Affinage

CACNA1A

Voltage-dependent P/Q-type calcium channel subunit alpha-1A · UniProt O00555

Round 2 corrected
Length
2506 aa
Mass
282.6 kDa
Annotated
2026-04-28
130 papers in source corpus 45 papers cited in narrative 45 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CACNA1A encodes the pore-forming α1A subunit of voltage-gated CaV2.1 (P/Q-type) calcium channels, which are the principal mediators of presynaptic Ca²⁺ influx driving neurotransmitter release at central and neuromuscular synapses, and are essential for cerebellar circuit function, cortical excitability, and synaptic plasticity. The α1A subunit couples Ca²⁺ entry to exocytosis through direct interaction of its domain II–III intracellular loop with SNARE proteins syntaxin and SNAP-25, while its C-terminal IQ-like motif binds calmodulin, CaBP1, and NCS-1 to confer Ca²⁺-dependent facilitation and inactivation that are required for short-term synaptic facilitation and long-term potentiation at hippocampal synapses (PMID:8692999, PMID:11865310, PMID:25447945, PMID:26755594, PMID:27799552). Channel gating is further modulated by Gβγ binding at two distinct sites (I–II loop and C-terminal tail), by β-subunit isoform-specific interactions, and by alternative splicing of the C-terminal region, while the locus additionally encodes α1ACT, a transcription factor produced via an internal IRES that drives Purkinje cell gene expression programs (PMID:9009193, PMID:9238069, PMID:9442082, PMID:12451115, PMID:23827678). Gain-of-function mutations (FHM1) enhance excitatory neurotransmission and facilitate cortical spreading depression and brainstem spreading depolarization linked to SUDEP, whereas loss-of-function mutations cause episodic ataxia type 2 and progressive cerebellar ataxia, and polyglutamine expansions in the α1ACT reading frame cause spinocerebellar ataxia type 6 through a nuclear toxicity mechanism (PMID:8898206, PMID:8988170, PMID:15003170, PMID:30649209, PMID:16595610, PMID:23827678).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1996 High

    Identification of CACNA1A as the gene encoding the brain P/Q-type Ca²⁺ channel α1 subunit, with FHM missense mutations (gain-of-function) and EA2 truncating mutations (loss-of-function), established that distinct mutation classes in a single ion channel gene produce different neurological diseases.

    Evidence Sequencing of all 47 exons in FHM and EA2 families; in vitro SNARE binding assays and co-IP from rat brain demonstrating synprint site interaction with syntaxin/SNAP-25

    PMID:8692999 PMID:8898206

    Open questions at the time
    • Functional consequences of individual FHM mutations on channel biophysics were not yet characterized
    • Whether synprint interaction is required for synaptic transmission in vivo was untested
  2. 1997 High

    Discovery that small polyglutamine expansions in the CACNA1A C-terminus cause SCA6 established a third allelic disease, while characterization of Gβγ binding to two distinct α1A sites (I–II loop and C-terminus) and β4-subunit C-terminal interactions defined the major modulatory domains on the channel.

    Evidence CAG repeat genotyping in ataxia families; in vitro binding and mutagenesis with Xenopus oocyte electrophysiology for Gβγ and β4 sites

    PMID:8988170 PMID:9009193 PMID:9238069 PMID:9442082

    Open questions at the time
    • Whether SCA6 pathogenesis is due to altered channel biophysics or a protein toxicity mechanism was unknown
    • Competition between Gβγ and β-subunit binding at the C-terminal site was not resolved in native neurons
  3. 2001 High

    Systematic functional characterization of EA2 mutations revealed that loss-of-function ranges from reduced current density and altered gating to complete abolition of channel activity, with impaired neuromuscular transmission in patients, while pharmacological studies confirmed CaV2.1 mediates nearly all evoked GABA release at cerebellar basket cell–Purkinje cell synapses.

    Evidence Patch-clamp in multiple expression systems and single-channel analysis of EA2 mutants; single-fiber EMG in patients; ω-agatoxin IVA block of sIPSCs in cerebellar slices

    PMID:11179022 PMID:11403683 PMID:11723274 PMID:11742003

    Open questions at the time
    • Whether EA2 mutations also impair channel trafficking was not addressed
    • Compensatory mechanisms at central synapses upon CaV2.1 loss were unexplored
  4. 2002 High

    Identification of calmodulin and CaBP1 as competitive regulators of CaV2.1 via the C-terminal IQ-like motif established the molecular basis for Ca²⁺-dependent facilitation and inactivation, while systematic splice variant characterization showed that combinatorial exon inclusion tunes current amplitude and inactivation properties.

    Evidence Co-IP from brain and transfected cells; patch-clamp electrophysiology with mutagenesis; transcript scanning PCR with functional expression of splice variants

    PMID:11865310 PMID:12235360 PMID:12451115

    Open questions at the time
    • Whether CaM-mediated facilitation/inactivation is required for synaptic plasticity in vivo was untested
    • Full combinatorial impact of all seven splice loci was not assessed
  5. 2004 High

    The FHM1 R192Q knock-in mouse demonstrated that CaV2.1 gain-of-function directly lowers the threshold for cortical spreading depression in vivo, providing the first causal link between a specific channel mutation and the migraine aura mechanism.

    Evidence Knock-in mouse with patch-clamp, NMJ recordings, and in vivo CSD induction

    PMID:15003170

    Open questions at the time
    • Whether the CSD phenotype is due to enhanced excitatory vs. reduced inhibitory transmission was not distinguished
    • Relevance to spontaneous migraine attacks in humans was inferential
  6. 2005 High

    The severe S218L FHM1 mutation was shown to open channels near resting potential with a large slowly-inactivating component, explaining why this mutation uniquely causes coma after minor trauma, while EA2 pore-region mutations were found to impair plasma membrane trafficking in addition to electrophysiological defects.

    Evidence Single-channel analysis in HEK293 and CaV2.1-null neurons for S218L; confocal imaging of GFP-tagged EA2 mutant channels

    PMID:15743764 PMID:15985579

    Open questions at the time
    • Whether trafficking defects contribute to progressive neurodegeneration in EA2 patients was not tested in vivo
    • Mechanism of trauma-triggered coma in S218L patients remained speculative
  7. 2006 High

    Proteolytic cleavage of the α1A C-terminus generating a nuclear-translocating fragment linked SCA6 polyQ toxicity to a nuclear mechanism, while lipid raft localization studies showed that CaV2.1–SNARE co-clustering in cholesterol-rich microdomains is functionally important for presynaptic Ca²⁺ signaling.

    Evidence Subcellular fractionation and nuclear immunostaining; GFP-tagged expression with cell viability assays; sucrose gradient fractionation and cholesterol depletion with electrophysiology

    PMID:14660672 PMID:16595610 PMID:16928863

    Open questions at the time
    • Identity of the protease cleaving the C-terminus was unknown
    • Whether raft disruption affects synaptic transmission at intact synapses in vivo was not shown
  8. 2010 High

    Circuit-level analysis of FHM1 KI mice revealed that CaV2.1 gain-of-function selectively enhances excitatory but not inhibitory cortical neurotransmission, with action potential waveform shape determining the expression of mutant channel effects across neuron types, explaining synapse-specific vulnerability.

    Evidence Cortical synaptic physiology in R192Q KI mice; AP waveform-clamp in brainstem vs. cortical neurons; synprint mutagenesis (A454T) disrupting SNARE interaction and exocytosis

    PMID:20080591 PMID:20194127 PMID:20484531

    Open questions at the time
    • Whether excitation/inhibition imbalance is sufficient for CSD initiation was not directly tested
    • Mechanism of selective vulnerability of excitatory synapses was correlative
  9. 2011 High

    Purkinje cell-specific and granule cell-specific conditional knockouts demonstrated that postnatal CaV2.1 loss in either cell type is independently sufficient to produce ataxia and absence epilepsy, while SCA6 polyQ expansions were shown to enhance pathogenic splicing that can be targeted therapeutically by isoform-specific RNAi.

    Evidence PCP2-Cre and rhombic-lip lineage-specific conditional KO mice with behavioral and electrophysiological phenotyping; mini-gene splicing reporters and AAV9-delivered miRNA-based RNAi in SCA6 mouse model

    PMID:21411672 PMID:21550405 PMID:21870131 PMID:23516282

    Open questions at the time
    • Whether simultaneous loss in both cell types produces synergistic effects was not tested
    • Long-term efficacy and safety of isoform-specific RNAi in vivo were not established
  10. 2013 High

    Discovery that CACNA1A is bicistronic — encoding the transcription factor α1ACT via an internal IRES — fundamentally expanded understanding of SCA6 as a transcriptionopathy, while nanoscale immunogold EM revealed functional CaV2.1 co-clustering with BK and SK2 channels at ~40 nm distance on Purkinje cell somata.

    Evidence IRES identification with bicistronic reporter assays; α1ACT transcription factor activity and neurite outgrowth assays; transgenic mouse model; SDS-digested freeze-fracture replica immunogold EM

    PMID:23426693 PMID:23827678

    Open questions at the time
    • Endogenous α1ACT target genes in Purkinje cells were not comprehensively identified
    • Whether CaV2.1–BK/SK2 co-clustering is dynamically regulated was unknown
  11. 2016 High

    IM-AA knock-in mice proved that Ca²⁺ sensor regulation of CaV2.1 through the IQ-like motif is required for both short-term synaptic facilitation and long-term potentiation at hippocampal synapses, and for spatial learning and memory, establishing a direct link between presynaptic CaV2.1 modulation and cognitive function.

    Evidence Patch-clamp in hippocampal slices from IM-AA KI mice; LTP induction protocols; fear conditioning and Barnes maze behavioral testing

    PMID:26755594 PMID:27799552

    Open questions at the time
    • Relative contributions of CaM vs. CaBP1 vs. NCS-1 to facilitation and LTP at these synapses were not dissected
    • Whether presynaptic facilitation defect fully accounts for postsynaptic LTP impairment was unclear
  12. 2019 High

    In vivo studies in S218L mice established brainstem spreading depolarization as the mechanism linking CaV2.1 gain-of-function to fatal seizure-related respiratory arrest (SUDEP), preventable by NMDA receptor antagonists, while functional characterization of novel CACNA1A mutations showed that both gain- and loss-of-function can produce severe developmental epileptic encephalopathies.

    Evidence DC potential recording, cardiorespiratory monitoring, and diffusion-weighted MRI in freely behaving S218L mice; NMDA antagonist pharmacology; whole-cell voltage-clamp of DEE mutations in HEK293 cells

    PMID:30649209 PMID:31468518 PMID:31628185

    Open questions at the time
    • Whether NMDA antagonists prevent SUDEP in human patients is untested
    • How opposite CaV2.1 dysfunctions converge on similar DEE phenotypes remains mechanistically unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the protease generating the nuclear α1A C-terminal fragment, the full transcriptional program controlled by α1ACT, how bidirectional CaV2.1 dysfunction converges on epileptic encephalopathy, and whether isoform-specific therapeutic strategies (RNAi, antisense) can be translated to human channelopathies.
  • Protease identity for C-terminal cleavage unknown
  • Comprehensive α1ACT target gene identification lacking
  • No structural model of full-length α1A at atomic resolution
  • Therapeutic translation of isoform-specific silencing not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 7 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 2
Pathway
R-HSA-112316 Neuronal System 8 R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-382551 Transport of small molecules 4
Partners
CABP1CACNA2D2CACNB4CALM1GNB1NCS1SNAP25STX1A
Complex memberships
CaV2.1 P/Q-type calcium channel complex (α1A/α2δ/β)

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 CACNA1A (then called CACNL1A4) encodes a brain-specific P/Q-type Ca2+ channel α1 subunit; missense mutations in conserved functional domains cause familial hemiplegic migraine (FHM) through gain-of-function, while frame-disrupting mutations cause episodic ataxia type 2 (EA2) through loss-of-function, establishing FHM and EA2 as allelic channelopathies. Sequencing of all 47 exons and flanking regions in FHM and EA2 families; functional domain mapping Cell High 8898206
1997 Small polyglutamine (CAG) expansions in the 3′ coding region of CACNA1A cause spinocerebellar ataxia type 6 (SCA6), establishing the gene as responsible for three distinct allelic neurological disorders depending on mutation type. CAG repeat genotyping in ataxia patients and controls; segregation analysis in affected families Nature genetics High 8988170
1996 The α1A subunit of CaV2.1 directly interacts with presynaptic SNARE proteins syntaxin and SNAP-25 via a synaptic protein interaction ('synprint') site in the intracellular loop connecting domains II and III (residues 722–1036), providing a molecular link between Ca2+ influx and exocytosis; this interaction is isoform-specific (BI isoform binds both; rbA binds only SNAP-25). In vitro binding assays; co-immunoprecipitation from rat brain membranes; competitive displacement Proceedings of the National Academy of Sciences of the United States of America High 8692999
1997 G-protein βγ complex directly inhibits CaV2.1 channels by binding to two sites on the α1A subunit: the cytoplasmic linker between domains I and II (overlapping the AID) and a second site in the C-terminal tail; mutation of a critical arginine in the AID abolished Gβγ binding and rendered the channel refractory to G-protein modulation. In vitro binding; Xenopus oocyte expression with mutagenesis; functional patch-clamp Nature High 9009193
1997 The C-terminal tail of the α1A subunit contains a second Gβγ-binding domain distinct from the I-II loop site; this C-terminal site mediates the inhibition of channel activity by G-protein-coupled receptors, and its binding is blocked by the α1-binding domain of the Cavβ subunit. In vitro binding; C-terminal truncation and chimera analysis; functional expression in Xenopus oocytes Proceedings of the National Academy of Sciences of the United States of America High 9238069
1998 The β4 subunit isoform specifically interacts with a second binding site located in the carboxyl-terminal cytoplasmic domain of the α1A subunit (distinct from the conserved AID), and the C-terminal region of β4 modulates channel inactivation kinetics. In vitro binding; deletion and chimera analysis of α1A C-terminus; electrophysiology The Journal of biological chemistry High 9442082
2002 Calmodulin (CaM) binds to the IQ-like motif in the C-terminal domain of CaV2.1 to mediate Ca2+-dependent inactivation and facilitation; CaBP1 also binds the same CaM-binding domain and inhibits CaV2.1 by enhancing inactivation and shifting the voltage dependence of activation, but does not support Ca2+-dependent facilitation. CaBP1 co-immunoprecipitates with α12.1 from brain. Co-immunoprecipitation from transfected cells and brain; patch-clamp electrophysiology; immunolocalization Nature neuroscience High 11865310
2002 All five FHM-linked missense mutations in CaV2.1 share two common functional consequences: increased Ca2+ influx through single channels (due to negatively shifted activation) and decreased maximal CaV2.1 current density when expressed in neurons (but not HEK cells), showing cell-type-dependent effects on channel density. Single-channel and whole-cell patch-clamp in HEK293 cells and cerebellar granule cells from Cav2.1 α1-/- mice Proceedings of the National Academy of Sciences of the United States of America High 12235360
2004 The FHM1 R192Q knock-in mouse shows gain-of-function of CaV2.1 channels (increased current density in cerebellar neurons, enhanced neuromuscular junction neurotransmission), and reduced threshold and increased velocity of cortical spreading depression (CSD), establishing that CaV2.1 gain-of-function directly lowers the threshold for CSD and cortical hyperexcitability. Knock-in mouse model; patch-clamp electrophysiology; neuromuscular junction recordings; in vivo CSD induction and recording Neuron High 15003170
2002 Systematic transcript scanning of human α1(2.1) identified seven loci of alternative splicing; combinatorial inclusion/exclusion of exons 43 and 44 primarily regulates current amplitude and Ca2+-dependent inactivation, demonstrating that splice variation is a key mechanism for tuning CaV2.1 functional diversity. Transcript scanning PCR; genomic sequence analysis; whole-cell patch-clamp electrophysiology with strength-current analysis The Journal of neuroscience : the official journal of the Society for Neuroscience High 12451115
2005 The severe FHM1 mutation S218L shifts CaV2.1 single-channel activation to sub-threshold voltages (channels open near resting potential), introduces a large slowly-inactivating current component, and accelerates recovery from inactivation — a unique combination that is larger in magnitude than other FHM mutations and can explain delayed cerebral edema and coma after minor head trauma. Single-channel and whole-cell patch-clamp in HEK293 cells and CaV2.1 α1-/- neurons expressing human mutant channels The Journal of biological chemistry High 15743764
2006 The C-terminal ~60–75 kDa fragment of the CaV2.1 α1A subunit is proteolytically cleaved from the full-length protein and translocates to Purkinje cell nuclei via nuclear localization signals; when the polyglutamine tract in this fragment is expanded (Q33, as in SCA6), it causes cell death in a nuclear-localization-dependent manner. Subcellular fractionation; nuclear immunostaining with CT-2 antiserum; GFP-tagged α1A expression in primary neurons; cell viability assays Human molecular genetics High 16595610
2006 CaV2.1 α1A and its accessory α2δ-2 subunit co-localize in cholesterol-rich lipid raft microdomains in cerebellum; disruption of rafts by cholesterol depletion enhances CaV2.1/α2δ-2/β4 currents, and R282A mutation in α2δ-2 reduces both gabapentin binding affinity (which is elevated in rafts) and functional enhancement of CaV2.1 currents. Sucrose density gradient fractionation; co-immunoprecipitation; patch-clamp electrophysiology; cholesterol depletion with methyl-β-cyclodextrin The Journal of neuroscience : the official journal of the Society for Neuroscience High 16928863
2003 Presynaptic P/Q-type CaV2.1 (but not L-type CaV1.2) channels are concentrated in lipid raft microdomains in nerve terminals, where they co-localize and interact with SNARE complexes; disruption of these microdomains impairs CaV2.1/SNARE colocalization and reduces Ca2+ influx in nerve terminals. Immunoisolation of detergent-insoluble complexes; flotation gradients; cholesterol depletion with saponin/methyl-β-cyclodextrin; Ca2+ imaging in nerve terminals The Journal of biological chemistry High 14660672
2013 The CACNA1A gene contains a bicistronic mRNA with a cryptic internal ribosomal entry site (IRES) in the α1A C-terminal coding region; the second cistron encodes a transcription factor α1ACT that regulates a program of genes for Purkinje cell development. When expressed with an expanded polyQ tract (SCA6), α1ACT loses transcription factor and neurite outgrowth activity, causes cell death in culture, and leads to cerebellar atrophy in transgenic mice. IRES identification; bicistronic reporter assays; transcription factor activity assays; neurite outgrowth assays; transgenic mouse model Cell High 23827678
2001 CaV2.1/α1A (P/Q-type) channels mediate essentially all action potential-evoked inhibitory GABA release from basket cell interneurons onto Purkinje cells in cerebellar slices, as demonstrated by near-complete block of sIPSCs by 200 nM ω-agatoxin IVA; immunostaining confirmed CaV2.1 co-localization with GAD at pericellular synapses on Purkinje cell somata. In vitro cerebellar slice patch-clamp electrophysiology with selective channel toxins; immunofluorescence co-localization The European journal of neuroscience High 11403683
2013 CaV2.1 in Purkinje cells shows two distribution patterns: a scattered somatodendritic gradient (2.5-fold higher density in distal dendrites) and high-density clusters on soma and primary dendrites that are virtually all co-clustered with BK and SK2 calcium-activated potassium channels at ~40 nm nearest-neighbor distance, suggesting CaV2.1-generated Ca2+ nanodomains activate these channels to limit depolarization. SDS-digested freeze-fracture replica labeling (high-sensitivity immunogold EM); double immunogold labeling in rat cerebellum The Journal of neuroscience : the official journal of the Society for Neuroscience High 23426693
2001 EA2-causing nonsense and missense mutations in CaV2.1 (R1281X, F1406C, R1549X) markedly reduce whole-cell calcium channel current density when expressed in COS7 cells; affected patients show jitter and blocking on single-fiber EMG, demonstrating that CaV2.1 loss-of-function impairs neuromuscular transmission. Patch-clamp in transfected COS7 cells; single-fiber electromyography in patients Neurology High 11723274
2001 EA2 and progressive ataxia mutations G293R, AY1593/1594D, and R1279Stop cause pronounced loss of P/Q-type channel function through reduced current density, altered voltage dependence, enhanced inactivation, and slowed recovery from inactivation; G293R reduces mean single-channel open time without changing conductance, indicating altered fast channel gating. Whole-cell and single-channel patch-clamp in Xenopus oocytes and tsA-201 cells expressing human α1A mutants The Journal of biological chemistry High 11742003
2001 A complete missense mutation (F1491S) in the putative S6 transmembrane segment of domain III of CACNA1A abolishes P/Q channel activity entirely when expressed with β4 and α2δ in HEK293 cells, even though the mutant protein is expressed, establishing complete loss-of-function as the mechanism underlying some EA2 cases. Patch-clamp recording in HEK293 cells; protein expression verified biochemically American journal of human genetics High 11179022
2011 Postnatal loss of CaV2.1 channels confined to Purkinje cells (using a PCP2-Cre conditional knock-in) recapitulates the full neurological phenotype of global Cacna1a ablation—ataxia, dyskinesia, and absence epilepsy—demonstrating that signaling defects arising in late infancy (not prenatal development) are sufficient to initiate these disorders. Conditional knock-in mouse (floxed-Citrine); Purkinje cell-specific Cre-mediated deletion; electrophysiology; behavioral phenotyping The Journal of neuroscience : the official journal of the Society for Neuroscience High 21411672
2012 Purkinje cell-specific ablation of CaV2.1 α1A (using Pcp2-Cre) causes cerebellar ataxia beginning at P12, well before Purkinje cell loss (P30–P45), and leads to secondary cell loss in granular and molecular layers; this establishes that Purkinje cell CaV2.1 is necessary for normal cerebellar circuit function and motor coordination. Conditional CaV2.1 knockout (Pcp2-Cre × floxed Cacna1a); histology; behavioral motor testing Cerebellum (London, England) High 21870131
2013 Postnatal loss of CaV2.1 channels confined to rhombic-lip-derived neurons (granule cells and mossy fiber pathways; quirky mice) reduces parallel fiber-to-Purkinje cell synaptic transmission during low-frequency stimulation and modulation of PC firing via granule cell input, and is sufficient to cause ataxia, dyskinesia, and absence epilepsy. Rhombic-lip lineage-specific conditional KO; electrophysiology in cerebellar slices; channelrhodopsin-2 optogenetic stimulation of granule cells; behavioral phenotyping The Journal of neuroscience : the official journal of the Society for Neuroscience High 23516282
2010 FHM1 R192Q knock-in mice show gain-of-function of neuronal CaV2.1 current with allele-dosage dependence; enhanced cortical excitatory neurotransmission (increased action potential-evoked Ca2+ influx and glutamate release probability at pyramidal cell synapses) but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses, with glutamate release enhancement causally linked to facilitation of CSD. Knock-in mouse; whole-cell patch-clamp; Ca2+ imaging; cortical synaptic physiology; CSD recording The Journal of physiology High 20194127
2015 S218L FHM1 KI mice show gain-of-function of excitatory neurotransmission (increased Ca2+ influx and glutamate release probability at pyramidal cell synapses) but not inhibitory; uniquely, a fraction of S218L CaV2.1 channels are open at resting membrane potential, suggesting tonic Ca2+ influx at sub-threshold voltages contributes to CSD facilitation in homozygous mice. Cortical neurons in microculture from KI mice; whole-cell patch-clamp; Ca2+ imaging; paired-pulse ratio analysis Frontiers in cellular neuroscience High 25741235
2010 The gain-of-function of CaV2.1 current in R192Q FHM1 KI neurons is expressed differently depending on action potential waveform: longer pyramidal cell APs (vs. calyx-of-Held APs) allow the negatively shifted activation of mutant channels to produce larger Ca2+ currents, explaining why cortical synapses but not calyx synapses show enhanced transmission in KI mice. Whole-cell patch-clamp in brainstem slices and cortical neurons from KI mice; AP waveform-clamp experiments Journal of neurophysiology High 20484531
2006 Conditional inactivation of floxed Cacna1a in all neurons causes severe ataxia, dystonia, and lethality (replicating global knockout); homozygous deletion causes ablation of CaV2.1-mediated neurotransmission at the neuromuscular junction and a compensatory upregulation of CaV2.3 (R-type) channels at that synapse. Conditional knockout mouse (floxed Cacna1a); electrophysiology at NMJ; pharmacological subtype dissection Genesis (New York, N.Y. : 2000) High 17146767
2009 RGK GTPases (Gem, Rem, Rem2) inhibit CaV2.1 channels by reducing current amplitude without altering voltage dependence or kinetics; this inhibition requires the β-interaction domain of the Cavβ subunit but is independent of Cavβ's current-potentiating capacity; the C-terminal ~80 amino acids of the RGK GTPase are sufficient for β-subunit binding and channel inhibition. Co-expression in Xenopus oocytes; whole-cell patch-clamp; domain deletion analysis; in vivo β-subunit interaction assays FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 19332647
2005 EA2 missense mutations C287Y and G293R (in the pore region) reduce CaV2.1 current density and impair plasma membrane targeting, as visualized by confocal imaging of GFP-tagged channels, suggesting protein misfolding and trafficking defects contribute to progressive cerebellar degeneration beyond mere electrophysiological loss of function. Whole-cell patch-clamp in transfected COS-7 cells; confocal fluorescence imaging of GFP-tagged CaV2.1 Neurology High 15985579
2001 Novel splice variants of Cacna1a cloned from individual mouse Purkinje cells (expressing >95% P-type current) contain additional N-terminal sequences, amino acid changes, and different C-termini but do not generate P-type current in cultured cells, suggesting post-translational modification or uncharacterized interacting proteins are required for P-type channel properties. Single-cell RT-PCR from isolated Purkinje cells; electrophysiology and pharmacology of expressed variants The Journal of biological chemistry Medium 11756409
2006 SCA6 knock-in mice (expressing human CaV2.1 with 28 polyQ repeats) show P-type (not Q-type) channel properties in Purkinje cells, identical to control knock-in mice; voltage dependence, inactivation, and current density are not different between SCA6 and control in native Purkinje cells, indicating that biophysical channel alteration may not be the primary SCA6 pathomechanism. Knock-in mouse model; patch-clamp of Purkinje cells from homozygous mice; ω-agatoxin IVA pharmacology Molecular and cellular neurosciences Medium 17188510
2016 Regulation of CaV2.1 channels by calmodulin and related calcium sensor proteins (disrupted by the IM-AA mutation in the IQ-like motif) is required for short-term synaptic facilitation at native hippocampal excitatory synapses; in IM-AA mice, paired-pulse facilitation is reduced ~50%, and EGTA-AM completely blocks facilitation, indicating dependence on brief local Ca2+ transients. Knock-in mouse (IM-AA mutation); patch-clamp in hippocampal slices; EGTA-AM chelation; mEPSC and EPSC recording Proceedings of the National Academy of Sciences of the United States of America High 26755594
2016 Calcium sensor regulation of CaV2.1 via the IQ-like motif is required for long-term potentiation (LTP) at Schaffer collateral-CA1 synapses and for spatial learning and memory; IM-AA mice show strongly reduced LTP to θ-burst and tetanic stimulation and deficits in context-dependent fear conditioning and Barnes maze, linking presynaptic CaV2.1 modulation to postsynaptic LTP induction. IM-AA knock-in mouse; LTP induction protocols in hippocampal slices; fear conditioning; Barnes maze; NMDA/AMPA ratio measurements Proceedings of the National Academy of Sciences of the United States of America High 27799552
2014 NCS-1 (neuronal calcium sensor-1/frequenin) directly interacts with the IQ-like motif and calmodulin-binding domain in the C-terminal domain of CaV2.1, reduces Ca2+-dependent inactivation, and induces short-term synaptic facilitation in superior cervical ganglion neurons expressing CaV2.1; this effect is lost with mutations in the IQ-like motif/CaM-binding domain. Co-immunoprecipitation; patch-clamp in SCG neurons; synaptic paired-pulse and train stimulation protocols; domain-specific mutagenesis Molecular and cellular neurosciences High 25447945
2014 NCS-1 directly binds the C-terminal cytoplasmic tail of CaV2.1 α-subunit, as demonstrated by in vitro pull-down of recombinant proteins, fluorescence spectrophotometry, isothermal titration calorimetry, NMR, and co-localization of fluorescently tagged proteins in mammalian cells; calmodulin can compete for this binding site. In vitro binding with recombinant proteins; fluorescence spectrophotometry; ITC; NMR; mammalian cell co-expression fluorescence imaging Biochemistry High 25188201
2010 A mutation in the first intracellular loop of CACNA1A (A454T) disrupts interaction of the P/Q channel with syntaxin 1A and SNAP-25, resulting in decreased exocytosis; it also impairs regulation of steady-state inactivation by Cavβ subunits, revealing the structural importance of the I-II loop for both SNARE protein modulation and vesicle exocytosis. Patch-clamp electrophysiology; exocytosis assay; co-immunoprecipitation of SNARE proteins; mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 20080591
2019 Both gain-of-function (A713T, V1396M — hyperpolarized activation shift, increased current) and loss-of-function (G230V, I1357S — reduced current density, decreased membrane expression) CACNA1A mutations cause severe developmental epileptic encephalopathies, demonstrating that either direction of CaV2.1 dysfunction can produce similarly severe DEE phenotypes. Whole-cell voltage-clamp in HEK293 cells; immunofluorescence microscopy for channel localization; 3D structural modeling Epilepsia High 31468518
2009 Compensatory loss of Cavβ2a subunit expression in Purkinje neurons lacking parvalbumin and calbindin D-28k leads to increased voltage-dependent inactivation of CaV2.1 P-type currents, demonstrating that β-subunit isoform switching is a cellular mechanism to preserve normal activity-dependent Ca2+ signals when Ca2+ buffering is reduced. Whole-cell patch-clamp in dissociated Purkinje neurons from PV/CB double-knockout mice; immunoblotting for β-subunit expression Journal of neurophysiology Medium 19906882
2019 In homozygous S218L CaV2.1 gain-of-function mice, brainstem spreading depolarization (SD) during seizures invades the ventrolateral medulla, initiating apnea and tissue hypoxia; NMDA receptor antagonists (MK-801, memantine) prevent seizure-related brainstem SD and apnea, supporting brainstem SD as the critical mechanism for fatal ictal apnea in SUDEP. In vivo DC potential recording, cardiorespiratory monitoring, local O2 measurement in freely behaving S218L mice; NMDA antagonist pharmacology The Journal of neuroscience : the official journal of the Society for Neuroscience High 31628185
2019 Fatal seizures in homozygous S218L CaV2.1 mice are preceded by cortical neuronal suppression and followed by brainstem spreading depolarization that correlates with respiratory arrest and cardiac arrest; diffusion-weighted MRI confirmed brainstem SD spatiotemporally associated with death, establishing a mechanistic link between CaV2.1 gain-of-function, brainstem SD, and SUDEP. Video-EEG monitoring; diffusion-weighted MRI under anaesthesia; freely behaving electrophysiology in S218L mice Brain : a journal of neurology High 30649209
2013 The FHM1 R192Q knock-in mutation causes constitutive up-regulation of P2X3 receptor responses in trigeminal ganglion sensory neurons; basal levels of CGRP and BDNF (but not TNFα) contribute to this up-regulation, suggesting enhanced CaV2.1-dependent neurotransmitter/neuromodulator release tonically sensitizes trigeminal nociceptors. Patch-clamp of primary trigeminal ganglion cultures from KI mice; pharmacological neutralization of CGRP, BDNF, TNFα PloS one Medium 23577145
2011 SCA6-causing CAG expansions in CaV2.1 enhance alternative splicing at the 3′ end of the transcript in a repeat-length-dependent manner, increasing levels of the polyQ-encoding splice isoform; RNAi specifically targeting this isoform (SIS-RNAi using miRNA-based delivery) selectively suppresses the pathogenic polyQ-CaV2.1 variant in human neuronal cells and prevents disease in a mouse SCA6 model. Mini-gene splicing reporter; quantitative RT-PCR; miRNA-based RNAi in human neuronal cell line; AAV9 mouse model of SCA6 Neurobiology of disease High 21550405
2014 CaV2.1 has a disproportionately greater contribution to synaptic transmission at low frequencies (<20 Hz) compared to high frequencies at hippocampal Schaffer collateral synapses; this frequency-dependent dominance shapes GABAB receptor-mediated presynaptic inhibition, revealing distinct functional roles of Cav2.1 vs. Cav2.2 and Cav2.3 in encoding information during complex activity patterns. Selective calcium channel toxin application (ω-agatoxin IVA, ω-conotoxin GVIA, SNX-482) during complex in vivo-derived stimulus trains in acute hippocampal slices Journal of neurophysiology Medium 24523520
2021 A CACNA1A P2455H missense variant in the distal C-terminus causes a depolarizing shift in the voltage dependence of both activation and inactivation and strongly reduces Ca2+-dependent inactivation, consistent with overall gain-of-function gating, suggesting altered CaV2.1-dependent synaptic communication in the trigeminal system may contribute to trigeminal neuralgia. Whole-cell patch-clamp of wild-type and P2455H mutant CaV2.1 channels in tsA-201 cells Molecular brain Medium 33413531
2022 The R1667P CACNA1A mutation causes complex mixed gain- and loss-of-function effects: hyperpolarized voltage dependence of activation and slowed deactivation (GOF) coexist with slowed activation kinetics and substantially reduced Ca2+ current density (LOF), resulting in diminished Ca2+ flux during action potential-like stimuli, demonstrating that severe CaV2.1 channelopathies cannot always be classified as purely GOF or LOF. Whole-cell patch-clamp of R1667P and WT CaV2.1 in tsA-201 cells; action potential-waveform clamp protocols; Ca2+ current integration Scientific reports Medium 35655070

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1838 8898206
1997 Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nature genetics 1332 8988170
2005 International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacological reviews 967 16382099
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 514 15003170
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
1992 Cloning and expression of a cardiac/brain beta subunit of the L-type calcium channel. The Journal of biological chemistry 363 1370480
1997 Direct binding of G-protein betagamma complex to voltage-dependent calcium channels. Nature 348 9009193
1993 A gene for familial hemiplegic migraine maps to chromosome 19. Nature genetics 313 8220421
2004 The DNA sequence and biology of human chromosome 19. Nature 271 15057824
1996 Isoform-specific interaction of the alpha1A subunits of brain Ca2+ channels with the presynaptic proteins syntaxin and SNAP-25. Proceedings of the National Academy of Sciences of the United States of America 247 8692999
1997 Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Human molecular genetics 232 9302278
2016 De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies. American journal of human genetics 216 27476654
2008 Amyloid beta oligomers (A beta(1-42) globulomer) suppress spontaneous synaptic activity by inhibition of P/Q-type calcium currents. The Journal of neuroscience : the official journal of the Society for Neuroscience 208 18216187
2002 Familial hemiplegic migraine mutations increase Ca(2+) influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proceedings of the National Academy of Sciences of the United States of America 205 12235360
1997 Direct interaction of gbetagamma with a C-terminal gbetagamma-binding domain of the Ca2+ channel alpha1 subunit is responsible for channel inhibition by G protein-coupled receptors. Proceedings of the National Academy of Sciences of the United States of America 192 9238069
2010 CaV2.1 channelopathies. Pflugers Archiv : European journal of physiology 172 20204399
2004 Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain : a journal of neurology 171 15483044
2002 Differential modulation of Ca(v)2.1 channels by calmodulin and Ca2+-binding protein 1. Nature neuroscience 164 11865310
2015 CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. European journal of human genetics : EJHG 157 25735478
1999 High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology 156 10371528
2013 Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6. Cell 142 23827678
2009 Role of voltage-gated calcium channels in epilepsy. Pflugers Archiv : European journal of physiology 138 20091047
2000 Shotgun sequencing of the human transcriptome with ORF expressed sequence tags. Proceedings of the National Academy of Sciences of the United States of America 135 10737800
1998 A beta 4 isoform-specific interaction site in the carboxyl-terminal region of the voltage-dependent Ca2+ channel alpha 1A subunit. The Journal of biological chemistry 133 9442082
2020 Groundwater pollution source identification and apportionment using PMF and PCA-APCA-MLR receptor models in a typical mixed land-use area in Southwestern China. The Science of the total environment 128 32610237
2006 The calcium channel alpha2delta-2 subunit partitions with CaV2.1 into lipid rafts in cerebellum: implications for localization and function. The Journal of neuroscience : the official journal of the Society for Neuroscience 125 16928863
2000 CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy. Neurology 124 11061267
1999 Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. American journal of human genetics 118 9915947
1997 Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1. American journal of human genetics 118 9311738
2001 Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2. American journal of human genetics 117 11179022
2002 Systematic identification of splice variants in human P/Q-type channel alpha1(2.1) subunits: implications for current density and Ca2+-dependent inactivation. The Journal of neuroscience : the official journal of the Society for Neuroscience 116 12451115
2006 C-termini of P/Q-type Ca2+ channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Human molecular genetics 114 16595610
2013 Quantitative localization of Cav2.1 (P/Q-type) voltage-dependent calcium channels in Purkinje cells: somatodendritic gradient and distinct somatic coclustering with calcium-activated potassium channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 112 23426693
2005 Specific kinetic alterations of human CaV2.1 calcium channels produced by mutation S218L causing familial hemiplegic migraine and delayed cerebral edema and coma after minor head trauma. The Journal of biological chemistry 111 15743764
2003 Calcium-binding protein 1 is an inhibitor of agonist-evoked, inositol 1,4,5-trisphosphate-mediated calcium signaling. The Journal of biological chemistry 111 14570872
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2003 Role of lipid microdomains in P/Q-type calcium channel (Cav2.1) clustering and function in presynaptic membranes. The Journal of biological chemistry 108 14660672
2001 Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Neurology 104 11320173
2001 Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission. Neurology 104 11723274
1997 SCA6 is caused by moderate CAG expansion in the alpha1A-voltage-dependent calcium channel gene. Human molecular genetics 104 9259275
1999 A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia. Neurology 99 10408533
2010 De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine. Neurology 94 20837964
2011 Delayed postnatal loss of P/Q-type calcium channels recapitulates the absence epilepsy, dyskinesia, and ataxia phenotypes of genomic Cacna1a mutations. The Journal of neuroscience : the official journal of the Society for Neuroscience 86 21411672
2021 From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing. Frontiers in neurology 85 33737904
2019 Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice. Brain : a journal of neurology 84 30649209
2009 Early seizures and cerebral oedema after trivial head trauma associated with the CACNA1A S218L mutation. Journal of neurology, neurosurgery, and psychiatry 84 19520699
2007 Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine. Neurology 82 18056581
2005 Opening of the blood-brain barrier preceding cortical edema in a severe attack of FHM type II. Neurology 81 15985592
2001 Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. The Journal of biological chemistry 81 11742003
2019 Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome. Epilepsia 77 31468518
2003 Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description of 5 families with familial hemiplegic migraine. Archives of neurology 72 12756131
2015 Mutations in HPCA cause autosomal-recessive primary isolated dystonia. American journal of human genetics 70 25799108
2002 Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine. Archives of neurology 70 12056940
2003 Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family. Archives of neurology 66 12707077
2016 Eye movement disorders are an early manifestation of CACNA1A mutations in children. Developmental medicine and child neurology 61 26814174
2004 Functional implications of a novel EA2 mutation in the P/Q-type calcium channel. Annals of neurology 60 15293273
2001 The Cav2.1/alpha1A (P/Q-type) voltage-dependent calcium channel mediates inhibitory neurotransmission onto mouse cerebellar Purkinje cells. The European journal of neuroscience 60 11403683
2010 Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2. Journal of the neurological sciences 59 20129625
2006 Migrainous vertigo: mutation analysis of the candidate genes CACNA1A, ATP1A2, SCN1A, and CACNB4. Headache 58 16866717
2006 Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. Molecular and cellular neurosciences 55 17188510
2005 Two novel CACNA1A gene mutations associated with episodic ataxia type 2 and interictal dystonia. Archives of neurology 54 15710862
1999 Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM. Human genetics 54 10987655
2021 CACNA1A-associated epilepsy: Electroclinical findings and treatment response on seizures in 18 patients. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 53 34102571
2019 Apnea Associated with Brainstem Seizures in Cacna1aS218L Mice Is Caused by Medullary Spreading Depolarization. The Journal of neuroscience : the official journal of the Society for Neuroscience 52 31628185
2008 CACNA1A mutation linking hemiplegic migraine and alternating hemiplegia of childhood. Cephalalgia : an international journal of headache 52 18498393
2001 Missense CACNA1A mutation causing episodic ataxia type 2. Archives of neurology 50 11176968
2014 Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature. Journal of neurology 47 24658662
2010 Congenital ataxia, mental retardation, and dyskinesia associated with a novel CACNA1A mutation. Journal of child neurology 46 20097664
2010 Insights into migraine mechanisms and CaV2.1 calcium channel function from mouse models of familial hemiplegic migraine. The Journal of physiology 45 20194127
1992 Excitation energy transfer from phycocyanin to chlorophyll in an apcA-defective mutant of Synechocystis sp. PCC 6803. The Journal of biological chemistry 45 1429645
2016 Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 43 28007337
2005 CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics. Neurology 43 15985579
2022 Clinical and genetic characterization of CACNA1A-related disease. Clinical genetics 42 35722745
2017 Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia. Scientific reports 42 28566750
2013 Postnatal loss of P/Q-type channels confined to rhombic-lip-derived neurons alters synaptic transmission at the parallel fiber to purkinje cell synapse and replicates genomic Cacna1a mutation phenotype of ataxia and seizures in mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 23516282
1994 On the discriminatory value of anti-HPCA-1 (CD-34) in the differential diagnosis of benign and malignant cutaneous vascular proliferations. The American Journal of dermatopathology 42 7526723
2015 Abnormal cortical synaptic transmission in CaV2.1 knockin mice with the S218L missense mutation which causes a severe familial hemiplegic migraine syndrome in humans. Frontiers in cellular neuroscience 41 25741235
2001 Novel Cav2.1 splice variants isolated from Purkinje cells do not generate P-type Ca2+ current. The Journal of biological chemistry 41 11756409
2012 Purkinje cell-specific ablation of Cav2.1 channels is sufficient to cause cerebellar ataxia in mice. Cerebellum (London, England) 40 21870131
2019 Phenotypic Characterization of Larval Zebrafish (Danio rerio) with Partial Knockdown of the cacna1a Gene. Molecular neurobiology 37 31875924
2018 The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families. Cephalalgia : an international journal of headache 37 29486580
2015 Paroxysmal tonic upward gaze as a presentation of de-novo mutations in CACNA1A. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 37 25596066
2006 A novel ATP1A2 mutation in a family with FHM type II. Cephalalgia : an international journal of headache 36 16472340
2019 Cognitive impairment in children with CACNA1A mutations. Developmental medicine and child neurology 35 31115040
2013 Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies. Molecular genetics & genomic medicine 35 24498617
2011 Neurovascular changes in prolonged migraine aura in FHM with a novel ATP1A2 gene mutation. Journal of neurology, neurosurgery, and psychiatry 35 22013243
2001 Investigation of the CACNA1A gene as a candidate for typical migraine susceptibility. American journal of medical genetics 35 11803518
2015 HPC-A dose prediction on the optia® cell separator based on a benchmark CE2 collection efficiency: Promoting clinical efficiency, minimizing toxicity, and allowing quality control. Journal of clinical apheresis 34 25619791
2008 Screen for CACNA1A and ATP1A2 mutations in sporadic hemiplegic migraine patients. Cephalalgia : an international journal of headache 33 18513263
2016 Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to long-term potentiation and spatial learning. Proceedings of the National Academy of Sciences of the United States of America 32 27799552
2009 Motor coordination impairment in aged heterozygous rolling Nagoya, Cav2.1 mutant mice. Brain research 32 19446536
2021 The complexities of CACNA1A in clinical neurogenetics. Journal of neurology 31 34806130
2006 Conditional inactivation of the Cacna1a gene in transgenic mice. Genesis (New York, N.Y. : 2000) 31 17146767
2003 Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits. Annals of neurology 31 14681882
2016 Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons. Proceedings of the National Academy of Sciences of the United States of America 30 26755594
2016 Next-generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2. Molecular genetics & genomic medicine 28 27066515
2013 Reduced sleep and low adenosinergic sensitivity in cacna1a R192Q mutant mice. Sleep 28 23288979
2013 The mechanism of functional up-regulation of P2X3 receptors of trigeminal sensory neurons in a genetic mouse model of familial hemiplegic migraine type 1 (FHM-1). PloS one 28 23577145
2014 Modulation of CaV2.1 channels by neuronal calcium sensor-1 induces short-term synaptic facilitation. Molecular and cellular neurosciences 27 25447945
2006 The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 27 16508934
2010 Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential. Journal of neurophysiology 26 20484531
2008 Enhanced circadian phase resetting in R192Q Cav2.1 calcium channel migraine mice. Annals of neurology 26 18825664
2016 The Genetics of Benign Paroxysmal Torticollis of Infancy: Is There an Association With Mutations in the CACNA1A Gene? Journal of child neurology 25 26961263
2015 Association study between polymorphisms in the CACNA1A, CACNA1C, and CACNA1H genes and drug-resistant epilepsy in the Chinese Han population. Seizure 25 26216687
2003 Absence of known familial hemiplegic migraine (FHM) mutations in the CACNA1A gene in patients with common migraine: implications for genetic testing. Clinical chemistry and laboratory medicine 25 12705332
2011 Splice isoform-specific suppression of the Cav2.1 variant underlying spinocerebellar ataxia type 6. Neurobiology of disease 24 21550405
2007 Motor and cognitive deficits in the heterozygous leaner mouse, a Cav2.1 voltage-gated Ca2+ channel mutant. Neurobiology of aging 24 17513018
2009 RGK GTPase-dependent CaV2.1 Ca2+ channel inhibition is independent of CaVbeta-subunit-induced current potentiation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 19332647
2002 Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy. European journal of human genetics : EJHG 23 12461694
2020 Application of APCA-MLR receptor model for source apportionment of char and soot in sediments. The Science of the total environment 22 32771758
2006 CACNA1A mutation in a EA-2 patient responsive to acetazolamide and valproic acid. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 22 16583725
2020 Rare CACNA1A mutations leading to congenital ataxia. Pflugers Archiv : European journal of physiology 21 32458086
2011 Early-onset cerebellar atrophy associated with mutation in the CACNA1A gene. Pediatric neurology 21 22000314
2003 Novel splice site CACNA1A mutation causing episodic ataxia type 2. Neurogenetics 21 14530926
1987 Expression of HPCA-1 and HLA-DR antigens on growth factor- and stroma-dependent colony forming cells. British journal of haematology 21 3606954
2021 A CACNA1A variant associated with trigeminal neuralgia alters the gating of Cav2.1 channels. Molecular brain 20 33413531
2018 Targeting the CACNA1A IRES as a Treatment for Spinocerebellar Ataxia Type 6. Cerebellum (London, England) 20 29374372
2022 CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications. Frontiers in molecular neuroscience 19 35600082
2010 A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis. Proceedings of the National Academy of Sciences of the United States of America 19 20080591
2009 Compensatory regulation of Cav2.1 Ca2+ channels in cerebellar Purkinje neurons lacking parvalbumin and calbindin D-28k. Journal of neurophysiology 19 19906882
2022 Complex effects on CaV2.1 channel gating caused by a CACNA1A variant associated with a severe neurodevelopmental disorder. Scientific reports 18 35655070
2014 A novel missense mutation in CACNA1A evaluated by in silico protein modeling is associated with non-episodic spinocerebellar ataxia with slow progression. European journal of medical genetics 18 24486772
2014 Distinct roles for Cav2.1-2.3 in activity-dependent synaptic dynamics. Journal of neurophysiology 18 24523520
2009 The ataxic Cacna1a-mutant mouse rolling nagoya: an overview of neuromorphological and electrophysiological findings. Cerebellum (London, England) 18 19484318
2008 CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine. Clinical genetics 18 18400034
1987 Fathead minnow FHM cells for use in in vitro cytotoxicity assays of aquatic pollutants. Ecotoxicology and environmental safety 18 3428209
2020 Ameliorative effect of curcumin on altered expression of CACNA1A and GABRD in the pathogenesis of FeCl3-induced epilepsy. Molecular biology reports 17 32803504
2014 Demonstration of binding of neuronal calcium sensor-1 to the cav2.1 p/q-type calcium channel. Biochemistry 17 25188201