Affinage

CACNA1A

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

Length
2506 aa
Mass
282.6 kDa
Annotated
2026-06-09
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CACNA1A encodes the pore-forming α1A subunit of the voltage-gated P/Q-type (CaV2.1) Ca2+ channel, a presynaptic channel that triggers action potential-evoked neurotransmitter release at cerebellar and neuromuscular synapses and is essential for cerebellar motor function (PMID:8898206, PMID:11403683, PMID:21870131). Its biophysics and synaptic output are tuned through the C-terminal cytoplasmic tail, which serves as a hub for direct association with calcium sensors—calmodulin, NCS-1, and VILIP-2 modulate Ca2+-dependent inactivation and facilitation, while constitutively bound CaMKII accelerates inactivation and supports short-term plasticity and synapsin-1 phosphorylation (PMID:16049183, PMID:18162541, PMID:23255606, PMID:25447945, PMID:25188201); disruption of this calcium-sensor regulation impairs hippocampal LTP and spatial memory (PMID:27799552). The channel is further regulated by Gβγ-mediated inhibition downstream of multiple GPCRs (mGluR1, GABAB, GHSR1a, muscarinic M1) and is targeted and compartmentalized at the membrane through ankyrin-B binding to the DII/III loop and through SNARE-associated presynaptic lipid microdomains (PMID:14660672, PMID:12704197, PMID:24394417, PMID:24688019, PMID:26283199, PMID:19883739). CACNA1A is allelically pleiotropic: gain-of-function missense mutations cause familial hemiplegic migraine by enhancing P/Q current and glutamate release to lower the threshold for cortical and brainstem spreading depolarization (PMID:8898206, PMID:20194127, PMID:30649209), loss-of-function truncating/missense mutations cause episodic ataxia type 2 by reducing current density, impairing membrane trafficking, and exerting dominant-negative β-subunit sequestration (PMID:8898206, PMID:15985579, PMID:17161621), and CAG/polyQ expansions cause SCA6 acting at least partly through a bicistronic IRES-encoded transcription factor, α1ACT, that loses transcriptional and neurite-outgrowth function when expanded (PMID:9302278, PMID:23827678). Beyond channel conduction, postsynaptic Purkinje-cell CaV2.1 governs heterosynaptic competition, biochemical compartmentalization, and cell survival in the cerebellum (PMID:21870131, PMID:22279216).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Established CACNA1A as the gene for the brain P/Q-type channel and that distinct mutation classes produce opposite functional consequences, defining it as the locus of allelic channelopathies.

    Evidence Exon sequencing of disease-causing missense and truncating mutations across FHM and EA2 families

    PMID:8898206

    Open questions at the time
    • Did not provide direct electrophysiological proof of gain- vs loss-of-function
    • Cerebellar versus cortical mechanism not resolved
  2. 1997 High

    Connected polyQ repeat expansion to SCA6 and placed EA2 and SCA6 on an allelic severity continuum, broadening the disease spectrum of one gene.

    Evidence CAG repeat sizing and intergenerational tracking in affected families; mouse ortholog mapping in tottering/leaner

    PMID:9060410 PMID:9302278

    Open questions at the time
    • Mechanism by which polyQ expansion causes degeneration unknown
    • Whether channel conduction is altered by the expansion not tested
  3. 2001 High

    Demonstrated directly that EA2 mutations reduce calcium current and that CaV2.1 mediates human neuromuscular transmission, grounding the loss-of-function model functionally.

    Evidence Patch-clamp of mutant constructs in COS7 cells and single-fiber EMG in patients

    PMID:11723274

    Open questions at the time
    • Trafficking versus gating contribution not separated
    • Heterologous current may not reflect native Purkinje behavior
  4. 2003 High

    Defined the molecular microenvironment of presynaptic CaV2.1, showing it is organized with SNARE proteins in lipid microdomains and physically coupled to mGluR1, explaining spatial regulation of release-triggering Ca2+.

    Evidence Immunoisolation, flotation gradients, cholesterol disruption, and reciprocal Co-IP with calcium imaging/electrophysiology

    PMID:12704197 PMID:14660672

    Open questions at the time
    • Stoichiometry of CaV2.1–SNARE assembly unresolved
    • In vivo relevance of microdomain disruption not tested
  5. 2005 High

    Showed EA2 mutations cause not only altered gating but also misfolding/trafficking defects, refining loss-of-function into multiple cellular mechanisms.

    Evidence Patch-clamp plus GFP-tagged channel confocal imaging of pore mutants in COS-7 cells; VILIP-2 modulation defined by deletion mutagenesis

    PMID:15985579 PMID:16049183

    Open questions at the time
    • Identity of trafficking/chaperone machinery unknown
    • VILIP-2 effect not validated in native terminals
  6. 2007 High

    Identified CaMKII as a constitutive C-terminal partner that modulates channel inactivation independent of its catalytic activity, establishing a structural rather than purely enzymatic regulatory mode.

    Evidence Binding assays and patch-clamp with CaMKII inhibitor and competing peptides in neurons; later kinase assays showing synapsin-1 phosphorylation

    PMID:18162541 PMID:23255606

    Open questions at the time
    • Binding site on C-terminus not mapped at residue level in first study
    • Link to in vivo plasticity left for later work
  7. 2010 High

    Provided causal in vivo proof that FHM1 mutations are gain-of-function, enhancing excitatory transmission and facilitating cortical spreading depression while sparing inhibition, defining the migraine mechanism.

    Evidence Electrophysiology, CSD thresholds, and glutamate release assays in R192Q/S218L knock-in mice; AP-waveform substitution at calyx of Held vs cortical neurons

    PMID:20194127 PMID:20484531

    Open questions at the time
    • Why some neuron types are spared depends on AP waveform but circuit-level migraine cause incomplete
    • Human CSD measurement not feasible
  8. 2012 High

    Dissociated CaV2.1's roles in motor function, cell survival, and cerebellar patterning, showing Purkinje-cell CaV2.1 is required for ataxia-free motor control and synaptic compartmentalization independently of cell death.

    Evidence Pcp2-Cre conditional knockout with behavior, histology, EM, and immunofluorescence; dominant-negative truncation Co-IP/electrophysiology

    PMID:17161621 PMID:21870131 PMID:22279216

    Open questions at the time
    • Molecular link between channel loss and degeneration unresolved
    • Mechanism of heterosynaptic competition not defined
  9. 2013 High

    Revealed a non-canonical mechanism for SCA6 by showing CACNA1A is bicistronic, encoding a polyQ-containing transcription factor α1ACT that loses function when expanded, separating the disease from channel conduction defects.

    Evidence IRES reporter assays, α1ACT transcription factor and neurite assays, transgenic polyQ mice; repeat-length-dependent splicing of polyQ isoform; native Purkinje patch-clamp showing unaltered channel properties

    PMID:17188510 PMID:21550405 PMID:23827678

    Open questions at the time
    • Relative contribution of α1ACT loss versus toxic gain not quantified
    • α1ACT target gene network incompletely mapped
  10. 2014 High

    Mapped the C-terminal calcium-sensor competition (NCS-1 vs calmodulin) and the ankyrin-B membrane-targeting interaction, defining the structural determinants of facilitation and surface trafficking.

    Evidence ITC/NMR/fluorescence binding with domain mutagenesis, SCG neuron synaptic recordings; Co-IP from native brain plus Y797E mutagenesis for ankyrin-B

    PMID:24394417 PMID:25188201 PMID:25447945

    Open questions at the time
    • In vivo consequence of NCS-1/CaM competition not established
    • Whether ankyrin-B loss causes disease phenotype untested
  11. 2015 Medium

    Cataloged the GPCR inhibitory pathways converging on CaV2.1, showing distinct G-protein routes (Gβγ voltage-dependent, Gi/o density reduction, Gq gating, PLC/PIP2) for GABAB, GHSR1a, and muscarinic regulation.

    Evidence Whole-cell patch-clamp with pharmacological pathway dissection in HEK, hypothalamic, and neostriatal neurons

    PMID:19883739 PMID:24688019 PMID:26283199

    Open questions at the time
    • Physiological settings where each pathway dominates unclear
    • Single-lab pharmacological inference
  12. 2016 High

    Linked C-terminal calcium-sensor regulation of CaV2.1 to higher cognitive function, showing it is required for hippocampal LTP and spatial memory.

    Evidence IM-AA knock-in mice with LTP recordings and Barnes maze/fear conditioning

    PMID:27799552

    Open questions at the time
    • Which specific calcium sensor mediates the behavioral effect not isolated
    • Presynaptic versus postsynaptic locus of LTP deficit unresolved
  13. 2019 High

    Extended FHM1 gain-of-function pathophysiology to lethal brainstem events, showing spreading depolarization in respiratory medulla initiates apnea and death, a mechanistic route to SUDEP.

    Evidence Brainstem DC potential, oximetry, MRI, and NMDA-antagonist rescue in S218L knock-in mice

    PMID:30649209 PMID:31628185

    Open questions at the time
    • Translation of NMDA-antagonist protection to humans untested
    • Trigger linking cortical to brainstem SD incompletely defined
  14. 2022 Medium

    Showed that pathogenic CaV2.1 mutations are not strictly GOF or LOF, with mixed biophysical effects producing net altered Ca2+ flux, complicating genotype–mechanism prediction.

    Evidence Whole-cell patch-clamp with AP-like stimuli for P2455H and R1667P mutants in tsA-201 cells

    PMID:33413531 PMID:35655070

    Open questions at the time
    • Heterologous biophysics may not predict native synaptic outcome
    • No in vivo model for these mutants

Open questions

Synthesis pass · forward-looking unresolved questions
  • How channel-level dysfunction, α1ACT transcriptional loss, and trafficking/partner defects are integrated to determine the specific clinical phenotype across the CACNA1A allelic spectrum remains unresolved.
  • No unified model converting biophysical/molecular change to phenotype
  • Therapeutic correction of LOF trafficking and polyQ effects unaddressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-112316 Neuronal System 3 R-HSA-74160 Gene expression (Transcription) 1
Partners
ANK2CALM1CAMK2GRM1NCSN1/NCS-1SNAP25STX1AVSNL1/VILIP-2
Complex memberships
CaV2.1 (P/Q-type) channel complexSNARE complex (syntaxin/SNAP-25/synaptotagmin association)

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 CACNA1A (CACNL1A4) encodes the brain-specific P/Q-type Ca2+ channel α1-subunit; missense mutations in conserved functional domains cause familial hemiplegic migraine (FHM) via a gain-of-function mechanism, while frameshift/truncating mutations cause episodic ataxia type-2 (EA-2) via loss of function, establishing these as allelic channelopathies. Exon sequencing of all 47 exons across multiple families, mutation identification by direct sequencing Cell High 8898206
1997 CAG repeat expansions in the 3'-end of CACNA1A cause spinocerebellar ataxia type 6 (SCA6), and the size of the expansion correlates with phenotypic severity (smaller expansions = EA2 phenotype, larger = progressive cerebellar ataxia), demonstrating that EA2 and SCA6 are allelic disorders of the same gene. CAG repeat sizing and sequence analysis of CACNA1A in affected families; intergenerational allele size tracking Human molecular genetics High 9302278
1997 Cacna1a mutations (tottering and leaner alleles) are the primary cause of seizures, cerebellar degeneration, and ataxia in mouse models, confirming the mouse Cacna1a gene is the ortholog of human CACNL1A4/CACNA1A. DNA sequencing, gene mapping, and expression analysis of mouse Cacna1a mutants Mammalian genome High 9060410
2001 EA2-causing nonsense and missense mutations (R1281X, F1406C, R1549X) in CACNA1A produce markedly decreased whole-cell calcium channel current densities in vitro, demonstrating loss-of-function as the mechanism; patients also showed abnormal neuromuscular junction transmission (jitter/blocking on SFEMG), implicating CaV2.1 in neuromuscular transmission. Patch-clamp recording in transfected COS7 cells; single-fiber electromyography in patients Neurology High 11723274
2001 CaV2.1/α1A (P/Q-type) channels mediate action potential-evoked inhibitory GABAergic neurotransmission onto cerebellar Purkinje cells via presynaptic localization at basket cell terminals, demonstrated by selective blockade with ω-agatoxin IVA and co-localization with glutamic acid decarboxylase. Whole-cell patch-clamp in cerebellar slices with selective VDCC antagonists; immunostaining with anti-Cav2.1 antibodies colocalized with GAD The European journal of neuroscience High 11403683
2003 Presynaptic CaV2.1 (P/Q-type) channels, but not CaV1.2 (L-type), are predominantly located in lipid microdomains (detergent-insoluble complexes) in presynaptic terminals, where they co-localize and interact with SNARE complex proteins (syntaxin, SNAP-25, synaptotagmin). Disruption of cholesterol-enriched microdomains impairs CaV2.1-SNARE co-localization and reduces calcium influx, indicating that lipid microdomains organize the exocytic machinery around CaV2.1. Immunoisolation of multiprotein complexes from detergent-insoluble fractions; flotation gradients; methyl-β-cyclodextrin/saponin treatment; calcium influx measurements in nerve terminals The Journal of biological chemistry High 14660672
2003 mGluR1 and CaV2.1 co-localize at Purkinje cell dendrites and form a heteromeric assembly via direct interaction between their C-terminal intracellular domains. mGluR1 inhibits CaV2.1-mediated Ca2+ increases in a ligand-independent manner, and this inhibition is enhanced by mGluR1 activation, establishing a direct physical and functional coupling that spatiotemporally regulates Ca2+ in glutamatergic transmission. Co-immunoprecipitation from brain and COS-7 cells; calcium imaging; whole-cell patch clamp in HEK 293 cells; confocal imaging of Purkinje cell dendrites The Journal of biological chemistry High 12704197
2004 The E147K missense mutation in CaV2.1α1 (CACNA1A) causes impaired calcium channel function (loss of function), producing an autosomal dominant phenotype of absence epilepsy with 3 Hz spike-wave EEG combined with cerebellar ataxia. Functional expression studies using human CACNA1A cDNA with E147K mutation; linkage analysis and DNA sequencing in affected family Brain Medium 15483044
2004 An EA2-associated missense mutation H1736L near the pore-forming region of CaV2.1 reduces current density, increases rate of inactivation, and shifts voltage dependence of activation to more positive values (overall loss of function), but also shows some gain-of-function biophysical changes. Acetazolamide had no direct action on wild-type or H1736L mutant channel properties. Whole-cell patch-clamp recordings in transfected cells; pharmacological testing with acetazolamide Annals of neurology Medium 15293273
2005 EA2-associated pore missense mutations C287Y and G293R in CaV2.1 cause reduced current expression AND deficiency in plasma membrane targeting (protein misfolding/trafficking defect), as shown by GFP-tagged channel imaging, suggesting that impaired channel trafficking — not only altered biophysics — contributes to progressive cerebellar ataxia. Whole-cell patch-clamp in transfected COS-7 cells; confocal fluorescence imaging of GFP-tagged CaV2.1 Neurology Medium 15985579
2005 VILIP-2 (visinin-like protein-2) binds to the CBD and IQ-like domain in the CaV2.1 C-terminus and slows Ca2+-dependent inactivation, thereby enhancing facilitation during extended stimulus trains — an effect distinct from calmodulin and CaBP1 modulation. Co-expression in tsA-201 cells; whole-cell patch-clamp; deletion mutagenesis of the calmodulin-binding domain and IQ-like domain The Journal of neuroscience High 16049183
2006 CaV2.1 channels with the SCA6 polyQ expansion (28 repeats) expressed in Purkinje cells of knock-in mice exhibit typical P-type channel properties (non-inactivating, highly ω-agatoxin IVA sensitive), and show no alteration in voltage dependence of activation/inactivation or current density compared to control knock-in mice, suggesting that channel property changes are not the primary pathogenic mechanism of SCA6 in native Purkinje cells. Patch-clamp recordings of Purkinje cells from homozygous SCA6 knock-in mice vs. control knock-in mice; pharmacological characterization Molecular and cellular neurosciences Medium 17188510
2006 Truncated CaV2.1 α1-subunits (EA2 mutations) exert dominant-negative suppression of wild-type CaV2.1 currents, and this effect depends on the truncation terminating distal to the alpha-interaction domain (AID) which mediates β-subunit binding. Only AID-bearing truncations co-immunoprecipitate β-subunits, implicating β-subunit sequestration as the dominant-negative mechanism. Transient co-expression of WT and truncated α1.2.1-GFP/RFP subunits; whole-cell patch clamp; co-immunoprecipitation; cellular imaging Molecular and cellular neurosciences Medium 17161621
2007 CaMKII constitutively associates with the C-terminal domain of CaV2.1 channels, and this binding (rather than catalytic activity) accelerates voltage-dependent inactivation, causes a negative shift in inactivation voltage dependence, and reduces Ca2+-dependent facilitation. A peptide blocking CaMKII binding to CaV2.1 reproduces the effects of kinase inhibition. Binding assays; whole-cell patch-clamp in neurons with CaMKII inhibitor peptides; peptide competition experiments Proceedings of the National Academy of Sciences of the United States of America High 18162541
2010 FHM1 knock-in mice (R192Q and S218L mutations) show allele dosage-dependent gain-of-function of P/Q-type Ca2+ current (activation at lower voltages), facilitated cortical spreading depression (CSD), and enhanced glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at fast-spiking interneurons. This establishes a causative link between CaV2.1 gain-of-function, enhanced excitatory transmission, and CSD facilitation as the migraine mechanism. Electrophysiology in knock-in mouse brain slices; CSD threshold measurements; glutamate release assays; inhibitory postsynaptic current recordings The Journal of physiology High 20194127
2010 FHM-1 R192Q CaV2.1 knock-in mice show gain-of-function in cortical layer 2/3 pyramidal cells (longer AP duration leads to larger Ca2+ influx) but not at the calyx of Held (short AP duration), demonstrating that the functional consequence of FHM1 mutations on synaptic Ca2+ influx depends on the action potential waveform of the specific neuron type. Whole-cell patch-clamp at calyx of Held and cortical pyramidal cells in knock-in and WT brain slices; AP waveform substitution experiments Journal of neurophysiology High 20484531
2012 Purkinje cell-specific knockout of CaV2.1 in mice causes cerebellar ataxia beginning at P12, prior to Purkinje cell loss (P30–P45), demonstrating that CaV2.1 in Purkinje cells is required for normal motor function independently of cell survival. Secondary degeneration of granule and molecular layers and reduced cerebellar nuclei volume also occur. Conditional knockout using Pcp2-Cre x floxed Cacna1a mice; behavioral assessment; histology Cerebellum (London, England) High 21870131
2012 Postsynaptic CaV2.1 in Purkinje cells is required for: (1) heterosynaptic competition between parallel fibers and climbing fibers; (2) Purkinje cell survival in zebrin II-negative compartments; and (3) posttranscriptional establishment of sharp PLCβ3/PLCβ4 boundaries and EAAT4 banding — biochemical compartmentalization of the cerebellum. PC-specific Cav2.1 knockout mice (Pcp2-Cre); electron microscopy; immunofluorescence; western blotting; behavioral and anatomical analyses The Journal of neuroscience High 22279216
2012 CaMKII binds directly to the C-terminal domain of CaV2.1; autophosphorylated CaMKII binding to CaV2.1 induces Ca2+-independent kinase activity and phosphorylation of synapsin-1. The signaling complex persists after dephosphorylation. This CaMKII–CaV2.1 complex regulates facilitation/inactivation of P/Q-type Ca2+ current and short-term synaptic plasticity in presynaptic terminals. In vitro binding assays; CaMKII autophosphorylation kinase assays; electrophysiology in transfected SCG neurons; competing peptide experiments The Journal of biological chemistry High 23255606
2013 CACNA1A encodes a bicistronic mRNA with an internal ribosomal entry site (IRES) in the α1A C-terminal coding region. The second cistron encodes a transcription factor, α1ACT, which drives expression of genes involved in Purkinje cell and neural development. When the polyQ tract (SCA6 expansion) is present in α1ACT, it loses transcription factor and neurite outgrowth function, causes cell death, and produces ataxia and cerebellar atrophy in transgenic mice. IRES discovery by reporter assays; α1ACT identification by expression constructs; gene expression profiling; neuronal differentiation assays; transgenic mouse model with expanded polyQ α1ACT Cell High 23827678
2013 R192Q knock-in Cacna1a mice show reduced sleep and low sensitivity to adenosinergic sleep induction (caffeine and CPA effects altered), consistent with the interpretation that A1 receptor modulation of sleep operates through CaV2.1 channels, and that the R192Q mutation renders channels less susceptible to G-protein inhibition by adenosine. Sleep EEG/EMG recordings in knock-in and WT mice; pharmacological challenge with caffeine and CPA (A1 agonist); behavioral sleep analysis Sleep Medium 23288979
2013 In FHM-1 R192Q knock-in mice, trigeminal ganglion sensory neurons show constitutive upregulation of P2X3 receptor responses that are contributed by basal CGRP and BDNF levels; prolonged CGRP receptor antagonism or BDNF neutralization reduced KI P2X3 currents to WT levels, placing CaV2.1 gain-of-function upstream of enhanced trophic factor signaling that sensitizes nociceptive neurons. Primary cultures of trigeminal ganglia from WT and R192Q KI mice; whole-cell patch-clamp; pharmacological neutralization of TNFα, CGRP, BDNF PloS one Medium 23577145
2014 Ankyrin-B associates with CaV2.1 (and CaV2.2) via its membrane-binding domain interacting with a conserved motif in the DII/III intracellular loop of CaV2.1. A single tyrosine-to-glutamate mutation (Y797E) in the ankyrin-binding motif abolishes ankyrin-B association in vitro and in vivo and disrupts proper CaV2.1 targeting in heterologous cells. Co-immunoprecipitation from cortex, cerebellum, brain stem; in vitro binding assays; heterologous expression with site-directed mutagenesis; cellular imaging The Journal of biological chemistry High 24394417
2014 NCS-1 directly binds to the IQ-like motif and calmodulin-binding domain (CBD) in the CaV2.1 C-terminal domain. NCS-1 reduces Ca2+-dependent inactivation of P/Q-type Ca2+ current via the IQ-like motif/CBD interaction and, when expressed in SCG neurons, induces facilitation of synaptic transmission in response to paired pulses and trains — an effect abolished by mutations in the IQ-like motif/CBD. Co-expression in tsA-201 cells; whole-cell patch-clamp; electrophysiology in SCG neurons; site-directed mutagenesis of IQ-like and CBD domains; synaptic transmission measurements Molecular and cellular neurosciences High 25447945
2014 NCS-1 directly binds the C-terminal cytoplasmic tail of the CaV2.1 α-subunit, and calmodulin can compete for this binding site, as demonstrated by in vitro binding, fluorescence spectrophotometry, isothermal titration calorimetry, NMR, and mammalian cell co-expression. In vitro binding of recombinant proteins; fluorescence spectrophotometry; ITC; NMR; co-expression of fluorescently tagged proteins in mammalian cells Biochemistry High 25188201
2014 GABAB receptor activation by baclofen inhibits CaV2.1 channels expressed in HEK cells by ~40%, with ~75% of this inhibition being voltage-dependent (Gβγ-mediated). Cyclized Vc1.1 (c-Vc1.1) does not affect CaV2.1 (negative finding), distinguishing it from its potent inhibition of CaV2.3. Whole-cell patch-clamp in HEK cells expressing human CaV2.1; pertussis toxin treatment; depolarizing paired-pulse protocols The Journal of general physiology Medium 24688019
2015 GHSR1a constitutive activity reduces CaV2.1 (and CaV2.2) currents via a Gi/o-dependent mechanism involving persistent reduction in channel density at the plasma membrane, while ghrelin-dependent GHSR1a activation causes reversible inhibition via a Gq-dependent pathway altering CaV2.1 gating — two distinct G-protein pathways for GHSR1a-mediated CaV2.1 inhibition. Whole-cell patch-clamp in rat/mouse hypothalamic neurons and heterologous expression system; pharmacological dissection of Gi/o vs. Gq pathways; constitutive vs. agonist-dependent receptor activation comparisons The Journal of general physiology High 26283199
2016 Regulation of CaV2.1 channels by calmodulin and related calcium sensor proteins (disrupted by the IM-AA mutation) is required for normal long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, and for spatial learning and memory in mice, linking presynaptic CaV2.1 calcium sensor regulation to hippocampal plasticity. Knock-in mice bearing IM-AA mutation disrupting CaM/calcium-sensor binding; LTP measurements by extracellular recording; NMDA/AMPA receptor current ratio; Barnes maze and fear conditioning behavioral assays Proceedings of the National Academy of Sciences of the United States of America High 27799552
2019 In homozygous Cacna1a S218L mice (gain-of-function CaV2.1), brainstem spreading depolarization (SD) occurs during fatal seizures and correlates with respiratory arrest leading to death; SD invasion into medullary respiratory centers initiates apnea and hypoxia. NMDA receptor antagonists (MK-801, memantine) prevent brainstem SD and apnea, identifying a mechanistic pathway from CaV2.1 gain-of-function to SUDEP. Electrophysiological recordings of brainstem DC potential and neuronal activity; cardiorespiratory monitoring; diffusion-weighted MRI; freely behaving homozygous S218L knock-in mice; pharmacological NMDA receptor blockade Brain High 30649209
2019 Brainstem spreading depolarization (SD) in the ventrolateral medulla, occurring during brainstem seizures in Cacna1a S218L mice, directly precedes local tissue hypoxia and apnea, demonstrating that SD invasion of respiratory nuclei initiates seizure-related apnea rather than hypoxia causing SD. Brainstem DC potential, neuronal activity, and tissue oxygen recordings in freely behaving S218L mice; seizure induction via inferior colliculus stimulation; NMDA antagonist treatment The Journal of neuroscience High 31628185
2021 A CACNA1A P2455H missense mutation in the distal C-terminus causes a depolarizing shift in voltage-dependence of both activation and inactivation, and strongly reduces calcium-dependent inactivation — consistent with overall gain-of-function — in heterologously expressed CaV2.1 channels, suggesting that altered CaV2.1-dependent synaptic communication in the trigeminal system contributes to trigeminal neuralgia. Whole-cell patch-clamp of wild-type and P2455H CaV2.1 expressed in tsA-201 cells Molecular brain Medium 33413531
2022 The R1667P CACNA1A mutation causes mixed gain-of-function (hyperpolarizing voltage-dependence of activation, slowed deactivation) and loss-of-function (slowed activation kinetics, reduced current density) effects, resulting in diminished integrated Ca2+ flux during action potential-like stimuli, demonstrating that pathological CaV2.1 mutations do not always represent purely GOF or LOF. Whole-cell patch-clamp recordings and action potential waveform stimuli in tsA-201 cells expressing R1667P and WT CaV2.1 Scientific reports Medium 35655070
2011 Pathogenic CAG repeat expansions in CaV2.1 (SCA6) enhance splicing at the 3' end of the transcript in a repeat-length-dependent manner, increasing levels of a polyQ-encoding CaV2.1 mRNA splice isoform. Splice isoform-specific RNAi targeting this polyQ-encoding variant selectively suppresses the disease-associated protein without affecting the main α1A channel. CaV2.1 mini-gene reporter system; RT-PCR for splice isoform quantitation; siRNA/miRNA-based silencing in human neuronal cell line and other cell-based models Neurobiology of disease Medium 21550405
2004 A CaV2.1 rocker mutation reduces Ca2+ channel current density in Purkinje cells and severely impairs parallel fiber–Purkinje cell synaptic transmission; however, presynaptic function (paired-pulse facilitation, Ca2+ sensitivity) is nearly normal, while postsynaptic AMPA receptor number and density are substantially decreased, indicating that CaV2.1 dysfunction preferentially affects postsynaptic receptor composition. Patch-clamp of acutely dissociated Purkinje cell somas; cerebellar slice recordings; freeze-fracture replica labeling EM for AMPA receptor quantitation The European journal of neuroscience High 17156361
2009 Muscarinic M1 receptor activation modulates CaV2.1 channels in neostriatal neurons via phosphoinositide hydrolysis: PLC inhibition abolishes modulation, PI-4K and PI-3K inhibition prevents reversibility, and intracellular PIP2 supply blocks all muscarinic modulation — establishing a PLC/PI(4,5)P2-dependent signaling pathway for M1 receptor regulation of CaV2.1. Whole-cell patch-clamp in rat neostriatal neurons; pharmacological inhibitors of PLC, PI-3K, PI-4K; intracellular PIP2 dialysis Neuroscience Medium 19883739

Source papers

Stage 0 corpus · 100 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 1842 8898206
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
2010 CaV2.1 channelopathies. Pflugers Archiv : European journal of physiology 175 20204399
2004 Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain : a journal of neurology 171 15483044
2015 CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. European journal of human genetics : EJHG 163 25735478
1999 High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology 156 10371528
1999 A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia. Neurology 147 10408534
2013 Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6. Cell 143 23827678
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 130 32610237
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
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 Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission. Neurology 106 11723274
2001 Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Neurology 104 11320173
1997 Mutations in the Cacnl1a4 calcium channel gene are associated with seizures, cerebellar degeneration, and ataxia in tottering and leaner mutant mice. Mammalian genome : official journal of the International Mammalian Genome Society 101 9060410
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
2021 From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing. Frontiers in neurology 90 33737904
2019 Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice. Brain : a journal of neurology 88 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
2007 Modulation of CaV2.1 channels by Ca2+/calmodulin-dependent protein kinase II bound to the C-terminal domain. Proceedings of the National Academy of Sciences of the United States of America 80 18162541
2005 Modulation of CaV2.1 channels by the neuronal calcium-binding protein visinin-like protein-2. The Journal of neuroscience : the official journal of the Society for Neuroscience 77 16049183
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
2002 Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine. Archives of neurology 70 12056940
2003 Direct interaction and functional coupling between metabotropic glutamate receptor subtype 1 and voltage-sensitive Cav2.1 Ca2+ channel. The Journal of biological chemistry 65 12704197
2012 Cav2.1 in cerebellar Purkinje cells regulates competitive excitatory synaptic wiring, cell survival, and cerebellar biochemical compartmentalization. The Journal of neuroscience : the official journal of the Society for Neuroscience 64 22279216
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
2015 Constitutive and ghrelin-dependent GHSR1a activation impairs CaV2.1 and CaV2.2 currents in hypothalamic neurons. The Journal of general physiology 55 26283199
2006 Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. Molecular and cellular neurosciences 55 17188510
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 54 31628185
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
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
2022 Clinical and genetic characterization of CACNA1A-related disease. Clinical genetics 45 35722745
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
2017 Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia. Scientific reports 44 28566750
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
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 39 31875924
2005 Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene. Journal of the neurological sciences 38 16325861
2001 CACNA1A gene polymorphisms in cluster headache. Cephalalgia : an international journal of headache 38 11843866
2019 Cognitive impairment in children with CACNA1A mutations. Developmental medicine and child neurology 37 31115040
2014 Differential Cav2.1 and Cav2.3 channel inhibition by baclofen and α-conotoxin Vc1.1 via GABAB receptor activation. The Journal of general physiology 37 24688019
2013 Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies. Molecular genetics & genomic medicine 37 24498617
2011 Neurovascular changes in prolonged migraine aura in FHM with a novel ATP1A2 gene mutation. Journal of neurology, neurosurgery, and psychiatry 36 22013243
2001 Investigation of the CACNA1A gene as a candidate for typical migraine susceptibility. American journal of medical genetics 35 11803518
2008 Screen for CACNA1A and ATP1A2 mutations in sporadic hemiplegic migraine patients. Cephalalgia : an international journal of headache 33 18513263
2021 The complexities of CACNA1A in clinical neurogenetics. Journal of neurology 32 34806130
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
2013 Protein kinase Cα and P-type Ca channel CaV2.1 in red blood cell calcium signalling. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 32 23817128
2003 Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits. Annals of neurology 31 14681882
2003 Custom distinctions in the interaction of G-protein beta subunits with N-type (CaV2.2) versus P/Q-type (CaV2.1) calcium channels. The Journal of general physiology 30 12771191
2013 Reduced sleep and low adenosinergic sensitivity in cacna1a R192Q mutant mice. Sleep 29 23288979
2010 Sporadic hemiplegic migraine and epilepsy associated with CACNA1A gene mutation. Epilepsy & behavior : E&B 29 20071244
2016 Next-generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2. Molecular genetics & genomic medicine 28 27066515
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
1998 A Japanese family with spinocerebellar ataxia type 6 which includes three individuals homozygous for an expanded CAG repeat in the SCA6/CACNL1A4 gene. Journal of the neurological sciences 28 9702684
2014 Ankyrin-B regulates Cav2.1 and Cav2.2 channel expression and targeting. The Journal of biological chemistry 27 24394417
2014 Modulation of CaV2.1 channels by neuronal calcium sensor-1 induces short-term synaptic facilitation. Molecular and cellular neurosciences 27 25447945
2012 Ca2+-independent activation of Ca2+/calmodulin-dependent protein kinase II bound to the C-terminal domain of CaV2.1 calcium channels. The Journal of biological chemistry 27 23255606
2010 CaV2.1 (P/Q channel) interaction with synaptic proteins is essential for depolarization-evoked release. Channels (Austin, Tex.) 27 20495360
2004 Presynaptic Cav2.1 and Cav2.2 differentially influence release dynamics at hippocampal excitatory synapses. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 15548655
2002 Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13. Neurology 27 12370474
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
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
2007 Novel CaV2.1 clone replicates many properties of Purkinje cell CaV2.1 current. The European journal of neuroscience 25 18001290
2004 A Purkinje cell specific GoLoco domain protein, L7/Pcp-2, modulates receptor-mediated inhibition of Cav2.1 Ca2+ channels in a dose-dependent manner. Brain research. Molecular brain research 25 15548431
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
2006 A CaV2.1 calcium channel mutation rocker reduces the number of postsynaptic AMPA receptors in parallel fiber-Purkinje cell synapses. The European journal of neuroscience 23 17156361
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
2006 Dominant-negative suppression of Cav2.1 currents by alpha(1)2.1 truncations requires the conserved interaction domain for beta subunits. Molecular and cellular neurosciences 22 17161621
2020 Rare CACNA1A mutations leading to congenital ataxia. Pflugers Archiv : European journal of physiology 21 32458086
2018 Targeting the CACNA1A IRES as a Treatment for Spinocerebellar Ataxia Type 6. Cerebellum (London, England) 21 29374372
2021 A CACNA1A variant associated with trigeminal neuralgia alters the gating of Cav2.1 channels. Molecular brain 20 33413531
2018 New CACNA1A deletions are associated to migraine phenotypes. The journal of headache and pain 20 30167989
2022 CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications. Frontiers in molecular neuroscience 19 35600082
2022 Complex effects on CaV2.1 channel gating caused by a CACNA1A variant associated with a severe neurodevelopmental disorder. Scientific reports 19 35655070
2009 Compensatory regulation of Cav2.1 Ca2+ channels in cerebellar Purkinje neurons lacking parvalbumin and calbindin D-28k. Journal of neurophysiology 19 19906882
2008 CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine. Clinical genetics 19 18400034
2020 CACNA1A Gene Variants in Eight Chinese Patients With a Wide Range of Phenotypes. Frontiers in pediatrics 18 33425808
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
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
2010 CaV2.1 channels are modulated by muscarinic M1 receptors through phosphoinositide hydrolysis in neostriatal neurons. Neuroscience 17 19883739
2009 Knockdown of Cav2.1 calcium channels is sufficient to induce neurological disorders observed in natural occurring Cacna1a mutants in mice. Biochemical and biophysical research communications 17 19854154

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