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FLASH GENE

Symbol

CACNA1A

contributors: mct - updated : 07-12-2021

HGNC name	calcium channel, voltage-dependent, P/Q type, alpha 1A subunit
HGNC id	1388

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001174080 (transcript variant 5) 47 splicing 8632 NP_001167551 - 2263 - 2021 34320921 NM_001127222 (transcript variant 4) 47 splicing 8628 NP_001120694 - 2506 - 2021 34320921 NM_001127221 (transcript variant 3) 46 splicing 8626 NP_001120693 - 2261 - 2021 34320921 NM_000068 (transcript variant 1) 47 splicing 8641 NP_000059 - 2266 - 2021 34320921 NM_023035 (transcript variant 2) 47 splicing 8646 NP_075461 - 2512 - 2021 34320921

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Lymphoid/Immune tonsils       highly Nervous brain hindbrain cerebellum cerebellar cortex highly Reproductive female system ovary     highly Visual eye       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol   granular cell Nervous Purkinje 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,cytoplasm
	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
	System Type Disorder Pubmed neurology ataxia   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