Affinage

CACNA1S

Voltage-dependent L-type calcium channel subunit alpha-1S · UniProt Q13698

Length
1873 aa
Mass
212.3 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CACNA1S encodes CaV1.1, the pore-forming α1S subunit of the skeletal muscle dihydropyridine receptor, which functions chiefly as a voltage sensor that conformationally couples membrane depolarization to RyR1-mediated SR Ca2+ release during excitation-contraction (EC) coupling (PMID:23321639, PMID:34546289). Among its four voltage-sensing domains, VSD-I dominates pore opening, contributing the most energy toward stabilizing open states, while VSDs II–IV activate faster in a manner compatible with RyR1 Ca2+ release kinetics (PMID:34546289). Functional expression and EC coupling depend on STAC3: its interaction with the proximal C-terminus is necessary and sufficient for minimal coupling, whereas its interaction with the II-III loop facilitates and enhances conformational coupling with RyR1 (PMID:40779452). The IQ motif is a structural and functional coupling site, required for both Ca2+ current and evoked Ca2+ transients (PMID:22162637), and mediates the weak calmodulin-dependent Ca2+-dependent inactivation that distinguishes CaV1.1 from CaV1.2 (PMID:17899167, PMID:18718913). Ca2+ permeation through the pore is dispensable for EC coupling but drives CaMKII activation, SR store refilling, and downstream Ras/Erk/mTORC1 signaling controlling protein synthesis and fiber type, as well as a CaMKII→NOS pathway regulating CD36 distribution and β-oxidation (PMID:25717360, PMID:26245899). Beyond contraction, CaV1.1 acts as a voltage sensor for IP3-dependent Ca2+ signals and frequency-dependent ATP release through pannexin-1, with which it is reciprocally coupled, linking excitation to transcriptional programs governing fiber phenotype (PMID:23321639, PMID:34636893). The channel is regulated by multiple partners: caveolin-3 binds the I-II loop and sets conductance (PMID:21262376); JP-45 binds the I-II loop and C-terminus to control functional channel expression (PMID:16638807); the γ1 subunit reduces current density specifically in the exon-29-containing adult isoform (PMID:35349630); and PKA is anchored via AKAP15 to the proteolytically cleaved distal C-terminus for cAMP-dependent potentiation (PMID:15793008). CACNA1S is the causative gene for hypokalaemic periodic paralysis, in which S4 arginine mutations create anomalous gating pore currents in the voltage sensor domains (PMID:8012389, PMID:7847370, PMID:29386226, PMID:34463712), and dominant and recessive mutations also cause a distinct DHPR congenital myopathy (PMID:28012042).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1995 High

    Establishing CACNA1S as the cause of hypokalaemic periodic paralysis and localizing the predominant mutations to S4 voltage-sensor arginines defined the channel's voltage-sensing region as the disease-relevant locus.

    Evidence Genome-wide linkage in three families and mutation/cosegregation analysis in 16 HypoPP families

    PMID:7847370 PMID:8012389

    Open questions at the time
    • Linkage and sequencing did not establish the biophysical mechanism by which S4 mutations cause paralysis
    • Incomplete penetrance of R528H was unexplained
  2. 2005 High

    Identifying in vivo proteolytic cleavage of the distal C-terminus and its docking of AKAP15/PKA explained how cAMP-dependent signaling potentiates CaV1.1 activity.

    Evidence Yeast two-hybrid mapping, mass spectrometry of purified skeletal muscle CaV1.1, and expression in nonmuscle cells

    PMID:15793008

    Open questions at the time
    • Did not establish the physiological trigger or magnitude of PKA potentiation in intact muscle
    • Protease responsible for cleavage not identified
  3. 2008 High

    Defining the molecular basis of calmodulin binding and Ca2+-dependent inactivation pinpointed IQ-motif residues that distinguish CaV1.1 from CaV1.2 gating behavior.

    Evidence Whole-cell patch-clamp and FRET in myotubes plus native-gel CaM binding and reciprocal IQ-motif mutagenesis

    PMID:17899167 PMID:18718913

    Open questions at the time
    • Functional consequence of weak CDI for muscle physiology not resolved
    • Did not address whether CaM contributes to RyR1 coupling
  4. 2009 Medium

    Characterizing the exon-29-lacking splice variant showed that developmental isoform switching tunes CaV1.1 voltage-dependence and Ca2+ influx, and kinetic modeling of HypoPP histidine mutants revealed loss-of-function gating shifts.

    Evidence Reconstitution in dysgenic myotubes with patch-clamp/Ca2+ imaging, and heterologous HEK-293 expression with kinetic modeling

    PMID:17333249 PMID:19134469

    Open questions at the time
    • The HypoPP gating studies used a heterologous/cardiac channel analog and were not independently replicated
    • Loss-of-function gating did not yet explain paradoxical depolarization
  5. 2011 Medium

    Demonstrating that the IQ motif is essential for EC coupling and that caveolin-3 binds the I-II loop to set conductance expanded the inventory of structural elements and regulatory partners controlling channel function.

    Evidence IQ-motif mutant rescue in dysgenic myotubes and GST pulldown/co-IP plus electrophysiology for caveolin-3

    PMID:21262376 PMID:22162637

    Open questions at the time
    • IQ-motif coupling role demonstrated in single lab
    • Mechanism by which caveolin-3 P104L lowers conductance not fully resolved
  6. 2013 Medium

    Identifying CaV1.1 as the voltage sensor for IP3 signals and pannexin-1-dependent ATP release, and a bumetanide-responsive role for chloride gradient in HypoPP, separated the channel's excitation-transcription role from contraction and clarified disease modulation.

    Evidence Null-myotube rescue with ATP/IP3/transcription readouts, and R528H knock-in mice with low-K+ challenge and pharmacology

    PMID:23321639 PMID:24142145

    Open questions at the time
    • Single-lab excitation-transcription findings
    • How chloride gradient interacts with gating pore currents not established
  7. 2015 Medium

    Knock-in of a pore mutation that abolishes Ca2+ permeation dissociated ion conduction from EC coupling, revealing a CaV1.1→CaMKII→Ras/Erk/mTORC1 and →NOS/CD36 metabolic signaling axis, while β1a peptide and raptor studies further defined modulation of the EC coupling complex.

    Evidence E1014K knock-in mice with imaging/biochemistry/force assays, β1a peptide perfusion with bilayer recordings, and muscle-specific raptor knockout with binding assays

    PMID:24507594 PMID:25431931 PMID:25717360 PMID:26245899

    Open questions at the time
    • Pathway linkages partly correlative and from single labs
    • Direct molecular targets of CaMKII in this context not fully mapped
  8. 2016 Medium

    Discovery that CACNA1S mutations cause a distinct DHPR congenital myopathy, that TnT3 transcriptionally regulates Cacna1s, and that a non-muscle CaV1.1 splice variant supports TCR Ca2+ entry broadened the channel's disease and physiological scope.

    Evidence Exome sequencing with patient-myotube Ca2+ assays, promoter-reporter and in vivo knockdown for TnT3, and T-cell siRNA with TCR Ca2+ flux

    PMID:26815481 PMID:26892246 PMID:28012042

    Open questions at the time
    • T-cell CaV1.1 role from single study
    • Genotype-phenotype correlation for congenital myopathy mutations incomplete
  9. 2021 High

    Voltage-clamp fluorometry resolved domain-specific roles of the four VSDs and established VSD-I as the primary driver of pore opening, while gating-pore-current measurements across S4 mutations established the anomalous-conduction mechanism of HypoPP requiring charge neutralization.

    Evidence Opto-electrophysiology with allosteric modeling, and cut-open oocyte voltage clamp of multiple HypoPP mutants with charge-conserving negative controls

    PMID:29386226 PMID:34463712 PMID:34546289 PMID:34636893

    Open questions at the time
    • How VSD-specific kinetics translate to RyR1 conformational coupling in situ not directly shown
    • Reciprocal CaV1.1/Panx1 coupling characterized in single lab
  10. 2022 High

    Dissecting γ1 subunit modulation showed that current reduction is exon-29-dependent and allosteric, linking adult splice isoform identity to channel current density.

    Evidence Patch-clamp in HEK293 with γ1 and CaV1.1a/CaV1.1e plus alanine mutagenesis and structural modeling

    PMID:35349630

    Open questions at the time
    • Allosteric mechanism inferred from modeling rather than direct structure
    • Physiological role of γ1 current reduction in adult muscle not established
  11. 2025 High

    Domain-specific dissection of STAC3 binding resolved that the proximal C-terminus interaction is necessary and sufficient for functional expression while the II-III loop interaction facilitates RyR1 coupling, integrating STAC3 into the EC coupling machinery and a human disorder.

    Evidence Selective STAC3-interaction disruption rescues in dysgenic myotubes with Ca2+ imaging/electrophysiology and patient genetic analysis

    PMID:40779452

    Open questions at the time
    • Structural basis of the two STAC3 contacts not resolved
    • How STAC3 binding cooperates with other partners during trafficking unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How VSD-specific gating, STAC3 binding, and the CaV1.1-RyR1 conformational interface integrate into a unified structural mechanism of EC coupling, and how this is perturbed across the spectrum of disease mutations, remains unresolved.
  • No high-resolution structural model of the gating-coupling transition is captured in the corpus
  • Mechanistic basis of incomplete penetrance and genotype-phenotype variability in HypoPP not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0060089 molecular transducer activity 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-397014 Muscle contraction 3
Partners
CACNB1CALM1CAV3JSRP1PANX1RYR1STAC3
Complex memberships
dihydropyridine receptor (DHPR)skeletal muscle triad EC coupling complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 CACNA1S (CACNL1A3) maps to chromosome 1q31-32, co-segregating with the hypokalaemic periodic paralysis (HypoPP) locus without recombinants, establishing it as the causative gene for HypoPP. Genome-wide linkage analysis using polymorphic dinucleotide repeats and intragenic microsatellite markers in three European families Nature genetics High 8012389
1995 Missense mutations Arg528His and Arg1239His in the voltage-sensor segment S4 of CACNA1S are the predominant causative mutations for hypokalemic periodic paralysis type 1 (HypoPP-1), with the Arg528His mutation showing incomplete penetrance. DNA sequence analysis and cosegregation analysis in 16 Caucasian HypoPP families American journal of human genetics High 7847370
2005 The distal C terminus of CaV1.1 (CACNA1S) is proteolytically cleaved in vivo at alanine 1664, and the cleaved distal C-terminal domain (aa 1802–1841) noncovalently associates with a proximal C-terminal region (aa 1556–1612) of the channel. This complex serves as the docking site for AKAP15 and PKA, which are required for cAMP-dependent potentiation of Ca2+ channel activity. Yeast two-hybrid deletion mapping, tandem mass spectrometry of purified skeletal muscle CaV1.1, and expression in mammalian nonmuscle cells Proceedings of the National Academy of Sciences of the United States of America High 15793008
2006 JP-45, a junctional SR protein, directly interacts with two domains of CaV1.1: the I-II loop (via the alpha-interacting domain) and the C-terminal region. The beta1a subunit reduces JP-45 interaction with the I-II loop. JP-45 overexpression decreases peak charge-movement and shifts voltage-dependence; JP-45 depletion decreases both CaV1.1 content and peak charge-movement, demonstrating that JP-45 regulates functional expression of CaV1.1. Co-immunoprecipitation, GST pulldown, charge-movement recordings in C2C12 myotubes with JP-45 overexpression or siRNA depletion Journal of cell science High 16638807
2007 CaV1.1 (CACNA1S) exhibits Ca2+-dependent inactivation (CDI) mediated by calmodulin: CDI is maximal (~30%) at potentials evoking peak inward current, eliminated by Ba2+ substitution or BAPTA, and abolished by expression of Ca2+-binding-deficient CaM1234. FRET imaging confirmed direct association of CaM with CaV1.1 in dysgenic myotubes. Whole-cell patch-clamp in mouse myotubes, FRET between fluorescently tagged CaV1.1 and CaM, overexpression of dominant-negative CaM1234 Pflugers Archiv : European journal of physiology High 17899167
2008 Sequence differences in the IQ motif of CaV1.1 (His1532, Met1537) compared to CaV1.2 (Tyr1657, Lys1662) underlie the weak CaM binding and absence of Ca2+-dependent inactivation in CaV1.1. Reciprocal substitution of these two residues into CaV1.2 eliminates CDI, while introduction of CaV1.2 residues into CaV1.1 confers CaM binding. Native gel electrophoresis of CaM binding to C-terminal peptides, expression of mutant channels in intact myotubes, whole-cell electrophysiology The Journal of biological chemistry High 18718913
2009 A CaV1.1 splice variant lacking exon 29 (CaV1.1Δ29) shows 30-mV left-shifted voltage-dependence of activation, eightfold increased current density, and accelerated kinetics compared to the adult isoform. This variant is expressed at high levels (~80%) in developing myotubes and supports skeletal EC coupling. Its robust Ca2+ influx substantially contributes to depolarization-induced Ca2+ transients in developing muscle. Expression of GFP-tagged CaV1.1Δ29 in dysgenic (α1S-null) myotubes, patch-clamp and Ca2+ imaging, analysis of human and mouse muscle expression levels Biophysical journal High 19134469
2009 R528H and R1239H/G mutations in CaV1.1 HypoPP-1 have 'loss-of-function' features: D4/S4 mutations shift channel equilibrium toward closed states (reduced open probability, shorter openings, smaller currents); D2/S4 mutation (R528H) slows activation. HypoPP histidine mutants favor a second open state (O2) with possibly lower channel selectivity. Heterologous expression of wild-type and HypoPP-1 mutations in HEK-293 cells, whole-cell patch-clamp, global kinetic model fitting Pflugers Archiv : European journal of physiology Medium 17333249
2011 The IQ motif (residues mutated to IQ→AA) of CaV1.1 is essential for Ca2+ current and excitation-contraction coupling: dysgenic myotubes expressing YFP-CaV1.1(AA) show neither Ca2+ currents nor evoked Ca2+ transients, despite normal targeting to the sarcolemma and normal maximal charge movement (Qmax), suggesting the IQ motif is a structural and functional coupling site between DHPR and RyR. Expression of IQ-motif mutant CaV1.1 in dysgenic myotubes, whole-cell Ca2+ current recordings, Ca2+ transient imaging, charge movement recordings Journal of biomedicine & biotechnology Medium 22162637
2011 Caveolin-3 directly interacts with the I-II loop of CaV1.1 (apparent affinity ~60 nM), co-localizes with DHPR within T-tubular membrane, and co-immunoprecipitates from triadic membrane preparations. Expression of the P104L caveolin-3 mutant or siRNA knockdown of caveolin-3 significantly decreases L-type Ca2+ channel maximal conductance. GST-fusion pulldown with CaV1.1 I-II loop peptides, co-immunoprecipitation from triadic membranes, immunolocalization, whole-cell patch-clamp in C2C12 myotubes with siRNA or mutant caveolin-3 expression The international journal of biochemistry & cell biology High 21262376
2013 CaV1.1 (α1S subunit) acts as voltage sensor for activation of IP3-dependent Ca2+ signals that regulate gene expression in skeletal muscle, and is required for frequency-dependent ATP release through pannexin-1 channels. Myotubes lacking CaV1.1-α1S release almost no ATP after electrical stimulation. ATP release and frequency-specific transcriptional programs (fast-to-slow transition) at 20 Hz (but not 90 Hz) require CaV1.1 function independently of its ion channel activity. Electrical stimulation of CaV1.1-α1S null myotubes, pharmacological blockade/activation of CaV1.1, ATP release measurements, IP3 measurements, gene expression analysis in adult flexor digitorum brevis fibers Journal of cell science High 23321639
2015 Ca2+ binding/permeation through the CaV1.1 pore (E1014K pore mutation abolishes it) is coupled to CaMKII activation and sarcoplasmic reticulum Ca2+ store refilling during sustained muscle activity. Loss of this permeation leads to decreased CaMKII and downstream Ras/Erk/mTORC1 signaling, reduced muscle protein synthesis, increased fatigue, decreased fiber size, and increased type IIb fibers. Knock-in mouse with E1014K CaV1.1 pore mutation, Ca2+ imaging, western blotting, proximity ligation assays, SUnSET protein synthesis assay, isolated muscle force-frequency and fatigue measurements Skeletal muscle High 25717360
2015 CaV1.1-mediated CaMKII activation (via Ca2+ permeation through E1014K pore) regulates the intracellular distribution of fatty acid transport protein CD36 and mitochondrial β-oxidation in skeletal muscle, through a CaV1.1→CaMKII→NOS pathway. Blocking this pathway decreases energy expenditure and increases body fat. E1014K knock-in mice, Ca2+ imaging, Western blotting, immunohistochemistry, pharmacological NOS inhibition, metabolic phenotyping The Journal of biological chemistry Medium 26245899
2016 Troponin T3 (TnT3) transcriptionally regulates Cacna1s (CaV1.1) expression by binding to the Cacna1s promoter. Knocking down TnT3 in vivo downregulates CaV1.1; TnT3 overexpression increases Cacna1s promoter activity; this effect requires the TnT3 nuclear localization sequence. Calpain inhibition prevents TnT3 fragmentation, restoring Cacna1s/CaV1.1 levels and muscle force in aging mice. In vivo TnT3 knockdown, Cacna1s promoter-reporter assays, TnT3 nuclear localization sequence truncation, calpain inhibitor (BDA-410) treatment in aged mice, muscle force measurements Aging cell Medium 26892246
2016 Recessive and dominant mutations in CACNA1S cause a distinct congenital myopathy (DHPR congenital myopathy) characterized by SR dilatation and impaired Ca2+ release induced by depolarization in cultured myotubes, with decreased CACNA1S protein levels. Exome sequencing in 11 patients, Ca2+ release measurements in cultured myotubes from patients, protein level quantification by western blot Acta neuropathologica Medium 28012042
2016 T cells express a specific CaV1.1 splice variant lacking exon 29 but with five new N-terminal exons substituting for exons 1 and 2. Knockdown of CaV1.1 in T cells abrogates Ca2+ entry after TCR stimulation, demonstrating that CaV1.1 channels are required for TCR-mediated Ca2+ entry. Sequencing and cloning of T cell CaV1.1 cDNA, overexpression in HEK293 cells, siRNA knockdown in T cells with Ca2+ flux measurements after TCR stimulation PloS one Medium 26815481
2018 Coexpression of STAC3 dramatically increases plasma membrane expression of human CaV1.1 in Xenopus oocytes, enabling functional studies. Using this system, HypoPP mutations R528H and R528G in S4 of domain II are shown to generate gating pore currents (anomalous conductance through the voltage sensor domain); R528H does not conduct protons unlike other R/H HypoPP mutations. Cut-open oocyte voltage clamp of human CaV1.1 coexpressed with α2-δ1b, β1a, and STAC3 in Xenopus oocytes; ionic current and gating charge measurements The Journal of general physiology High 29386226
2021 Each of the four voltage-sensing domains (VSDs) of human CaV1.1 has unique biophysical properties: VSD-I activation kinetics match ionic current activation and contributes the most energy (~75 meV) toward stabilizing open states, driving CaV1.1 pore opening primarily. VSDs II, III, and IV activate faster, compatible with RYR1 Ca2+ release kinetics. The R174W charge-neutralizing mutation in VSD-I abolishes CaV1.1 current at physiological potentials without affecting other VSDs. Opto-electrophysiology (voltage clamp fluorometry) measuring VSD-specific fluorescence changes plus ionic currents in human CaV1.1 expressed in Xenopus oocytes; allosteric model analysis; VSD-I R174W mutant characterization The Journal of general physiology High 34546289
2021 CaV1.1 domain III (DIII) HypoPP mutations R897S and R900G generate gating pore currents, while R900S does not. R897S (R1 of DIII) produces exceptionally large gating pore currents correlating with severe clinical phenotype. The previously reported charge-conserving R897K does not produce gating pore currents, consistent with requirement for charge neutralization to create anomalous VSD conduction. Expression of DIII CaV1.1 HypoPP mutants with STAC3 in Xenopus oocytes, cut-open oocyte voltage clamp for gating pore current measurement The Journal of general physiology High 34463712
2021 CaV1.1 and Pannexin-1 (Panx1) regulate each other reciprocally in skeletal muscle. CaV1.1 knockdown causes chronically elevated extracellular ATP at rest, disrupting normal Panx1 activity control. Conversely, Panx1 knockdown impairs both transcription activation and CaV1.1 control of contraction. This bidirectional coupling links excitation-contraction and excitation-transcription processes. Knockdown of CaV1.1 or Panx1 in adult skeletal muscle fibers, measurement of extracellular ATP, Ca2+ transients, force, and gene expression The Journal of general physiology Medium 34636893
2022 The γ1 subunit reduces CaV1.1 current density by >50% specifically for the adult (CaV1.1a, contains exon 29) splice variant but not the embryonic (CaV1.1e, lacks exon 29) variant. This current-reducing effect depends on inclusion of exon 29 and is distinct from γ1's effect on voltage-dependence of inactivation (which occurs in both variants). Molecular modeling suggests ionic interactions between the IVS3-S4 loop (encoded by exon 29) and γ1, with allosteric mechanism rather than direct contact mediating current reduction. Stable HEK293 cell lines expressing α2δ-1, β3, STAC3 with γ1 and CaV1.1a or CaV1.1e; patch-clamp electrophysiology; alanine substitution mutagenesis; molecular structure modeling The Journal of general physiology High 35349630
2025 STAC3 interaction with the CaV1.1 proximal C-terminus is necessary and sufficient for CaV1.1 functional expression and minimal EC coupling, while STAC3 interaction with the II-III loop of CaV1.1 is not essential for EC coupling but facilitates and enhances conformational coupling with RyR1. A patient with STAC3 disorder carrying a mutation deleting the II-III loop-interacting domain confirms this functional distinction. Expression of CaV1.1 constructs with selective STAC3-interaction domain disruptions in dysgenic myotubes, Ca2+ imaging, electrophysiology, patient genetic analysis JCI insight High 40779452
2015 Raptor (mTORC1) ablation in skeletal muscle alters the ratio of ryanodine receptors to DHPRs (CaV1.1), increases voltage sensor-uncoupled RyRs, and increases frequency and mass of elementary calcium release events (sparks) in FDB fibers, while not significantly affecting global Ca2+ transient amplitude, indicating mTORC1 signaling modulates the composition and function of the EC coupling complex including CaV1.1. Muscle-specific raptor knockout mice, 3H-ryanodine and 3H-PN200-110 equilibrium binding, Ca2+ imaging in FDB fibers, hyper-osmotic shock spark analysis The Biochemical journal Medium 25431931
2020 CACNA1S haploinsufficiency renders cells and mice resistant to New World arenavirus (Junín and Tacaribe) infection, and reduces the dosage of VGCC antagonists needed to block infection, demonstrating that the α1S voltage-gated calcium channel is required for cellular binding and entry of these arenaviruses. CACNA1S haploinsufficient cell lines and mice infected with Junín and Tacaribe virus; VGCC antagonist dose-response experiments Proceedings of the National Academy of Sciences of the United States of America Medium 32719120
2021 MRTF-A (myocardin-related transcription factor A) activates CACNA1S transcription by binding to a CarG box in the CACNA1S promoter. In mdx mice, MRTF-A expression is decreased and phosphorylation increased, correlating with reduced CACNA1S expression and impaired Ca2+ release through CaV1.1. Promoter-reporter assay with CarG box, ChIP/binding assay, qPCR and western blot in mdx mice, Ca2+ release measurements Journal of biosciences Low 33969828
2015 The β1a490-508 peptide (19 residues from C-terminal tail of the CaV1.1 β1a subunit) is sufficient to potentiate voltage-dependent Ca2+ release flux (~49% increase) and RyR1 channel activity in adult skeletal muscle fibers, and also increases CaV1.1 Ca2+ currents, demonstrating that the β1a C-terminal tail modulates EC coupling between CaV1.1 and RyR1. Voltage-clamp of adult skeletal muscle fibers with peptide perfusion, Ca2+ release flux measurements, RyR1 single-channel bilayer recordings; scrambled peptide negative control Biophysical journal Medium 24507594
2015 Antibody previously reported to detect CACNA1S (CaV1.1) at ON bipolar cell dendritic tips in retina cross-reacts with GPR179; mass spectrometry of immunoprecipitated protein failed to detect CACNA1S peptides. This negative finding undermines proposed role of CACNA1S in DBC (depolarizing bipolar cell) signal transduction based solely on immunohistochemistry. Western blot, immunoprecipitation followed by mass spectrometric peptide identification, immunohistochemistry in GPR179 mutant retinas and HEK293T cells expressing GPR179 Visual neuroscience Medium 27471951
2013 CaV1.1-R528H knock-in mice develop hypokalaemic periodic paralysis, and treatment with bumetanide (a chloride cotransporter inhibitor) protects against muscle weakness from low K+ challenge in vitro and loss of muscle excitability in vivo, demonstrating a critical role of the chloride gradient in modulating susceptibility to ictal weakness caused by CACNA1S mutations. CaV1.1-R528H knock-in mouse model, in vitro low-K+ challenge with force measurements, in vivo glucose+insulin infusion with EMG, bumetanide treatment Brain : a journal of neurology Medium 24142145

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Mapping of the hypokalaemic periodic paralysis (HypoPP) locus to chromosome 1q31-32 in three European families. Nature genetics 203 8012389
2016 Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. Acta neuropathologica 98 28012042
1995 Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families. American journal of human genetics 98 7847370
2009 The role of CACNA1S in predisposition to malignant hyperthermia. BMC medical genetics 95 19825159
2008 Effects of presynaptic mutations on a postsynaptic Cacna1s calcium channel colocalized with mGluR6 at mouse photoreceptor ribbon synapses. Investigative ophthalmology & visual science 92 18952919
2005 Sites of proteolytic processing and noncovalent association of the distal C-terminal domain of CaV1.1 channels in skeletal muscle. Proceedings of the National Academy of Sciences of the United States of America 84 15793008
2009 A CaV1.1 Ca2+ channel splice variant with high conductance and voltage-sensitivity alters EC coupling in developing skeletal muscle. Biophysical journal 74 19134469
2015 Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness. Anesthesiology 61 25658027
2001 Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia. Clinical genetics 61 11260227
1993 Assignment of the human gene for the alpha 1 subunit of the skeletal muscle DHP-sensitive Ca2+ channel (CACNL1A3) to chromosome 1q31-q32. Genomics 54 7916735
2013 Cav1.1 controls frequency-dependent events regulating adult skeletal muscle plasticity. Journal of cell science 48 23321639
2015 Ca(2+) permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca(2+) signaling to sustain muscle function. Skeletal muscle 40 25717360
2010 A report of fulminant malignant hyperthermia in a patient with a novel mutation of the CACNA1S gene. Canadian journal of anaesthesia = Journal canadien d'anesthesie 40 20431982
2005 Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family. Journal of molecular medicine (Berlin, Germany) 37 15726306
2002 Mutations linked to familial hypokalaemic periodic paralysis in the calcium channel alpha1 subunit gene (Cav1.1) are not associated with thyrotoxic hypokalaemic periodic paralysis. Clinical endocrinology 37 11940049
1994 Genetic heterogeneity in hypokalemic periodic paralysis (hypoPP). Human genetics 36 7959693
2016 Comparison of pathogenicity prediction tools on missense variants in RYR1 and CACNA1S associated with malignant hyperthermia. British journal of anaesthesia 35 27147545
1997 Identification of mutations in the CACNL1A3 gene in 13 families of Scandinavian origin having hypokalemic periodic paralysis and evidence of a founder effect in Danish families. American journal of medical genetics 33 9066893
2006 The junctional SR protein JP-45 affects the functional expression of the voltage-dependent Ca2+ channel Cav1.1. Journal of cell science 31 16638807
2021 The distinct role of the four voltage sensors of the skeletal CaV1.1 channel in voltage-dependent activation. The Journal of general physiology 30 34546289
2018 Stac3 enhances expression of human CaV1.1 in Xenopus oocytes and reveals gating pore currents in HypoPP mutant channels. The Journal of general physiology 30 29386226
2009 Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a South American family. Journal of human genetics 30 19779499
2015 Ca2+ Binding/Permeation via Calcium Channel, CaV1.1, Regulates the Intracellular Distribution of the Fatty Acid Transport Protein, CD36, and Fatty Acid Metabolism. The Journal of biological chemistry 29 26245899
2016 CACNA1S expression in mouse retina: Novel isoforms and antibody cross-reactivity with GPR179. Visual neuroscience 28 27471951
2015 Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families. Anaesthesia and intensive care 28 25735680
2013 Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis. Brain : a journal of neurology 27 24142145
2007 Ca2+/CaM-dependent inactivation of the skeletal muscle L-type Ca2+ channel (Cav1.1). Pflugers Archiv : European journal of physiology 27 17899167
1986 Immunohistochemical localization of the MHS-5 antigen in principal cells of human seminal vesicle epithelium. The Anatomical record 27 3706782
2015 Regulation of L-type Voltage Gated Calcium Channel CACNA1S in Macrophages upon Mycobacterium tuberculosis Infection. PloS one 26 25915405
1996 The structure of the gene encoding the human skeletal muscle alpha 1 subunit of the dihydropyridine-sensitive L-type calcium channel (CACNL1A3). Genomics 26 8838325
2016 Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice. Aging cell 25 26892246
2005 Skeletal muscle dihydropyridine-sensitive calcium channel (CACNA1S) gene mutations in chinese patients with hypokalemic periodic paralysis. The American journal of the medical sciences 25 15711422
2016 Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia. Physiological genomics 24 28011884
2008 Early onset of hypokalaemic periodic paralysis caused by a novel mutation of the CACNA1S gene. Journal of medical genetics 23 18835861
2009 Severe respiratory phenotype caused by a de novo Arg528Gly mutation in the CACNA1S gene in a patient with hypokalemic periodic paralysis. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 22 19822448
2004 A family of hypokalemic periodic paralysis with CACNA1S gene mutation showing incomplete penetrance in women. Internal medicine (Tokyo, Japan) 22 15098604
2008 Sequence differences in the IQ motifs of CaV1.1 and CaV1.2 strongly impact calmodulin binding and calcium-dependent inactivation. The Journal of biological chemistry 21 18718913
2021 Mutations associated with hypokalemic periodic paralysis: from hotspot regions to complete analysis of CACNA1S and SCN4A genes. Neurogenetics 20 34608571
2017 Rhabdomyolysis and fluctuating asymptomatic hyperCKemia associated with CACNA1S variant. European journal of neurology 20 29193480
2014 Localization of Cacna1s to ON bipolar dendritic tips requires mGluR6-related cascade elements. Investigative ophthalmology & visual science 19 24519419
2011 A novel mutation in CACNA1S gene associated with hypokalemic periodic paralysis which has a gender difference in the penetrance. Journal of molecular neuroscience : MN 18 21845430
2021 Gating pore currents occur in CaV1.1 domain III mutants associated with HypoPP. The Journal of general physiology 16 34463712
2014 β1a490-508, a 19-residue peptide from C-terminal tail of Cav1.1 β1a subunit, potentiates voltage-dependent calcium release in adult skeletal muscle fibers. Biophysical journal 15 24507594
2020 CACNA1S haploinsufficiency confers resistance to New World arenavirus infection. Proceedings of the National Academy of Sciences of the United States of America 14 32719120
2016 Progressive impairment of CaV1.1 function in the skeletal muscle of mice expressing a mutant type 1 Cu/Zn superoxide dismutase (G93A) linked to amyotrophic lateral sclerosis. Skeletal muscle 14 27340545
2011 Caveolin-3 is a direct molecular partner of the Cav1.1 subunit of the skeletal muscle L-type calcium channel. The international journal of biochemistry & cell biology 14 21262376
2006 Exclusion of linkage of the RYR1, CACNA1S, and ATP2A1 genes to recurrent exertional rhabdomyolysis in Thoroughbreds. American journal of veterinary research 14 16881852
2020 PharmGKB summary: very important pharmacogene information for CACNA1S. Pharmacogenetics and genomics 13 31851124
2016 T Cell Receptor Mediated Calcium Entry Requires Alternatively Spliced Cav1.1 Channels. PloS one 13 26815481
2018 Genetic Evidence Supporting the Role of the Calcium Channel, CACNA1S, in Tooth Cusp and Root Patterning. Frontiers in physiology 12 30319441
2007 Gating of the HypoPP-1 mutations: I. Mutant-specific effects and cooperativity. Pflugers Archiv : European journal of physiology 12 17333249
2023 CACNA1S Variant Associated With a Myalgic Myopathy Phenotype. Neurology 10 37679049
2022 Calcium current modulation by the γ1 subunit depends on alternative splicing of CaV1.1. The Journal of general physiology 10 35349630
2015 Raptor ablation in skeletal muscle decreases Cav1.1 expression and affects the function of the excitation-contraction coupling supramolecular complex. The Biochemical journal 10 25431931
1994 Refined localization of the alpha 1-subunit of the skeletal muscle L-type voltage-dependent calcium channel (CACNL1A3) to human chromosome 1q32 by in situ hybridization. Genomics 10 8188298
2021 Pannexin-1 and CaV1.1 show reciprocal interaction during excitation-contraction and excitation-transcription coupling in skeletal muscle. The Journal of general physiology 9 34636893
2018 Distinct transcriptomic changes in E14.5 mouse skeletal muscle lacking RYR1 or Cav1.1 converge at E18.5. PloS one 9 29543863
1994 The use of a seminal vesicle specific protein (MHS-5 antigen) for diagnosis of agenesis of vas deferens and seminal vesicles in azoospermic men. Journal of andrology 9 7721663
2023 A novel CACNA1S gene variant in a child with hypokalemic periodic paralysis: a case report and literature review. BMC pediatrics 8 37784084
2016 Novel regulations of MEF2-A, MEF2-D, and CACNA1S in the functional incompetence of adipose-derived mesenchymal stem cells by induced indoxyl sulfate in chronic kidney disease. Cytotechnology 8 27550174
2015 Mutation analysis of CACNA1S and SCN4A in patients with hypokalemic periodic paralysis. Molecular medicine reports 8 26252573
2011 The IQ motif is crucial for Cav1.1 function. Journal of biomedicine & biotechnology 8 22162637
2007 Hypokalaemic periodic paralysis due to the CACNA1S R1239H mutation in a large African family. Neuromuscular disorders : NMD 8 17418573
2007 Myopathy as the first symptom of hypokalemic periodic paralysis--case report of a girl from a Polish family with CACNA1S (R1239G) mutation. Advances in medical sciences 8 18229654
1989 Purification of low molecular weight forms of seminal vesicle specific antigen by immunoaffinity chromatography on bound monoclonal antibody MHS-5. Journal of reproductive immunology 8 2600936
2019 Hypokalemic periodic paralysis due to CACNA1S gene mutation. Neurosciences (Riyadh, Saudi Arabia) 7 31380823
2023 CACNA1S mutation-associated dental anomalies: A calcium channelopathy. Oral diseases 6 36825457
2020 The expanding phenotype of hypokalemic periodic paralysis in a Japanese family with p.Val876Glu mutation in CACNA1S. Molecular genetics & genomic medicine 6 32104981
2019 Strength and muscle structure preserved during long-term therapy in a patient with hypokalemic periodic paralysis (Cav1.1-R1239G). Journal of neurology 6 30937521
2003 Identification of new polymorphisms in the CACNA1S gene. Clinical chemistry and laboratory medicine 6 12636044
2000 Does the A3333G mutation in the CACNL1A3 gene, detected in malignant hyperthermia, also occur in central core disease? Genetic testing 6 11216663
2023 A Mutation in CACNA1S Is Associated with Multiple Supernumerary Cusps and Root Maldevelopment. Diagnostics (Basel, Switzerland) 5 36900039
2023 Congenital Myopathy as a Phenotypic Expression of CACNA1S Gene Mutation: Case Report and Systematic Review of the Literature. Genes 5 37510268
2015 The R900S mutation in CACNA1S associated with hypokalemic periodic paralysis. Neuromuscular disorders : NMD 5 26433613
2017 De novo Mutation in CACNA1S Gene in a 20-Year-Old Man Diagnosed with Metabolic Myopathy. Archives of Iranian medicine 4 29048924
2015 Apparent lack of physical or functional interaction between CaV1.1 and its distal C terminus. The Journal of general physiology 4 25779869
2007 Absence of regulation of the T-type calcium current by Cav1.1, beta1a and gamma1 dihydropyridine receptor subunits in skeletal muscle cells. Pflugers Archiv : European journal of physiology 4 17906876
2002 No evidence of mutations in the CACNA1S gene in the UK malignant hyperthermia population. British journal of anaesthesia 4 12066739
1997 [Mutation analysis of the CACNL1A3 gene in Japanese hypokalemic periodic paralysis families]. Nihon rinsho. Japanese journal of clinical medicine 4 9436445
2023 Case report: A novel CACNA1S mutation associated with hypokalemic periodic paralysis. Frontiers in neurology 3 37840943
2020 Morphological Alterations of the Sarcotubular System in Permanent Myopathy of Hereditary Hypokalemic Periodic Paralysis with a Mutation in the CACNA1S Gene. Journal of neuropathology and experimental neurology 3 33184660
1992 The detection of prostate specific antigen, MHS-5, and other markers in invasive prostate cancer and seminal vesicle. The Journal of urology 3 1373781
2025 Terahertz wave induces the structural and functional changes in voltage-gated calcium channel Cav1.1: A molecular dynamics study. The Journal of chemical physics 2 40277085
2025 STAC3 binding to CaV1.1 II-III loop is nonessential but critically supports skeletal muscle excitation-contraction coupling. JCI insight 2 40779452
2024 Two zebrafish cacna1s loss-of-function variants provide models of mild and severe CACNA1S-related myopathy. Human molecular genetics 2 37930228
2024 Case report: Dihydropyridine receptor (CACNA1S) congenital myopathy, a novel phenotype with early onset periodic paralysis. Frontiers in neurology 2 38426167
2024 Early-Onset Autosomal Dominant Myopathy with Vacuolated Fibers and Tubular Aggregates but No Periodic Paralysis, in a Patient with the c.1583G>A (p.R528H) mutation in the CACNA1S Gene. Journal of neuromuscular diseases 2 38788083
2023 Biallellic variants in CACNA1S cause fetal akinesia sequence, progressive hydrops and stillbirth. Prenatal diagnosis 2 38111203
2021 Case Report: A Novel CACNA1S Mutation Associated With Hypokalemic Periodic Paralysis in a Chinese Family. Frontiers in genetics 2 34777470
2021 Vacuolar Myopathy Associated to CACNA1S Mutation as a Rare Cause of Late-Onset Limb-Girdle Myopathy: A Case Report. Cureus 2 34804722
2007 Gating of the HypoPP-1 mutations: II. Effects of a calcium-channel agonist BayK 8644. Pflugers Archiv : European journal of physiology 2 17333247
2006 [R1239H mutation of CACNA1S gene in a Chinese family with hypokalaemic periodic paralysis]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 16767662
2025 CACNA1S-associated triadopathy presenting with myalgia, muscle weakness, and asymptomatic hyperCKemia. Therapeutic advances in neurological disorders 1 40018084
2025 Troponin T3 ameliorates sepsis-induced diaphragm dysfunction in rats through modulation of Cacna1s. Biochemical and biophysical research communications 1 40460485
2024 Core myopathy in two siblings with a biallelic variant in the CACNA1S gene-A case series study. Clinical case reports 1 39104734
2022 Novel CACNA1S mutation in hypokalaemic periodic paralysis. BMJ case reports 1 35039355
2021 MRTF-A regulates Ca2+ release through CACNA1S. Journal of biosciences 1 33969828
2020 CACNA1S Arg528Cys mutation in a young Chinese man with thyrotoxic hypokalemic periodic paralysis. Clinical case reports 1 33088529
2011 [The relationships between the single nueleotide polymorphisms of CACNA1S gene 11 exon and thyrotoxic hypokalemic periodic paralysis in the people of Han Nationality in Sichuan Province, China]. Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi 1 21774221
2008 Cloning, sequencing and identification of single nucleotide polymorphisms of partial sequence on the porcine CACNA1S gene. Science in China. Series C, Life sciences 1 18368309

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