Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

KCNA1 (Q09470) - Overview - Molecular Target Synopsis

Protein


KCNA1, Potassium voltage-gated channel subfamily A member 1
UniProt Q09470

Also Known as KCNA1_HUMAN, KCNA1

Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the kidney (PubMed:19903818). Contributes to the regulation of the membrane potential and nerve signaling, and prevents neuronal hyperexcitability (PubMed:17156368). Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:19912772). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNA7, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:12077175, PubMed:17156368). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation of delayed rectifier potassium channels (PubMed:12077175, PubMed:17156368). In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA1 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure (PubMed:19912772, PubMed:19968958, PubMed:19307729, PubMed:19903818). In contrast, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (PubMed:17156368). Regulates neuronal excitability in hippocampus, especially in mossy fibers and medial perforant path axons, preventing neuronal hyperexcitability. Response to toxins that are selective for KCNA1, respectively for KCNA2, suggests that heteromeric potassium channels composed of both KCNA1 and KCNA2 play a role in pacemaking and regulate the output of deep cerebellar nuclear neurons (By similarity). May function as down-stream effector for G protein-coupled receptors and inhibit GABAergic inputs to basolateral amygdala neurons (By similarity). May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA) release (By similarity). Plays a role in regulating the generation of action potentials and preventing hyperexcitability in myelinated axons of the vagus nerve, and thereby contributes to the regulation of heart contraction (By similarity). Required for normal neuromuscular responses (PubMed:11026449, PubMed:17136396). Regulates the frequency of neuronal action potential firing in response to mechanical stimuli, and plays a role in the perception of pain caused by mechanical stimuli, but does not play a role in the perception of pain due to heat stimuli (By similarity). Required for normal responses to auditory stimuli and precise location of sound sources, but not for sound perception (By similarity). The use of toxins that block specific channels suggest that it contributes to the regulation of the axonal release of the neurotransmitter dopamine (By similarity). Required for normal postnatal brain development and normal proliferation of neuronal precursor cells in the brain (By similarity). Plays a role in the reabsorption of Mg(2+) in the distal convoluted tubules in the kidney and in magnesium ion homeostasis, probably via its effect on the membrane potential (PubMed:23903368, PubMed:19307729). Homotetramer and heterotetramer with other channel-forming alpha subunits, such as KCNA2, KCNA4, KCNA5, KCNA6 and KCNA7 (PubMed:12077175, PubMed:17156368). Channel activity is regulated by interaction with the beta subunits KCNAB1 and KCNAB2 (PubMed:12077175, PubMed:17156368). Identified in a complex with KCNA2 and KCNAB2 (PubMed:11086297). Interacts (via C-terminus) with the PDZ domains of DLG1, DLG2 and DLG4 (By similarity). Interacts with LGI1 within a complex containing LGI1, KCNA4 and KCNAB1 (By similarity). Interacts (via N-terminus) with STX1A; this promotes channel inactivation (By similarity). Interacts (via N-terminus) with the heterodimer formed by GNB1 and GNG2; this promotes channel inactivation (By similarity). Can interact simultaneously with STX1A and the heterodimer formed by GNB1 and GNG2 (By similarity). Interacts (via cytoplasmic N-terminal domain) with KCNRG; this inhibits channel activity (PubMed:19968958). Interacts with ANK3; this inhibits channel activity (PubMed:23903368).

Isoforms / Transcripts (Protein Coding)


Protein Length Ensembl Gene Ensembl Transcript Ensembl Protein Uniprot Isoform
669ENSG00000111262ENST00000382545ENSP00000371985
495Q09470-1

Drugs


KCNA1 is targeted by Approved Drug Dalfampridine. (see details)
Dalfampridine

Sub-cellular localization


UniProt: KCNA1 is active in the following subcellular-locations: axon, cell junction, cell membrane, cell projection, cytoplasmic vesicle, dendrite, endoplasmic reticulum, membrane, perikaryon, presynaptic cell membrane, synapse.
GO terms: KCNA1 is active in the following subcellular-locations: apical plasma membrane, axon, axon terminus, calyx of Held, cell junction, cell surface, cytoplasmic vesicle, cytosol, dendrite, endoplasmic reticulum, glutamatergic synapse, integral component of membrane, integral component of plasma membrane, integral component of postsynaptic membrane, integral component of presynaptic membrane, juxtaparanode region of axon, neuronal cell body, paranode region of axon, perikaryon, plasma membrane, presynaptic membrane, synapse, voltage-gated potassium channel complex.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project KCNA1 has gain in 5 cell-lines, loss in 3 cell-lines and no signal in 997 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: MCF7, HL_60, SK_OV_3

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: NCI-H209, NCI-H446, NCI-H345

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, NHLF, HSMM

(see details)

RNA Interference


KCNA1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: . (see details)

3D Structures


For KCNA1 there are:
1 structures (1 chains) solved
0 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


KCNA1 has been screened with 202 compounds (245 bioactivities), 127 compounds have bioactivities that show binding affinity of <= 500nM (130 bioactivities). (see details)