KCNE5

KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.[5][6]

KCNE5
Identifiers
Aliases	KCNE5, KCNE1L, potassium voltage-gated channel subfamily E regulatory subunit 5
External IDs	OMIM: 300328 MGI: 1913490 HomoloGene: 8177 GeneCards: KCNE5
Gene location (Human) Chr. X chromosome (human)[1] Band Xq23 Start 109,623,700 bp[1] End 109,625,172 bp[1]
Gene location (Mouse) Chr. X chromosome (mouse)[2] Band X|X F2 Start 142,304,752 bp[2] End 142,306,294 bp[2]
Gene ontology Molecular function • ion channel binding • voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization • potassium channel regulator activity • GO:0001948 protein binding • voltage-gated potassium channel activity • delayed rectifier potassium channel activity • voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization Cellular component • integral component of membrane • membrane • voltage-gated potassium channel complex • cell membrane Biological process • regulation of atrial cardiac muscle cell membrane repolarization • regulation of heart contraction • cardiac muscle contraction • ventricular cardiac muscle cell action potential • ion transport • regulation of cation channel activity • atrial cardiac muscle cell action potential • potassium ion transmembrane transport • positive regulation of potassium ion transmembrane transport • negative regulation of potassium ion transmembrane transport • regulation of membrane repolarization • regulation of heart rate by cardiac conduction • regulation of potassium ion transmembrane transport • regulation of ventricular cardiac muscle cell membrane repolarization • membrane repolarization during cardiac muscle cell action potential • membrane repolarization during action potential • membrane repolarization during ventricular cardiac muscle cell action potential • negative regulation of delayed rectifier potassium channel activity • potassium ion export across plasma membrane • negative regulation of potassium ion export across plasma membrane Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	23630	66240
Ensembl	ENSG00000176076	ENSMUSG00000090122
UniProt	Q9UJ90	Q9QZ26
RefSeq (mRNA)	NM_012282	NM_021487
RefSeq (protein)	NP_036414	NP_067462
Location (UCSC)	Chr X: 109.62 – 109.63 Mb	Chr X: 142.3 – 142.31 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Voltage-gated potassium (K_v) channels 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. KCNE5 encodes a membrane protein, KCNE5 (originally named KCNE1-L) that has sequence similarity to the KCNE1 gene product, a member of the potassium channel, voltage-gated, isk-related subfamily.[6]

The KCNE gene family comprises five genes in the human genome, each encoding a type I membrane protein. The KCNE subunits are potassium channel regulatory subunits that do not pass currents themselves but alter the properties of potassium channel pore-forming alpha subunits. KCNE5 is thus far the least-studied member of the KCNE family, but it is known to regulate a number of different K_v channel subtypes. KCNE5 co-assembles with KCNQ1, a K_v alpha subunit best known for its role in ventricular repolarization and in multiple epithelia. This co-assembly induces a +140 mV shift in voltage dependence of activation (when co-expressed in CHO cells) which would inhibit KCNQ1 activity across the normal physiological voltage range in most tissues.[7]

KCNE5 also inhibits activity of channels formed with KCNQ1 and KCNE1.[8] While reportedly not affecting KCNQ2, KCNQ2/3 or KCNQ5 channel activity, KCNE5 inhibits KCNQ4 in CHO cells[7] but not in oocytes.[9]

Although it has no known effects on hERG (K_v11.1) or K_v1.x family channel activity, KCNE5 inhibits K_v2.1 activity 50% and accelerates activation, slows deactivation and accelerates the recovery from closed state inactivation of channels formed by K_v2.1 and the 'silent' alpha subunit, K_v6.4.[10]

KCNE5 was previously reported to not regulate K_v4.2 or K_v4.3, but has been found to accelerate, and left-shift the voltage dependence of, inactivation of K_v4.3-KChIP2 channel complexes.[11]

Structure

The KCNE family subunits are type I membrane proteins with an extracellular N-terminus and intracellular C-terminus.[12] The transmembrane domain is alpha helical in KCNE1, 2 and 3 and predicted to also be helical in KCNE4 and KCNE5. The acknowledged role of members of the KCNE family is as K_v channel beta subunits, regulating the functional properties of K_v alpha subunits, with all three segments of the beta subunit contributing to binding, functional modulation and/or trafficking modulation to a greater or lesser degree. The high resolution structure of KCNE5 has not yet been determined, as of 2016. KCNE5 is an X-linked gene encoding a 143 residue protein in Homo sapiens.[5]

Tissue distribution

Human KCNE5 transcripts are most highly expressed in cardiac and skeletal muscle, spinal cord and brain, and it is also detectable in placenta.[5][13] In mice, Kcne5 transcript was detected in embryonic cranial nerve migrating crest cells, ganglia, somites and myoepicaridal layer.[5]

Clinical significance

This intronless gene is deleted in AMME contiguous gene syndrome and is potentially involved in the cardiac and neurologic abnormalities found in the AMME contiguous gene syndrome.[5]

KCNE5 is expressed in the human placenta and its expression increases in preeclampsia, although causality has not been established for this phenomenon.[13]

Inherited sequence variants in human KCNE5 are associated with atrial fibrillation and Brugada syndrome. Atrial fibrillation is the most common chronic cardiac arrhythmia, affecting 2-3 million in the United States alone, predominantly in the aging population. A minority of cases are linked to ion channel gene mutations, whereas the majority are associated with structural heart defects. Brugada syndrome is a relatively rare but lethal ventricular arrhythmia most commonly linked to voltage-gated sodium channel gene SCN5A mutations, but also associated with some K_v channel gene sequence variants.

KCNE5 mutation L65F is associated with atrial fibrillation and upregulates KCNQ1-KCNE1 currents when co-expressed with these subunits. In contrast, a polymorphism in KCNE5 encoding a P33S substitution was found to be less common in atrial fibrillation patients than in control subjects,[14] although these findings were at odds with those of other studies.[15]

KCNE5-Y81H was detected in a man with a type 1 Brugada pattern body-surface electrocardiogram, while KCNE5-D92E:E93X was detected in another case of Brugada and associated with premature sudden death in other male family members, but not females - significant because KCNE5 is an X-linked gene. These two gene variants did not affect KCNQ1-KCNE1 currents when co-expressed in CHO cells, but produced larger currents than wild-type KCNE5 when coexpressed with K_v4.3-KChIP2, giving a possible mechanism for Brugada syndrome, i.e., increased ventricular Ito density.[16]

A KCNE5 non-coding region gene variant, the G variant of the rs697829 A/G polymorphism, has also been reported to associate with prolonged QT interval and higher hazard ratio for death, compared to the G variant.[17]

Notes

References

1. GRCh38: Ensembl release 89: ENSG00000176076 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000090122 - 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. Piccini M, Vitelli F, Seri M, Galietta LJ, Moran O, Bulfone A, Banfi S, Pober B, Renieri A (September 1999). "KCNE1-like gene is deleted in AMME contiguous gene syndrome: identification and characterization of the human and mouse homologs". Genomics. 60 (3): 251–7. doi:10.1006/geno.1999.5904. PMID 10493825.
6. "Entrez Gene: KCNE1L".
7. Angelo K, Jespersen T, Grunnet M, Nielsen MS, Klaerke DA, Olesen SP (October 2002). "KCNE5 induces time- and voltage-dependent modulation of the KCNQ1 current". Biophysical Journal. 83 (4): 1997–2006. Bibcode:2002BpJ....83.1997A. doi:10.1016/S0006-3495(02)73961-1. PMC 1302289. PMID 12324418.
8. Ravn LS, Aizawa Y, Pollevick GD, Hofman-Bang J, Cordeiro JM, Dixen U, Jensen G, Wu Y, Burashnikov E, Haunso S, Guerchicoff A, Hu D, Svendsen JH, Christiansen M, Antzelevitch C (March 2008). "Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation". Heart Rhythm. 5 (3): 427–35. doi:10.1016/j.hrthm.2007.12.019. PMC 2515863. PMID 18313602.
9. Strutz-Seebohm N, Seebohm G, Fedorenko O, Baltaev R, Engel J, Knirsch M, Lang F (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.
10. 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. doi:10.1038/srep12813. PMC 4525287. PMID 26242757.
11. 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.
12. 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.
13. Mistry HD, McCallum LA, Kurlak LO, Greenwood IA, Broughton Pipkin F, Tribe RM (September 2011). "Novel expression and regulation of voltage-dependent potassium channels in placentas from women with preeclampsia". Hypertension. 58 (3): 497–504. doi:10.1161/HYPERTENSIONAHA.111.173740. PMID 21730298.
14. Ravn LS, Hofman-Bang J, Dixen U, Larsen SO, Jensen G, Haunsø S, Svendsen JH, Christiansen M (August 2005). "Relation of 97T polymorphism in KCNE5 to risk of atrial fibrillation". The American Journal of Cardiology. 96 (3): 405–7. doi:10.1016/j.amjcard.2005.03.086. PMID 16054468.
15. Mann SA, Otway R, Guo G, Soka M, Karlsdotter L, Trivedi G, Ohanian M, Zodgekar P, Smith RA, Wouters MA, Subbiah R, Walker B, Kuchar D, Sanders P, Griffiths L, Vandenberg JI, Fatkin D (March 2012). "Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk". Journal of the American College of Cardiology. 59 (11): 1017–25. doi:10.1016/j.jacc.2011.11.039. PMID 22402074.
16. Ohno S, Zankov DP, Ding WG, Itoh H, Makiyama T, Doi T, Shizuta S, Hattori T, Miyamoto A, Naiki N, Hancox JC, Matsuura H, Horie M (June 2011). "KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation". Circulation: Arrhythmia and Electrophysiology. 4 (3): 352–61. doi:10.1161/CIRCEP.110.959619. PMID 21493962.
17. Palmer BR, Frampton CM, Skelton L, Yandle TG, Doughty RN, Whalley GA, Ellis CJ, Troughton RW, Richards AM, Cameron VA (March 2012). "KCNE5 polymorphism rs697829 is associated with QT interval and survival in acute coronary syndromes patients". Journal of Cardiovascular Electrophysiology. 23 (3): 319–24. doi:10.1111/j.1540-8167.2011.02192.x. PMID 21985337.

Further reading

• Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y, Liang B, Lin J, Liu Y, Liu B, Zhou Q, Zhang D, Wang R, Ma N, Su X, Niu K, Pei Y, Xu W, Chen Z, Wan H, Cui J, Barhanin J, Chen Y (November 2004). "Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation". American Journal of Human Genetics. 75 (5): 899–905. doi:10.1086/425342. PMC 1182120. PMID 15368194.
• Hofman-Bang J, Jespersen T, Grunnet M, Larsen LA, Andersen PS, Kanters JK, Kjeldsen K, Christiansen M (July 2004). "Does KCNE5 play a role in long QT syndrome?". Clinica Chimica Acta; International Journal of Clinical Chemistry. 345 (1–2): 49–53. doi:10.1016/j.cccn.2004.02.033. PMID 15193977.
• Ravn LS, Hofman-Bang J, Dixen U, Larsen SO, Jensen G, Haunsø S, Svendsen JH, Christiansen M (August 2005). "Relation of 97T polymorphism in KCNE5 to risk of atrial fibrillation". The American Journal of Cardiology. 96 (3): 405–7. doi:10.1016/j.amjcard.2005.03.086. PMID 16054468.
• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Ravn LS, Aizawa Y, Pollevick GD, Hofman-Bang J, Cordeiro JM, Dixen U, Jensen G, Wu Y, Burashnikov E, Haunso S, Guerchicoff A, Hu D, Svendsen JH, Christiansen M, Antzelevitch C (March 2008). "Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation". Heart Rhythm. 5 (3): 427–35. doi:10.1016/j.hrthm.2007.12.019. PMC 2515863. PMID 18313602.
• 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.

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