Details for: KCNA2

Gene ID: 3737

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: KCNA2

Ensembl ID: ENSG00000177301

Description: potassium voltage-gated channel subfamily A member 2

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • cerebral cortex neuron CL0010012
    CSI 5.24
    rCSI 21.36%
    PRS 81.69
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 3.72
    rCSI 13.38%
    PRS 73.13
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.64
    rCSI 3.28%
    PRS 73.01
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.28
    rCSI 2.93%
    PRS 76.37
  • inhibitory interneuron CL0000498
    CSI 2.23
    rCSI 5.15%
    PRS 79.61
  • VIP GABAergic cortical interneuron CL4023016
    CSI 1.85
    rCSI 2.21%
    PRS 75.28
  • retinal ganglion cell CL0000740
    CSI 1.59
    rCSI 3.52%
    PRS 77.96
  • astrocyte of the cerebral cortex CL0002605
    CSI 1.58
    rCSI 3.54%
    PRS 75.72
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.53
    rCSI 2.57%
    PRS 75.21
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.52
    rCSI 2.45%
    PRS 76.35
  • central nervous system neuron CL2000029
    CSI 1.52
    rCSI 11.18%
    PRS 80
  • L6b glutamatergic cortical neuron CL4023038
    CSI 1.43
    rCSI 4.47%
    PRS 76.56
  • L2/3 intratelencephalic projecting glutamatergic neuron CL4030059
    CSI 1.37
    rCSI 2.97%
    PRS 77.84
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 1.24
    rCSI 4.08%
    PRS 77.15
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.16
    rCSI 27.97%
    PRS 73.2
  • direct pathway medium spiny neuron CL4023026
    CSI 1.15
    rCSI 27.43%
    PRS 72.93
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 0.98
    rCSI 2.35%
    PRS 78.14
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 0.79
    rCSI 1.92%
    PRS 72.94
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 0.76
    rCSI 2.85%
    PRS 75.46
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 0.69
    rCSI 2.16%
    PRS 78.43
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 0.68
    rCSI 4%
    PRS 75.7
  • ON midget ganglion cell CL4033046
    CSI 0.32
    rCSI 6.52%
    PRS 80.1

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

Loading network (please wait)...

Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [KCNA2](/details-gene/3737) encodes the Potassium voltage-gated channel subfamily A member 2, a protein that forms a critical component of the voltage-gated potassium channel complex. These channels are fundamental to regulating neuronal excitability by contributing to the repolarization phase of the action potential. Expression data shows that [KCNA2](/details-gene/3737) is a highly significant gene within the central nervous system, with pronounced expression in diverse neuronal subtypes, including [cerebral cortex neuron](/details-cell/CL0010012)s, both glutamatergic and GABAergic varieties. Its function is essential for processes such as [neuronal action potential](/details-go/GO:0019228) propagation and the maintenance of membrane potential. Genetic variants in [KCNA2](/details-gene/3737) are associated with neurological disorders, as indicated by its clinical association with OMIM entry [176262](https://omim.org/entry/176262). ## Cellular Roles and Expression Landscape The expression profile of [KCNA2](/details-gene/3737) firmly establishes its role as a key regulator of neuronal function, particularly within the cerebral cortex. **Overall**, the gene shows its highest significance in [cerebral cortex neuron](/details-cell/CL0010012) (CSI: 5.24), indicating it is a defining marker for this broad cell category. Its importance extends across functionally distinct neuronal populations. It is highly significant in excitatory neurons, such as the [L5 extratelencephalic projecting glutamatergic cortical neuron](/details-cell/CL4023041) (CSI: 3.72), as well as a wide array of inhibitory interneurons, including [pvalb GABAergic cortical interneuron](/details-cell/CL4023018) (CSI: 2.64), [sst GABAergic cortical interneuron](/details-cell/CL4023017) (CSI: 2.28), and [VIP GABAergic cortical interneuron](/details-cell/CL4023016) (CSI: 1.85). This broad expression across both excitatory and inhibitory circuits suggests a fundamental role in maintaining the delicate balance of cortical activity. Beyond the cortex, its expression in [retinal ganglion cell](/details-cell/CL0000740) points to a broader role in neuronal signaling throughout the CNS. While predominantly neuronal, its moderate significance in [astrocyte of the cerebral cortex](/details-cell/CL0002605) may suggest a secondary role in glial cell function. ## Pathways and Molecular Function The molecular functions of [KCNA2](/details-gene/3737) are intrinsically linked to its role as an ion channel. It is a core component of the [Voltage-gated potassium channel complex](/details-go/GO:0008076) and exhibits [Voltage-gated potassium channel activity](/details-go/GO:0005249), specifically contributing to [Delayed rectifier potassium channel activity](/details-go/GO:0005251). This activity is central to the biological process of [Potassium ion transmembrane transport](/details-go/GO:0071805), which is essential for repolarizing the cell membrane during a [Neuronal action potential](/details-go/GO:0019228). Consistent with its expression in neurons, [KCNA2](/details-gene/3737) is localized to critical subcellular compartments for neural signaling, including the [Axon](/details-go/GO:0030424), [Dendrite](/details-go/GO:0030425), [Presynaptic membrane](/details-go/GO:0042734), and [Postsynaptic membrane](/details-go/GO:0045211). Its specific localization to the [Juxtaparanode region of axon](/details-go/GO:0044224) is critical for regulating nerve impulse propagation in myelinated axons, as supported by research showing its association with Caspr2 ([Link](https://doi.org/10.1016/s0896-6273(00)81049-1)). Functionally, these roles are integrated within the broader context of the [Neuronal system](/details-reactome/R-HSA-112316) pathway, specifically as part of the [Voltage gated potassium channels](/details-reactome/R-HSA-1296072) machinery. ## Research Directions Given the critical role of [KCNA2](/details-gene/3737) in governing neuronal excitability, future research should focus on its contribution to neurological disease and its potential as a therapeutic target. **Proposed Hypotheses:** 1. Disease-associated mutations in [KCNA2](/details-gene/3737) found in patients with epilepsy or developmental encephalopathy directly alter the channel's biophysical properties (e.g., voltage-sensitivity, activation/inactivation kinetics), leading to network hyperexcitability in cortical circuits involving [L5 extratelencephalic projecting glutamatergic cortical neuron](/details-cell/CL4023041) and [pvalb GABAergic cortical interneuron](/details-cell/CL4023018)s. 2. Post-translational modifications of the KCNA2 protein, such as phosphorylation, dynamically regulate its localization and function at the presynaptic terminal, thereby modulating neurotransmitter release and contributing to mechanisms of synaptic plasticity. This is supported by studies showing its regulation by tyrosine phosphorylation ([Link](https://doi.org/10.1007/s004240000406)). **Experimental Approach:** To test the first hypothesis, a powerful approach would be to use CRISPR-Cas9 to introduce a specific patient-derived missense mutation into the endogenous [KCNA2](/details-gene/3737) locus in human induced pluripotent stem cells (iPSCs). These edited iPSCs, along with their isogenic wild-type controls, would be differentiated into a mixed culture of cortical neurons. Multi-electrode array (MEA) recordings could then be used to assess network-level activity, such as synchronized bursting and overall firing rates. Furthermore, single-cell patch-clamp electrophysiology would allow for a detailed characterization of potassium currents and action potential waveforms in individual neurons, directly linking the specific mutation to a quantifiable cellular and network-level phenotype. **Therapeutic Potential:** As a voltage-gated ion channel, [KCNA2](/details-gene/3737) is a highly "druggable" target. For neurological disorders caused by gain-of-function mutations that lead to neuronal hyperexcitability (e.g., certain forms of epilepsy), a therapeutic strategy of **inhibition** with specific channel blockers would be pursued. Conversely, for loss-of-function mutations leading to neuronal dysfunction, channel activators or potentiators could restore normal function. The primary challenge for any [KCNA2](/details-gene/3737)-targeted therapy is its widespread and vital role across numerous neuronal subtypes; therefore, developing highly specific small molecule modulators or gene therapies with cell-type-specific delivery systems will be essential to minimize off-target effects and achieve a viable therapeutic window.

Genular Protein ID: 1853824512

Symbol: KCNA2_HUMAN

Name: Potassium voltage-gated channel subfamily A member 2

UniProtKB Accession Codes:

P16389 A0A024R0D3 A8K1Z6 Q86XG6

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CORUM 1 CTD 1 ChEBI 1 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 4 DrugCentral 1 EMBL 6 Ensembl 7 ExpressionAtlas 1 GO 37 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 5 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PIR 1 PRINTS 4 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 1 RefSeq 8 Rhea 1 SMART 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 19912772

Title: Human potassium channel genes: molecular cloning and functional expression.

PubMed ID: 19912772

DOI: 10.1016/1044-7431(90)90004-n

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 8495559

Title: Heteromultimeric assembly of human potassium channels. Molecular basis of a transient outward current?

PubMed ID: 8495559

DOI: 10.1161/01.res.72.6.1326

PubMed ID: 10624965

Title: Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels.

PubMed ID: 10624965

DOI: 10.1016/s0896-6273(00)81049-1

PubMed ID: 11211111

Title: Role of receptor protein tyrosine phosphatase alpha (RPTPalpha) and tyrosine phosphorylation in the serotonergic inhibition of voltage-dependent potassium channels.

PubMed ID: 11211111

DOI: 10.1007/s004240000406

PubMed ID: 11086297

Title: Subunit composition and novel localization of K+ channels in spinal cord.

PubMed ID: 11086297

DOI: 10.1002/1096-9861(20000101)429:1<166::aid-cne13>3.0.co;2-y

PubMed ID: 16473933

Title: Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells.

PubMed ID: 16473933

DOI: 10.1073/pnas.0511197103

PubMed ID: 17917103

Title: Ionic channel function in action potential generation: current perspective.

PubMed ID: 17917103

DOI: 10.1007/s12035-007-8001-0

PubMed ID: 19713757

Title: The molecular basis for the actions of Kvbeta1.2 on the opening and closing of the Kv1.2 delayed rectifier channel.

PubMed ID: 19713757

DOI: 10.4161/chan.3.5.9558

PubMed ID: 20220134

Title: Biochemical characterization of kappaM-RIIIJ, a Kv1.2 channel blocker: evaluation of cardioprotective effects of kappaM-conotoxins.

PubMed ID: 20220134

DOI: 10.1074/jbc.m109.068486

PubMed ID: 22649228

Title: Altered distribution of juxtaparanodal kv1.2 subunits mediates peripheral nerve hyperexcitability in type 2 diabetes mellitus.

PubMed ID: 22649228

DOI: 10.1523/jneurosci.0719-12.2012

PubMed ID: 23769686

Title: Activation of lysophosphatidic acid receptor by gintonin inhibits Kv1.2 channel activity: involvement of tyrosine kinase and receptor protein tyrosine phosphatase alpha.

PubMed ID: 23769686

DOI: 10.1016/j.neulet.2013.05.048

PubMed ID: 24613312

Title: SLEEPLESS is a bifunctional regulator of excitability and cholinergic synaptic transmission.

PubMed ID: 24613312

DOI: 10.1016/j.cub.2014.02.026

PubMed ID: 25477152

Title: Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: proposal for a new channelopathy.

PubMed ID: 25477152

DOI: 10.1111/cge.12542

PubMed ID: 25751627

Title: De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.

PubMed ID: 25751627

DOI: 10.1038/ng.3239

PubMed ID: 27864847

Title: Diagnostic targeted resequencing in 349 patients with drug-resistant pediatric epilepsies identifies causative mutations in 30 different genes.

PubMed ID: 27864847

DOI: 10.1002/humu.23149

PubMed ID: 32833227

Title: Tracking the motion of the KV1.2 voltage sensor reveals the molecular perturbations caused by a de novo mutation in a case of epilepsy.

PubMed ID: 32833227

DOI: 10.1113/jp280438

PubMed ID: 34576077

Title: A novel KCNA2 variant in a patient with non-progressive congenital ataxia and epilepsy: functional characterization and sensitivity to 4-aminopyridine.

PubMed ID: 34576077

DOI: 10.3390/ijms22189913

PubMed ID: 35439054

Title: An epilepsy-associated KV1.2 charge-transfer-center mutation impairs KV1.2 and KV1.4 trafficking.

PubMed ID: 35439054

DOI: 10.1073/pnas.2113675119

PubMed ID: 37883018

Title: Two epilepsy-associated variants in KCNA2 (KV 1.2) at position H310 oppositely affect channel functional expression.

PubMed ID: 37883018

DOI: 10.1113/jp285052

Sequence Information:

  • Length: 499
  • Mass: 56717
  • Checksum: 4B03F1B46A826C39
  • Sequence:
    • MTVATGDPAD EAAALPGHPQ DTYDPEADHE CCERVVINIS GLRFETQLKT LAQFPETLLG 
DPKKRMRYFD PLRNEYFFDR NRPSFDAILY YYQSGGRLRR PVNVPLDIFS EEIRFYELGE 
EAMEMFREDE GYIKEEERPL PENEFQRQVW LLFEYPESSG PARIIAIVSV MVILISIVSF 
CLETLPIFRD ENEDMHGSGV TFHTYSNSTI GYQQSTSFTD PFFIVETLCI IWFSFEFLVR 
FFACPSKAGF FTNIMNIIDI VAIIPYFITL GTELAEKPED AQQGQQAMSL AILRVIRLVR 
VFRIFKLSRH SKGLQILGQT LKASMRELGL LIFFLFIGVI LFSSAVYFAE ADERESQFPS 
IPDAFWWAVV SMTTVGYGDM VPTTIGGKIV GSLCAIAGVL TIALPVPVIV SNFNYFYHRE 
TEGEEQAQYL QVTSCPKIPS SPDLKKSRSA STISKSDYME IQEGVNNSNE DFREENLKTA 
NCTLANTNYV NITKMLTDV