KCNE3

Potassium channel, voltage gated subfamily E regulatory beta subunit 3
Identifiers
Symbols KCNE3 ; HOKPP; HYPP; MiRP2
External IDs OMIM: 604433 MGI: 1891124 HomoloGene: 3994 GeneCards: KCNE3 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 10008 57442
Ensembl ENSG00000175538 ENSMUSG00000035165
UniProt Q9Y6H6 Q9WTW2
RefSeq (mRNA) NM_005472 NM_001190869
RefSeq (protein) NP_005463 NP_001177798
Location (UCSC) Chr 11:
74.45 – 74.47 Mb		 Chr 7:
100.18 – 100.18 Mb
PubMed search

Potassium voltage-gated channel, Isk-related family, member 3 (KCNE3), also known as MinK-related peptide 2 (MiRP2) is a protein that in humans is encoded by the KCNE3 gene.[1][2]

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. KCNE3 encodes a member of the five-strong KCNE family of voltage-gated potassium (Kv) channel ancillary or β subunits.

KCNE3 is best known for modulating the KCNQ1 Kv α subunit, but it also regulates hERG, Kv2.1, Kv3.x, Kv4.x and Kv12.2 in heterologous co-expression experiments and/or in vivo.

Co-assembly with KCNE3 converts KCNQ1 from a voltage-dependent delayed rectifier K+ channel to a constitutively open K+ channel with an almost linear current/voltage (I/V) relationship.[3] KCNQ1-KCNE3 channels have been detected in the basolateral membrane of mouse small intestinal crypts, where they provide a driving force to regulate Cl- secretion.[4] Specific amino acids within the transmembrane segment (V72) and extracellular domain (D54 and D55) of KCNE3 are important for its control of KCNQ1 voltage dependence.[5][6] D54 and D55 interact electrostatically with R237 in the S4 segment of the KCNQ1 voltage sensor, helping to stabilize S4 in the activated state, which in turn locks open the channel unless the cell is held at a strongly hyperpolarizing (negative) membrane potential. The ability of KCNQ1-KCNE3 channels to remain open at weakly negative membrane potentials permits their activity in non-excitable, polarized epithelial cells such as those in the intestine.

KCNE3 also interacts with hERG, and when co-expressed in Xenopus laevis oocytes KCNE3 inhibits hERG activity by an unknown mechanism. It is not known whether hERG-KCNE3 complexes oocur in vivo.[3]

KCNE3 interacts with Kv2.1 in vitro and forms complexes with it in rat heart and brain. KCNE3 slows Kv2.1 activation and deactivation. KCNE3 can also regulate channels of the Kv3 subfamily, which are best known for permitting ultrarapid firing of neurons because of the extremely fast gating (activation and deactivation). KCNE3 moderately slows Kv3.1 and Kv3.2 activation and deactivation, and moderately speeds their C-type inactivation.[7][8] It is possible that KCNE3 (and KCNE1 and 2) regulation of Kv3.1 and Kv3.2 helps to increase functional diversity within the Kv3 subfamily.[9] KCNE3 also regulates Kv3.4, augments its current by increasing the unitary conductance and by left-shifting the voltage dependence such that the channel can open at more negative voltages. This may allow Kv3.4-KCNE3 channels to contribute to setting resting membrane potential.[10]

KCNE3 inhibits the fast inactivating Kv channel Kv4.3, which generates the transient outward Kv current (Ito) in human cardiac myocytes).[11] similarly, KCNE3 was recently found to inhibit Kv4.2, and it is thought that this regulation modulates spike frequency and other electrical properties of auditory neurons.[12]

Kv12.2 channels were found to be inhibited by endogenous KCNE3 (and KCNE1) subunits in Xenopus laevis oocytes. Thus, silencing of endogenous KCNE3 or KCNE1 using siRNA increases the macroscopic current of exogenously expressed Kv12.2. Kv12.2 forms a tripartite complex with KCNE1 and KCNE3 in oocytes, and may do so in mouse brain.[13] Previously, endogenous oocyte KCNE3 and KCNE1 were also found to inhibit exogenous hERG activity and slow the gating of exogenous Kv2.1.[14][15]

Structure

KCNE proteins are type I membrane proteins, and each assembles with one or more types of Kv channel α subunit to modulate their gating kinetics and other functional parameters. KCNE3 has a larger predicted extracellular domain, and smaller predicted intracellular domain, in terms of primary structure, when compared to other KCNE proteins.[16] As with other KCNE proteins, the transmembrane segment of KCNE3 is thought to be α-helical, and the extracellular domain also adopts a partly helical structure.[17] KCNE3, like KCNE1 and possibly other KCNE proteins, are thought to make contact with the S4 of one α subunit and the S6 of another α subunit within the tetramer of Kv α subunits in a complex. No studies have as yet reported the number of KCNE3 subunits within a functional channel complex; it is likely to be either 2 or 4.

Tissue distribution

KCNE3 is most prominently expressed in the colon, small intestine, and specific cell types in the stomach.[18] It is also detectable in the kidney and trachea, and depending on the species is also reportedly expressed at lower levels in the brain, heart and skeletal muscle. Specifically, KCNE3 was detected in rat, horse and human heart,[8][19][20] but not in mouse heart.[4][21] Some have observed KCNE3 expression in rat brain, rat and human skeletal muscle, and the mouse C2C12 skeletal muscle cell line, others have not detected it in these tissues in the mouse.[4][7][10][22]

Clinical significance

Genetic disruption of the Kcne3 gene in mice impairs intestinal cyclic AMP-stimulated chloride secretion via disruption of intestinal KCNQ1-KCNE3 channels that are important for regulating the chloride current. KCNE3 also performs a similar function in mouse tracheal epithelium. Kcne3 deletion in mice also predisposes to ventricular arrhythmogenesis, but KCNE3 expression is not detectable in mouse heart. The mechanism for ventricular arrhythmogenesis was demonstrated to be indirect, and associated with autoimmune attack of the adrenal gland and secondary hyperaldosteronism (KCNE3 is not detectable in the adrenal gland). The elevated serum aldosterone predisposes to arrhythmias triggered in a coronary artery ligation ischemia/reperfusion injury model. Blockade of the aldosterone receptor with spironolactone removed the ventricular arrhythmia predisposition in Kcne3-/- mice. Kcne3 deletion also impairs auditory function because of the loss of regulation of Kv4.2 channels by KCNE3 in spiral ganglion neurons (SGNs) of the auditory system. KCNE3 is thought to regulate SGN firing properties and membrane potential via its modulation of Kv4.2.[12]

Mutations in human KCNE3 have been associated with hypokalemic periodic paralysis[1] and Brugada syndrome.[23]

The association with the R83H mutation in KCNE3 is controversial and other groups have detected the same mutation in individuals not exhibiting symptoms of periodic paralysis.[24] The mutation may instead be a benign polymorphism, or else it requires another genetic or environmental 'hit' before it becomes pathogenic. Kv channels formed by Kv3.4 and R83H-KCNE3 have impaired function compared to wild-type channels, are less able to open at negative potentials and are sensitive to proton block during acidosis.[10][25]

KCNE3-linked Brugada syndrome is thought to arise because of mutant KCNE3 being unable to inhibit Kv4.3 channels in ventricular myocytes as it is suggested to do in healthy individuals. It appears that, unlike in mice, KCNE3 expression is detectable in human heart. It has not been reported whether people with KCNE3 mutations also have adrenal gland-related symptoms such as hyperaldosteronism.

KCNE3 mutations have been suggested to associate with Ménière’s disease in Japanese, a condition that presents as tinnitus, spontaneous vertigo, and periodic hearing loss,[26] however this association is also controversial and was not observed in a Caucasian population.[27] In a study of tinnitus utilizing deep resequencing analysis, the authors were not able to prove or disprove association of KCNE3 sequence variation with tinnitus.[28]

See also

References

  1. 1 2 "Entrez Gene: KCNE3 potassium voltage-gated channel, Isk-related family, member 3".
  2. ↑ Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA (Apr 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.
  3. 1 2 Schroeder BC, Waldegger S, Fehr S, Bleich M, Warth R, Greger R, Jentsch TJ (Jan 2000). "A constitutively open potassium channel formed by KCNQ1 and KCNE3". Nature 403 (6766): 196–9. doi:10.1038/35003200. PMID 10646604.
  4. 1 2 3 Preston P, Wartosch L, Günzel D, Fromm M, Kongsuphol P, Ousingsawat J, Kunzelmann K, Barhanin J, Warth R, Jentsch TJ (Mar 2010). "Disruption of the K+ channel beta-subunit KCNE3 reveals an important role in intestinal and tracheal Cl- transport". The Journal of Biological Chemistry 285 (10): 7165–75. doi:10.1074/jbc.M109.047829. PMID 20051516.
  5. ↑ Melman YF, Krumerman A, McDonald TV (Jul 2002). "A single transmembrane site in the KCNE-encoded proteins controls the specificity of KvLQT1 channel gating". The Journal of Biological Chemistry 277 (28): 25187–94. doi:10.1074/jbc.M200564200. PMID 11994278.
  6. ↑ Choi E, Abbott GW (May 2010). "A shared mechanism for lipid- and beta-subunit-coordinated stabilization of the activated K+ channel voltage sensor". FASEB Journal 24 (5): 1518–24. doi:10.1096/fj.09-145219. PMID 20040519.
  7. 1 2 McCrossan ZA, Lewis A, Panaghie G, Jordan PN, Christini DJ, Lerner DJ, Abbott GW (Sep 2003). "MinK-related peptide 2 modulates Kv2.1 and Kv3.1 potassium channels in mammalian brain". The Journal of Neuroscience 23 (22): 8077–91. PMID 12954870.
  8. 1 2 McCrossan ZA, Roepke TK, Lewis A, Panaghie G, Abbott GW (Mar 2009). "Regulation of the Kv2.1 potassium channel by MinK and MiRP1". The Journal of Membrane Biology 228 (1): 1–14. doi:10.1007/s00232-009-9154-8. PMC 2849987. PMID 19219384.
  9. ↑ Lewis A, McCrossan ZA, Abbott GW (Feb 2004). "MinK, MiRP1, and MiRP2 diversify Kv3.1 and Kv3.2 potassium channel gating". The Journal of Biological Chemistry 279 (9): 7884–92. doi:10.1074/jbc.M310501200. PMID 14679187.
  10. 1 2 3 Abbott GW, Butler MH, Bendahhou S, Dalakas MC, Ptacek LJ, Goldstein SA (Jan 2001). "MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis". Cell 104 (2): 217–31. doi:10.1016/s0092-8674(01)00207-0. PMID 11207363.
  11. ↑ Lundby A, Olesen SP (Aug 2006). "KCNE3 is an inhibitory subunit of the Kv4.3 potassium channel". Biochemical and Biophysical Research Communications 346 (3): 958–67. doi:10.1016/j.bbrc.2006.06.004. PMID 16782062.
  12. 1 2 Wang W, Kim HJ, Lee JH, Wong V, Sihn CR, Lv P, Perez Flores MC, Mousavi-Nik A, Doyle KJ, Xu Y, Yamoah EN (Jun 2014). "Functional significance of K+ channel β-subunit KCNE3 in auditory neurons". The Journal of Biological Chemistry 289 (24): 16802–13. doi:10.1074/jbc.M113.545236. PMID 24727472.
  13. ↑ Clancy SM, Chen B, Bertaso F, Mamet J, Jegla T (22 July 2009). "KCNE1 and KCNE3 beta-subunits regulate membrane surface expression of Kv12.2 K(+) channels in vitro and form a tripartite complex in vivo". PLOS ONE 4 (7): e6330. doi:10.1371/journal.pone.0006330. PMID 19623261.
  14. ↑ Anantharam A, Lewis A, Panaghie G, Gordon E, McCrossan ZA, Lerner DJ, Abbott GW (Apr 2003). "RNA interference reveals that endogenous Xenopus MinK-related peptides govern mammalian K+ channel function in oocyte expression studies". The Journal of Biological Chemistry 278 (14): 11739–45. doi:10.1074/jbc.M212751200. PMID 12529362.
  15. ↑ Gordon E, Roepke TK, Abbott GW (Feb 2006). "Endogenous KCNE subunits govern Kv2.1 K+ channel activation kinetics in Xenopus oocyte studies". Biophysical Journal 90 (4): 1223–31. doi:10.1529/biophysj.105.072504. PMID 16326911.
  16. ↑ Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA (Apr 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.
  17. ↑ Kang C, Vanoye CG, Welch RC, Van Horn WD, Sanders CR (Feb 2010). "Functional delivery of a membrane protein into oocyte membranes using bicelles". Biochemistry 49 (4): 653–5. doi:10.1021/bi902155t. PMID 20044833.
  18. ↑ Grahammer F, Warth R, Barhanin J, Bleich M, Hug MJ (Nov 2001). "The small conductance K+ channel, KCNQ1: expression, function, and subunit composition in murine trachea". The Journal of Biological Chemistry 276 (45): 42268–75. doi:10.1074/jbc.M105014200. PMID 11527966.
  19. ↑ Finley MR, Li Y, Hua F, Lillich J, Mitchell KE, Ganta S, Gilmour RF, Freeman LC (Jul 2002). "Expression and coassociation of ERG1, KCNQ1, and KCNE1 potassium channel proteins in horse heart". American Journal of Physiology. Heart and Circulatory Physiology 283 (1): H126–38. doi:10.1152/ajpheart.00622.2001. PMID 12063283.
  20. ↑ Delpón E, Cordeiro JM, Núñez L, Thomsen PE, Guerchicoff A, Pollevick GD, Wu Y, Kanters JK, Larsen CT, Hofman-Bang J, Burashnikov E, Christiansen M, Antzelevitch C (Aug 2008). "Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome". Circulation. Arrhythmia and Electrophysiology 1 (3): 209–18. doi:10.1161/CIRCEP.107.748103. PMC 2585750. PMID 19122847.
  21. ↑ Hu Z, Crump SM, Anand M, Kant R, Levi R, Abbott GW (Feb 2014). "Kcne3 deletion initiates extracardiac arrhythmogenesis in mice". FASEB Journal 28 (2): 935–45. doi:10.1096/fj.13-241828. PMID 24225147.
  22. ↑ Pannaccione A, Boscia F, Scorziello A, Adornetto A, Castaldo P, Sirabella R, Taglialatela M, Di Renzo GF, Annunziato L (Sep 2007). "Up-regulation and increased activity of KV3.4 channels and their accessory subunit MinK-related peptide 2 induced by amyloid peptide are involved in apoptotic neuronal death". Molecular Pharmacology 72 (3): 665–73. doi:10.1124/mol.107.034868. PMID 17495071.
  23. ↑ Delpón E, Cordeiro JM, Núñez L, Thomsen PE, Guerchicoff A, Pollevick GD, Wu Y, Kanters JK, Larsen CT, Hofman-Bang J, Burashnikov E, Christiansen M, Antzelevitch C (Aug 2008). "Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome". Circulation. Arrhythmia and Electrophysiology 1 (3): 209–18. doi:10.1161/CIRCEP.107.748103. PMC 2585750. PMID 19122847.
  24. ↑ Sternberg D, Tabti N, Fournier E, Hainque B, Fontaine B (Sep 2003). "Lack of association of the potassium channel-associated peptide MiRP2-R83H variant with periodic paralysis". Neurology 61 (6): 857–9. doi:10.1212/01.wnl.0000082392.66713.e3. PMID 14504341.
  25. ↑ Abbott GW, Butler MH, Goldstein SA (Feb 2006). "Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2-Kv3.4 potassium channels in periodic paralysis". FASEB Journal 20 (2): 293–301. doi:10.1096/fj.05-5070com. PMID 16449802.
  26. ↑ Doi K, Sato T, Kuramasu T, Hibino H, Kitahara T, Horii A, Matsushiro N, Fuse Y, Kubo T (2005). "Ménière's disease is associated with single nucleotide polymorphisms in the human potassium channel genes, KCNE1 and KCNE3". ORL; Journal for Oto-Rhino-Laryngology and Its Related Specialties 67 (5): 289–93. doi:10.1159/000089410. PMID 16374062.
  27. ↑ Campbell CA, Della Santina CC, Meyer NC, Smith NB, Myrie OA, Stone EM, Fukushima K, Califano J, Carey JP, Hansen MR, Gantz BJ, Minor LB, Smith RJ (Jan 2010). "Polymorphisms in KCNE1 or KCNE3 are not associated with Ménière disease in the Caucasian population". American Journal of Medical Genetics. Part A 152A (1): 67–74. doi:10.1002/ajmg.a.33114. PMID 20034061.
  28. ↑ Sand PG, Langguth B, Kleinjung T (7 September 2011). "Deep resequencing of the voltage-gated potassium channel subunit KCNE3 gene in chronic tinnitus". Behavioral and Brain Functions 7: 39. doi:10.1186/1744-9081-7-39. PMID 21899751.

Further reading

External links

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