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KCNE4

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KCNE4
Identifiers
AliasesKCNE4, MIRP3, potassium voltage-gated channel subfamily E regulatory subunit 4
External IDsOMIM: 607775; MGI: 1891125; HomoloGene: 10959; GeneCards: KCNE4; OMA:KCNE4 - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 1: 78.79 – 78.8 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 (Kv) 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 (Kv) channel ancillary or β subunits.[7]

KCNE4 is best known for modulating the KCNQ1 Kv α subunit, but it also regulates KCNQ4, Kv1.x, Kv2.1, Kv4.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 Kv1.1 and Kv1.3 channels when co-expressed in HEK cells and in Xenopus laevis oocytes, while leaving Kv1.2 and Kv1.4 currents unaffected.[13] KCNE4 augments Kv1.5 current and surface expression twofold in CHO cells (but had no effect in Xenopus oocytes). Kcne4 deletion from mice impaired currents attributable to Kv1.5, in ventricular myocytes.[14]

KCNE4 inhibited Kv2.1 currents by 90% but had little to no effect on currents generated by heteromers of Kv2.1 with the regulatory α subunit Kv6.4.[15]

KCNE4 slows activation and inactivation of Kv4.2 channels, and induces overshoot upon recovery from inactivation. Co-expression with KChIP2 produces intermediate gating kinetics in complexes with Kv4.2 and KCNE4.[16] Deletion of Kcne4 in mice impaired ventricular myocyte Ito, a current generated at least in part by Kv4.2.[14]

Although mouse KCNE4 reportedly had no effect on Kv4.3 when coexpressed in oocytes,[13] human KCNE4 was found to accelerate inactivation and recovery from inactivation of Kv4.3-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

Notes

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000152049 – Ensembl, May 2017
  2. ^ a b c 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 Kv7.4 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. ^ a b Grunnet M, Rasmussen HB, Hay-Schmidt A, Rosenstierne M, Klaerke DA, Olesen SP, Jespersen T (September 2003). "KCNE4 is an inhibitory subunit to Kv1.1 and Kv1.3 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. ^ a b c 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 Kv2.1 and heterotetrameric Kv2.1/Kv6.4 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 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.
  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. ^ a b 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

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

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