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FLASH GENE
Symbol CACNA1A contributors: mct - updated : 30-04-2014
HGNC name calcium channel, voltage-dependent, P/Q type, alpha 1A subunit
HGNC id 1388
Corresponding disease
BPTI benign paroxysmal torticollis of infancy
EA2 episodic ataxia, type 2
EIEE42 epileptic encephalopathy, early infantile, 42
MHP1 migraine, familial hemiplegic, 1
SCA6 spinocerebellar ataxia 6
Location 19p13.13      Physical location : 13.317.255 - 13.617.274
Synonym name
  • brain calcium channel 1
  • voltage- gated calcium channel subunit alpha Cav2.1
  • calcium channel, L type, alpha-1 polypeptide isoform 4
  • Synonym symbol(s) CACNL1A4, SCA6, MHP1, MHP, Cav2.1, EA2, APCA, HPCA, FHM
    DNA
    TYPE functioning gene
    STRUCTURE 300.02 kb     57 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    motif repetitive sequence   triplet
    text structure
  • structure gene
  • containing a CAG repeat in 3'utr (exon 47)
  • MAPPING cloned Y linked N status confirmed
    Map pter - D19S221 - D19S914 - CACNA1A - D19S840 - D19S892 - cen
    Text see MHP1
    RNA
    TRANSCRIPTS type messenger
    text at least five other alternative forms
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    47 splicing 8632 - 2263 - -
    47 splicing 8628 - 2506 - -
    46 splicing 8626 - 2261 - -
    47 splicing 8641 - 2266 - -
    47 splicing 8646
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Lymphoid/Immunetonsils   highly
    Nervousbrainhindbraincerebellumcerebellar cortexhighly
    Reproductivefemale systemovary  highly
    Visualeye   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
     granular cell
    NervousPurkinje cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • four transmembrane domains (4TM) of high homology
  • six alpha helical membrane spanning segments
  • S4 domains functioning as the voltage sensor of calcium channel, the four loops between TMS5/S6 composing the pore forming unit
  • a C terminal CAG repeat
  • conjugated GlycoP
    HOMOLOGY
    interspecies ortholog to Cacna1a, Mus musculus
    ortholog to Cacna1a, Rattus norvegicus
    ortholog to cacna1aa, Danio rerio
    Homologene
    FAMILY
  • calcium channel alpha-1 subunits family
  • CATEGORY transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,nucleus
    text integral membrane protein
    basic FUNCTION
  • calcium voltage-gated channel (VDCC), P/Q type, fore forming subunit, mediating the entry of calcium ions into excitable cells
  • involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death
  • essential in the generation of gamma-band activity and resultant cognitive function
  • CACNA1A, CACNA1B, preferentially accumulate at neuromuscular junctions (NMJs) active zones and play essential role in synaptic transmission in conjunction with the active zone protein BSN
  • involved in pre- and postsynaptic Ca(2+) signaling, gene expression, and several genetic neurological disorders
  • had a greater fractional contribution to synaptic transmission at low frequencies than at high frequencies
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS development , nervous system
    PATHWAY
    metabolism
    signaling
    a component
  • a multisubunit complex composed of alpha-1, beta, alpha2 / delta and gamma subunits
  • INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • CA2+
  • protein
  • synaptotagmin I, SYT1
  • differential regulation of CACNA1A channels by Calmodulin, HPCAL4, CABP1, and other neurospecific Ca2+-binding proteins is a potentially important determinant of Ca2+ entry in neurotransmission
  • CSNK2B, AMIGO2, TUBB2B, ARHGAP22
  • NOVA2 controls alternative splicing in CACNA1A and CACNA1B
  • role for CALB2 in directly modulating effectors such as CACNA1A, which may have major consequences for Ca(2+) signaling and neuronal excitability
  • presynaptic scaffolding protein BSN localizes specifically CACNA1A to active zones via molecular interaction with the RIM-binding proteins (RBPs)
  • GHSR-mediated inhibition of CACNA1A, CACNA1B attenuates GABA release in hypothalamic neurons, a mechanism that could contribute to neuronal activation through the disinhibition of postsynaptic neurons
  • cell & other
    REGULATION
    inhibited by HPCAL4, that inhibits inactivation and enhances facilitation of CACNA1A channels
    Other modulated by Ca2+-binding protein 1
    ASSOCIATED DISORDERS
    corresponding disease(s) EA2 , MHP1 , SCA6 , BPTI , EIEE42
    Susceptibility
  • to idiopathic generalized epilepsy
  • to epileptic encephalopathies (EEs)
  • Variant & Polymorphism SNP , other
  • deletions that include CACNA1A and a single truncating mutation have been associated with EE
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyataxia 
    lysosomal accumulation and storage of mutant SCA6 within Purkinje cells is associated with toxicity, therefore decreasing the mutant load either by activating the autophagic response or by lysosomal exocytosis may be an effective therapeutic strategy for
    ANIMAL & CELL MODELS
  • Cacna1a mutated in tg and tg(la) mice leads to selective degeneration of cerebellar neurons
  • Cacna1a deficient mice develop a rapidly progressive neurological deficit with specific characteristics of ataxia and dystonia before dying approximately 3-4 weeks after birth
  • knockin mouse model carrying the human pure FHM-1 R192Q mutation display ncreased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, anda reduced threshold and increased velocity of cortical spreading depression
  • mice lacking P/Q-type calcium channels (Cav2.1) have no cortical gamma-band-dependent columnar activation involving cortical inhibitory interneuron activity
  • mice expressing hyperexpanded polyglutamine (Sca6(84Q))
  • developed progressive motor impairment and aggregation of mutant Ca(V)2.1 channels
  • mice with R192Q mutation in Cacna1 gene show a more than twofold enhanced adjustment of behavioral wheel-running activity and electroencephalographic patterns, and enhanced shifts of electrical activity of suprachiasmatic nucleus neurons in vivo
  • female S218L and R192Q Cacna1a mutant mice are more susceptible to spreading depression and neurological deficits than males
  • Cacna1a(S218L) mice display an exquisite sensitivity to cortical spreading depression (CSD), with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus
  • MPI-118Q KI mice faithfully recapitulated the key phenotypic features of SCA6 and revealed a lysosomal contribution to SCA6 pathogenesis