeutics 16 16326920
2020 De novo CACNA1G variants in developmental delay and early-onset epileptic encephalopathies. Journal of the neurological sciences 15 32736238
2018 CAV3.1 knockdown suppresses cell proliferation, migration and invasion of prostate cancer cells by inhibiting AKT. Cancer management and research 15 30410396
2010 Different distribution of Cav3.2 and Cav3.1 transcripts encoding T-type Ca(2+) channels in the embryonic heart of mice. Biomedical research (Tokyo, Japan) 15 21079360
2009 Expanded alternative splice isoform profiling of the mouse Cav3.1/alpha1G T-type calcium channel. BMC molecular biology 15 19480703
2005 T-type calcium channel trigger p21ras signaling pathway to ERK in Cav3.1-expressed HEK293 cells. Brain research 15 16054119
2006 Transforming growth factor-beta1 and bone morphogenetic protein-2 downregulate CaV3.1 channel expression in mouse C2C12 myoblasts. Journal of cellular physiology 14 16883604
2021 Overexpression of T-type calcium channel Cav3.1 in oral squamous cell carcinoma: association with proliferation and anti-apoptotic activity. Journal of molecular histology 12 33394292
2011 Lack of CaV3.1 channels causes severe motor coordination defects and an age-dependent cerebellar atrophy in a genetic model of essential tremor. Biochemical and biophysical research communications 12 21621520
2008 The CaV3.1 T-type Ca2+channel contributes to voltage-dependent calcium currents in rat outer hair cells. Brain research 12 18294617
2020 Upregulated lncRNA CACNA1G-AS1 aggravates the progression of colorectal cancer by downregulating p53. European review for medical and pharmacological sciences 11 31957825
2021 Cav3.1 t-type calcium channel is critical for cell proliferation and survival in newly generated cells of the adult hippocampus. Acta physiologica (Oxford, England) 10 33393208
2011 Roscovitine inhibits CaV3.1 (T-type) channels by preferentially affecting closed-state inactivation. The Journal of pharmacology and experimental therapeutics 10 22088954
2018 Up-regulation of Cav3.1 expression in SH-SY5Y cells induced by lidocaine hydrochloride. Artificial cells, nanomedicine, and biotechnology 9 29327607
2006 Gating of the expressed T-type Cav3.1 calcium channels is modulated by Ca2+. Acta physiologica (Oxford, England) 9 16634780
2014 Bone morphogenetic protein-4 induces upregulation of Cav3.1 Ca²⁺ channels in HL-1 atrial myocytes. Pflugers Archiv : European journal of physiology 8 24510064
2022 Computational epigenetic landscape analysis reveals association of CACNA1G-AS1, F11-AS1, NNT-AS1, and MSC-AS1 lncRNAs in prostate cancer progression through aberrant methylation. Scientific reports 7 35715447
2015 Compensatory reduction of Cav3.1 expression in thalamocortical neurons of juvenile rats of WAG/Rij model of absence epilepsy. Epilepsy research 6 26656778
2012 Insulin-mediated upregulation of T-type Ca2+ currents in GH3 cells is mediated by increased endosomal recycling and incorporation of surface membrane Cav3.1 channels. Cell calcium 6 22770883
2009 A small peptide inhibitor of the low voltage-activated calcium channel Cav3.1. Molecular pharmacology 6 19193827
2021 The T-type Calcium Channel Cav3.1 in Y79 Retinoblastoma Cells is Regulated by the Epidermal Growth Factor Receptor via the MAPK Signaling Pathway. Current eye research 5 34674590
2008 The relationship between single-channel and whole-cell conductance in the T-type Ca2+ channel CaV3.1. Biophysical journal 5 18375519
2024 The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND. Genetics in medicine : official journal of the American College of Medical Genetics 4 39674904
2021 Downregulation of Cav3.1 T-type Calcium Channel Expression in Age-related Hearing Loss Model. Current medical science 4 34403092
2023 CD19, ALDH18A1, and CACNA1G as Significant Hub Genes in End-Stage Osteoarthritis. Iranian journal of public health 3 38435769
2009 Identification of functional corticosteroid response elements involved in regulation of Cacna1g expression in cardiac myocytes. Molecular and cellular biochemistry 3 19705257
2022 Knockdown of the long non-coding RNA CACNA1G-AS1 enhances cytotoxicity and apoptosis of human diffuse large B cell lymphoma by regulating miR-3160-5p. Experimental and therapeutic medicine 2 36160896
2022 Paroxysmal Tonic Upgaze in a Patient With Congenital Ataxia due to a De Novo Missense Variant of CACNA1G. Pediatric neurology 2 36508879
2018 Short- and long-term roles of phosphatidylinositol 4,5-bisphosphate PIP2 on Cav3.1- and Cav3.2-T-type calcium channel current. Pathophysiology : the official journal of the International Society for Pathophysiology 2 30528337
2013 Construction and identification of the pshRNA-CACNA1G-SH-SY5Ycells targeted to silence Cav3.1 mRNA expression. Biomedical reports 2 24649007
2025 CACNA1G, A Heterotaxy Candidate Gene, Plays a Role in Ciliogenesis and Left-Right Patterning in Xenopus tropicalis. Genesis (New York, N.Y. : 2000) 1 40008628
2025 The Functional Interplay among GAD2, GABRG2, and CACNA1G Genes in Cancers. Asian Pacific journal of cancer prevention : APJCP 1 40849687
2024 CACNA1G Causes Dominantly Inherited Myoclonus-Ataxia with Intellectual Disability: A Case Report. Cerebellum (London, England) 1 39287920
2022 Stimulated phosphorylation of ERK in mouse kidney mesangial cells is dependent upon expression of Cav3.1. BMC nephrology 1 35710406
2021 Variant in CACNA1G as a Possible Genetic Modifier of Neonatal Epilepsy in an Infant with a De Novo SCN2A Mutation. Journal of pediatric genetics 1 37090830
2020 Expression and functions of N-type Cav2.2 and T-type Cav3.1 channels in rat vasopressin neurons under normotonic conditions. The journal of physiological sciences : JPS 1 33059597
2026 Cav3.1 is a neuronal leucine sensor that mediates satiety and weight loss in response to dietary protein. Cell metabolism 0 42025169
2025 Electrophysiological classification of CACNA1G gene variants associated with neurodevelopmental and neurological disorders. Frontiers in pharmacology 0 41111510
2024 Unmasking early colorectal cancer clues: in silico and in vitro investigation of downregulated IGF2, SOCS1, MLH1, and CACNA1G in SSA polyps. Molecular biology reports 0 38874740
2020 The expression of Cav3.1 on T-type calcium channels of rats with subarachnoid hemorrhage. Saudi journal of biological sciences 0 32565706

Missed literature

Know a paper Affinage missed for CACNA1G? Flag it for the maintainers and the community.

No submissions yet.