SCN2A

Sodium channel protein type 2 subunit alpha, also known as Na_v1.2, is a membrane protein encoded by the SCN2A gene in humans.^[5] It represents one member of the sodium channel alpha subunit gene family. The SCN2A gene is located on chromosome 2 (2q24.3) in proximity to two other voltage-gated sodium channel genes, namely SCN1A and SCN9A.^[6] Na_v1.2 is distributed throughout the human central nervous system where it plays a major role in the initiation and propagation of action potentials. It is absent from peripheral tissues.^[6] Pathologic mutations in the SCN2A gene cause a broad spectrum of neurological conditions, such as epilepsy, autism spectrum disorders and/or developmental delay, called SCN2A-related disorders.^[7]

SCN2A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KAV, 4JPZ
Identifiers
Aliases	SCN2A, BFIC3, BFIS3, BFNIS, EIEE11, HBA, HBSCI, HBSCII, NAC2, Na(v)1.2, Nav1.2, SCN2A1, SCN2A2, sodium voltage-gated channel alpha subunit 2, DEE11, EA9
External IDs	OMIM: 182390; MGI: 98248; HomoloGene: 75001; GeneCards: SCN2A; OMA:SCN2A - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q24.3 Start 165,194,993 bp[1] End 165,392,310 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 C1.3|2 38.61 cM Start 65,451,115 bp[2] End 65,597,791 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in middle temporal gyrus Brodmann area 23 cerebellar vermis entorhinal cortex cerebellar hemisphere parietal lobe postcentral gyrus superior frontal gyrus right hemisphere of cerebellum endothelial cell Top expressed in piriform cortex lobe of cerebellum cerebellar vermis primary motor cortex amygdala anterior amygdaloid area dorsomedial hypothalamic nucleus subiculum cingulate gyrus ventromedial nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function sodium channel activity voltage-gated ion channel activity ion channel activity voltage-gated sodium channel activity Cellular component voltage-gated sodium channel complex integral component of membrane membrane intrinsic component of plasma membrane sodium channel complex plasma membrane node of Ranvier integral component of plasma membrane intracellular anatomical structure intercalated disc T-tubule axon paranode region of axon glutamatergic synapse integral component of presynaptic membrane Biological process membrane depolarization during action potential sodium ion transport regulation of ion transmembrane transport ion transport transmembrane transport myelination neuronal action potential sodium ion transmembrane transport nervous system development intrinsic apoptotic signaling pathway in response to osmotic stress neuron apoptotic process memory cellular response to hypoxia Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6326 110876 Ensembl ENSG00000136531 ENSMUSG00000075318 UniProt Q99250 B1AWN6 RefSeq (mRNA) NM_001040142 NM_001040143 NM_021007 NM_001371246 NM_001371247 NM_001099298 NM_001346679 NM_001346680 RefSeq (protein) NP_001035232 NP_001035233 NP_066287 NP_001358175 NP_001358176 NP_001092768 NP_001333608 NP_001333609 Location (UCSC) Chr 2: 165.19 – 165.39 Mb Chr 2: 65.45 – 65.6 Mb PubMed search [3] [4]
Wikidata
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Structure

The SCN2A gene is composed of 27 exons and comprises more than 150 kilobases. There are two major splice variants known, a neonatal isoform and an adult isoform, which differ in one amino acid at position 209 (Asn versus Asp).^[6] The neonatal isoform might limit neuronal excitability during development.^[7]: 23 The voltage-gated sodium channel Na_v1.2 encoded by the SCN2A gene consists of 2005 amino acids.^[6] This single polypeptide forms a pseudotetrameric channel of four similar domains (I - IV) where each domain contains 6 transmembrane segments, including a voltage sensing region, a pore forming region and an ion-selectivity filter.^[8] In the living organism, Na_v1.2 is a transmembrane glycoprotein complex composed of a large alpha subunit (encoded by the SCN2A gene) and one or more regulatory beta subunits (encoded by SCNxB genes).^[9]

Function

The principal function of Na_v1.2, similar to other members of the voltage-gated sodium channel family, is to mediate sodium influx into neurons upon membrane depolarization, thereby generating and propagating action potentials across distinct neuronal subtypes.^[6]

Na_v1.2 functions mainly in excitatory neurons in cortical structures similar to Na_v1.6,^[6] whereas expression of Na_v1.1 (encoded by the SCN1A gene) is found in mutual distinct, inhibitory neuronal classes.^[10] However, the distribution of Na_v1.2 changes during development. Na_v1.2 channels are initially expressed at the axon initial segments (the site of action potential initiation) of excitatory pyramidal cells in the hippocampus and cortex, but their levels decline during development. At the age of 1–2 years Na_v1.6 gradually becomes the predominant channel type at the distal axon initial segment and axonal nodes of Ranvier as neurons mature. At this stage, Na_v1.2 is restricted to the portion of the axon initial segment closest to the cell body^[6] and in dendrites.^[7] In mature neurons, Na_v1.2 is distributed only throughout unmyelinated axons.^[7] In contrast, its expression pattern in the cerebellum seems to persist throughout development, suggesting distinct roles for Na_v1.2 in mature neurons of the neocortex and cerebellum.^[6] When Na_v1.6 takes over the initiation of action potentials, Na_v1.2 might play a crucial role in driving their backpropagation into dendrites. This backpropagation could impact activity-dependent processes such as synaptic maturation, plasticity, and gene transcription.^[6][7]

The activity of Na_v1.2 is influenced by several factors, such as protein-protein interactions, posttranslational modifications (e.g. phosphorylation), and changes in intracellular Ca2+ concentration.^[7]

Clinical significance

Mutations in the SCN2A gene can cause a broad spectrum of disorders collectively referred to as SCN2A-related disorders. These include cases of autism,^[6] self-limited epilepsy, early infantile developmental and epileptic encephalopathy, later onset developmental and epileptic encephalopathy, infantile spasms, SCN2A-related disorders without epilepsy, episodic ataxia, and further movement disorders.^[7] Two major groups of SCN2A mutations can be distinguished based on their functional consequences and response to seizure medication: gain of function mutations, typically associated with seizure onset within the first three months of life, and loss of function mutations, in which seizures begin after the first three months or may never occur. The former group tends to benefit from treatment with sodium channel blockers, whereas in the latter, such treatment is often ineffective or may even exacerbate seizures.^[11] Notably, SCN2A is known to be the most prominent genetic risk factor for autism-spectrum-disorders.^[6]

SCN2A gene mutations have also been identified in bitemporal glucose hypometabolism,^[12] and bipolar disorder.^[13]

See also

• paralytic - SCN2A ortholog in Drosophila