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]

Function

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]

Structure

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]

Tissue distribution

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]

Clinical significance

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.

See also

• Voltage-gated potassium channel

Notes

References

1. GRCh38: Ensembl release 89: ENSG00000152049 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000047330 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA (April 1999). "MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia". Cell. 97 (2): 175–87. doi:10.1016/S0092-8674(00)80728-X. PMID 10219239. S2CID 8507168.
6. "Entrez Gene: KCNE4 potassium voltage-gated channel, Isk-related family, member 4".
7. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA (April 1999). "MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia". Cell. 97 (2): 175–87. doi:10.1016/S0092-8674(00)80728-X. PMID 10219239. S2CID 8507168.
8. Grunnet M, Jespersen T, Rasmussen HB, Ljungstrøm T, Jorgensen NK, Olesen SP, Klaerke DA (July 2002). "KCNE4 is an inhibitory subunit to the KCNQ1 channel". The Journal of Physiology. 542 (Pt 1): 119–30. doi:10.1113/jphysiol.2002.017301. PMC 2290389. PMID 12096056.
9. Ciampa EJ, Welch RC, Vanoye CG, George AL (February 2011). "KCNE4 juxtamembrane region is required for interaction with calmodulin and for functional suppression of KCNQ1". The Journal of Biological Chemistry. 286 (6): 4141–9. doi:10.1074/jbc.M110.158865. PMC 3039368. PMID 21118809.
10. Lundquist AL, Manderfield LJ, Vanoye CG, Rogers CS, Donahue BS, Chang PA, Drinkwater DC, Murray KT, George AL (February 2005). "Expression of multiple KCNE genes in human heart may enable variable modulation of I(Ks)". Journal of Molecular and Cellular Cardiology. 38 (2): 277–87. doi:10.1016/j.yjmcc.2004.11.012. PMID 15698834.
11. Jepps TA, Carr G, Lundegaard PR, Olesen SP, Greenwood IA (December 2015). "Fundamental role for the KCNE4 ancillary subunit in K_v7.4 regulation of arterial tone". The Journal of Physiology. 593 (24): 5325–40. doi:10.1113/JP271286. PMC 4704525. PMID 26503181.
12. Strutz-Seebohm N, Seebohm G, Fedorenko O, Baltaev R, Engel J, Knirsch M, Lang F (15 August 2006). "Functional coassembly of KCNQ4 with KCNE-beta- subunits in Xenopus oocytes". Cellular Physiology and Biochemistry. 18 (1–3): 57–66. doi:10.1159/000095158. PMID 16914890.
13. Grunnet M, Rasmussen HB, Hay-Schmidt A, Rosenstierne M, Klaerke DA, Olesen SP, Jespersen T (September 2003). "KCNE4 is an inhibitory subunit to K_v1.1 and K_v1.3 potassium channels". Biophysical Journal. 85 (3): 1525–37. Bibcode:2003BpJ....85.1525G. doi:10.1016/S0006-3495(03)74585-8. PMC 1303329. PMID 12944270.
14. Crump SM, Hu Z, Kant R, Levy DI, Goldstein SA, Abbott GW (January 2016). "Kcne4 deletion sex- and age-specifically impairs cardiac repolarization in mice". FASEB Journal. 30 (1): 360–9. doi:10.1096/fj.15-278754. PMC 4684512. PMID 26399785.
15. David JP, Stas JI, Schmitt N, Bocksteins E (5 August 2015). "Auxiliary KCNE subunits modulate both homotetrameric K_v2.1 and heterotetrameric K_v2.1/K_v6.4 channels". Scientific Reports. 5: 12813. Bibcode:2015NatSR...512813D. doi:10.1038/srep12813. PMC 4525287. PMID 26242757.
16. Levy DI, Cepaitis E, Wanderling S, Toth PT, Archer SL, Goldstein SA (July 2010). "The membrane protein MiRP3 regulates K_v4.2 channels in a KChIP-dependent manner". The Journal of Physiology. 588 (Pt 14): 2657–68. doi:10.1113/jphysiol.2010.191395. PMC 2916995. PMID 20498229.
17. Radicke S, Cotella D, Graf EM, Banse U, Jost N, Varró A, Tseng GN, Ravens U, Wettwer E (September 2006). "Functional modulation of the transient outward current Ito by KCNE beta-subunits and regional distribution in human non-failing and failing hearts". Cardiovascular Research. 71 (4): 695–703. doi:10.1016/j.cardiores.2006.06.017. PMID 16876774.
18. Levy DI, Wanderling S, Biemesderfer D, Goldstein SA (August 2008). "MiRP3 acts as an accessory subunit with the BK potassium channel". American Journal of Physiology. Renal Physiology. 295 (2): F380–7. doi:10.1152/ajprenal.00598.2007. PMC 2519185. PMID 18463315.
19. Abbott GW (May 2016). "Novel exon 1 protein-coding regions N-terminally extend human KCNE3 and KCNE4". FASEB Journal. 30 (8): 2959–69. doi:10.1096/fj.201600467R. PMC 6137956. PMID 27162025.
20. Levy DI, Cepaitis E, Wanderling S, Toth PT, Archer SL, Goldstein SA (July 2010). "The membrane protein MiRP3 regulates Kv4.2 channels in a KChIP-dependent manner". The Journal of Physiology. 588 (Pt 14): 2657–68. doi:10.1113/jphysiol.2010.191395. PMC 2916995. PMID 20498229.
21. Jepps TA, Carr G, Lundegaard PR, Olesen SP, Greenwood IA (December 2015). "Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone". The Journal of Physiology. 593 (24): 5325–40. doi:10.1113/JP271286. PMC 4704525. PMID 26503181.
22. Zeng ZY, Pu JL, Tan C, Teng SY, Chen JH, Su SY, Zhou XY, Zhang S, Li YS, Wang FZ, Gu DF (November 2005). "[The association of single nucleotide polymorphism of slow delayed rectifier K+ channel genes with atrial fibrillation in Han nationality Chinese]". Zhonghua Xin Xue Guan Bing Za Zhi. 33 (11): 987–91. PMID 16563243.
23. Ma KJ, Li N, Teng SY, Zhang YH, Sun Q, Gu DF, Pu JL (January 2007). "Modulation of KCNQ1 current by atrial fibrillation-associated KCNE4 (145E/D) gene polymorphism". Chinese Medical Journal. 120 (2): 150–4. doi:10.1097/00029330-200701020-00017. PMID 17335661.

Further reading

• Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Grunnet M, Jespersen T, Rasmussen HB, Ljungstrøm T, Jorgensen NK, Olesen SP, Klaerke DA (July 2002). "KCNE4 is an inhibitory subunit to the KCNQ1 channel". The Journal of Physiology. 542 (Pt 1): 119–30. doi:10.1113/jphysiol.2002.017301. PMC 2290389. PMID 12096056.
• Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S (September 2004). "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions". Genome Research. 14 (9): 1711–8. doi:10.1101/gr.2435604. PMC 515316. PMID 15342556.
• Grunnet M, Olesen SP, Klaerke DA, Jespersen T (March 2005). "hKCNE4 inhibits the hKCNQ1 potassium current without affecting the activation kinetics". Biochemical and Biophysical Research Communications. 328 (4): 1146–53. doi:10.1016/j.bbrc.2005.01.071. PMID 15707997.
• Lundquist AL, Turner CL, Ballester LY, George AL (January 2006). "Expression and transcriptional control of human KCNE genes". Genomics. 87 (1): 119–28. doi:10.1016/j.ygeno.2005.09.004. PMID 16303284.
• Zeng Z, Tan C, Teng S, Chen J, Su S, Zhou X, Wang F, Zhang S, Gu D, Makielski JC, Pu J (2007). "The single nucleotide polymorphisms of I(Ks) potassium channel genes and their association with atrial fibrillation in a Chinese population". Cardiology. 108 (2): 97–103. doi:10.1159/000095943. PMID 17016049. S2CID 33745848.

External links

• 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.