KCNE4

KCNE4
Identifiers
Aliases	KCNE4, MIRP3, potassium voltage-gated channel subfamily E regulatory subunit 4
External IDs	OMIM: 607775; MGI: 1891125; HomoloGene: 10959; GeneCards: KCNE4; OMA:KCNE4 - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q36.1 Start 223,052,190 bp[1] End 223,198,399 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1|1 C4 Start 78,794,475 bp[2] End 78,797,745 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in saphenous vein gallbladder tibial arteries pericardium smooth muscle tissue Achilles tendon myometrium islet of Langerhans testicle ascending aorta Top expressed in ascending aorta aortic valve calvaria efferent ductule dermis tunica media of zone of aorta condyle carotid body uterus vas deferens More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding voltage-gated ion channel activity transmembrane transporter binding voltage-gated potassium channel activity potassium channel activity delayed rectifier potassium channel activity potassium channel regulator activity voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization Cellular component apical plasma membrane membrane integral component of membrane voltage-gated potassium channel complex Biological process ion transport potassium ion transmembrane transport potassium ion transport regulation of ion transmembrane transport regulation of ventricular cardiac muscle cell membrane repolarization ventricular cardiac muscle cell action potential membrane repolarization during action potential regulation of heart rate by cardiac conduction membrane repolarization during ventricular cardiac muscle cell action potential negative regulation of delayed rectifier potassium channel activity potassium ion export across plasma membrane Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23704 57814 Ensembl ENSG00000152049 ENSMUSG00000047330 UniProt Q8WWG9 Q9WTW3 RefSeq (mRNA) NM_080671 NM_021342 RefSeq (protein) NP_542402 NP_067317 Location (UCSC) Chr 2: 223.05 – 223.2 Mb Chr 1: 78.79 – 78.8 Mb PubMed search [3] [4]
Wikidata
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Potassium voltage-gated channel subfamily E member 4, originally named MinK-related peptide 3 or MiRP3 when it was discovered, is a protein that in humans is encoded by the KCNE4 gene.^[5][6]

Voltage-gated potassium channels (K_v) represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. The KCNE4 gene encodes KCNE4 (originally named MinK-related peptide 3 or MiRP3), a member of the KCNE family of voltage-gated potassium (K_v) channel ancillary or β subunits.^[7]

KCNE4 is best known for modulating the KCNQ1 K_v α subunit, but it also regulates KCNQ4, K_v1.x, K_v2.1, K_v4.x and BK α subunits in heterologous co-expression experiments and/or in vivo. KCNE4 often, but not always, acts as an inhibitory subunit to suppress potassium channel function, but this varies depending on the channel subtype.

KCNE4 strongly inhibits the KCNQ1 potassium channel, which is known to play important roles in human cardiac myocyte repolarization, and in multiple epithelial cell types.^[8] KCNE4 inhibition of KCNQ1 requires calmodulin, which binds to both KCNQ1 and KCNE4.^[9] KCNE4 can also inhibit complexes formed by KCNQ1 and KCNE1.^[10] KCNE4 has no known effect on KCNQ2, KCNQ3 or KCNQ5 channels, but augments activity of KCNQ4 in HEK cells, mesenteric artery^[11] and Xenopus laevis oocytes.^[12]

KCNE4 strongly inhibits K_v1.1 and K_v1.3 channels when co-expressed in HEK cells and in Xenopus laevis oocytes, while leaving K_v1.2 and K_v1.4 currents unaffected.^[13] KCNE4 augments K_v1.5 current and surface expression twofold in CHO cells (but had no effect in Xenopus oocytes). Kcne4 deletion from mice impaired currents attributable to K_v1.5, in ventricular myocytes.^[14]

KCNE4 inhibited K_v2.1 currents by 90% but had little to no effect on currents generated by heteromers of K_v2.1 with the regulatory α subunit K_v6.4.^[15]

KCNE4 slows activation and inactivation of K_v4.2 channels, and induces overshoot upon recovery from inactivation. Co-expression with KChIP2 produces intermediate gating kinetics in complexes with K_v4.2 and KCNE4.^[16] Deletion of Kcne4 in mice impaired ventricular myocyte Ito, a current generated at least in part by K_v4.2.^[14]

Although mouse KCNE4 reportedly had no effect on K_v4.3 when coexpressed in oocytes,^[13] human KCNE4 was found to accelerate inactivation and recovery from inactivation of K_v4.3-KChIP2 complexes.^[17]

KCNE4 has also been found to regulate the large-conductance Ca2+-activated potassium channel, BK. KCNE4 inhibits BK activity by positive-shifting the voltage dependence of BK activation and accelerating BK protein degradation.^[18]

KCNE4 is a type 1 membrane protein, with the transmembrane segment predicted to be alpha-helical. No studies have as yet reported the number of KCNE4 subunits within a functional channel complex; it is likely to be either 2 or 4. The majority of studies of KCNE4 function, structure-function relationships and effects of pathological gene sequence variants within KCNE4 have utilized the widely reported 170 residue version of the protein encoded by exon 2 of the human KCNE4 gene. However, in 2016 a longer form of the KCNE4 protein, termed KCNE4L, was discovered. An additional N-terminal portion of 51 residues, encoded by exon 1 of the human KCNE4 gene, were found to also be expressed in multiple human tissues, extending the human protein to 221 residues, by far the longest of the KCNE subunits. Human KCNE4L exhibits some functional differences to the shorter 170 residue form now also termed KCNE4S. KCNE4L is predicted to also be expressed in other mammals, reptiles, amphibians and fish, although the house mouse (Mus musculus) appears to only express KCNE4S because the KCNE4L start site is lacking in the house mouse genome.^[19]

Human KCNE4L transcripts are most highly expressed in uterus, and next most highly expressed in atria, adrenal gland, lymph nodes, pituitary gland, spleen and ureter. KCNE4L transcript is also detectable in cervix, colon, optic nerve, ovary, oviduct, pancreas, skin, retina, spinal cord, stomach, thymus, and vagina.^[19]

In the rat heart, KCNE4 protein co-localizes with Kv4.2, a channel that KCNE4 also functionally regulates.^[20] In mouse heart, KCNE4 is preferentially expressed in ventricles versus atria, and in young adult males much more than young adult females. This is because cardiac KCNE4 expression is positively regulated by dihydrotestosterone.^[14] In rat mesenteric artery, KCNE4 augments KCNQ4 channel activity to regulate arterial tone.^[21]

A single polymorphism in the KCNE4 intracellular N-terminal domain, E145D, has been reported to affect predisposition to the relatively common chronic cardiac arrhythmia, atrial fibrillation, in Chinese populations,^[22] and to impair the ability of KCNE4 to inhibit KCNQ1.^[23] If KCNE4 inhibits KCNQ1 in the atrium, it is conceivable that removing this inhibition could shorten the atrial effective refractory period, which could predispose to atrial fibrillation, but this mechanism has not yet been substantiated with in vivo data.

• Voltage-gated potassium channel

The 2016 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: Geoffrey W Abbott (30 July 2016). "KCNE4 and KCNE5: K(+) channel regulation and cardiac arrhythmogenesis". Gene. Gene Wiki Review Series. 593 (2): 249–260. doi:10.1016/J.GENE.2016.07.069. ISSN 0378-1119. PMC 5166581. PMID 27484720. Wikidata Q38916407.

• KCNE4+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.