The KCNE2 K⁺ Channel Regulatory Subunit: Ubiquitous Influence, Complex Pathobiology

Overview

Journal Gene

Specialty Molecular Biology

Date 2015 Jul 1

PMID 26123744

Citations 36

Authors

Geoffrey W Abbott

Affiliations

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Abstract

The KCNE single-span transmembrane subunits are encoded by five-member gene families in the human and mouse genomes. Primarily recognized for co-assembling with and functionally regulating the voltage-gated potassium channels, the broad influence of KCNE subunits in mammalian physiology belies their small size. KCNE2 has been widely studied since we first discovered one of its roles in the heart and its association with inherited and acquired human Long QT syndrome. Since then, physiological analyses together with human and mouse genetics studies have uncovered a startling array of functions for KCNE2, in the heart, stomach, thyroid and choroid plexus. The other side of this coin is the variety of interconnected disease manifestations caused by KCNE2 disruption, involving both excitable cells such as cardiomyocytes, and non-excitable, polarized epithelia. Kcne2 deletion in mice has been particularly instrumental in illustrating the potential ramifications within a monogenic arrhythmia syndrome, with removal of one piece revealing the unexpected complexity of the puzzle. Here, we review current knowledge of the function and pathobiology of KCNE2.

Citing Articles

The Multifunctional Role of KCNE2: From Cardiac Arrhythmia to Multisystem Disorders.

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Precision medicine for long QT syndrome: patient-specific iPSCs take the lead.

Yu Y, Deschenes I, Zhao M Expert Rev Mol Med. 2023; 25:e5.

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Clinically Relevant Variants Causing KCNQ1-KCNE2 Gain-of-Function Affect the Ca Sensitivity of the Channel.

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Disruption of protein quality control of the human ether-à-go-go related gene K channel results in profound long QT syndrome.

Ledford H, Ren L, Thai P, Park S, Timofeyev V, Sirish P Heart Rhythm. 2021; 19(2):281-292.

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References

Sanguinetti M, Curran M, Zou A, Shen J, Spector P, Atkinson D . Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. 1996; 384(6604):80-3. DOI: 10.1038/384080a0. View

Gordon E, Panaghie G, Deng L, Bee K, Roepke T, Krogh-Madsen T . A KCNE2 mutation in a patient with cardiac arrhythmia induced by auditory stimuli and serum electrolyte imbalance. Cardiovasc Res. 2007; 77(1):98-106. DOI: 10.1093/cvr/cvm030. View

Sabater-Lleal M, Malarstig A, Folkersen L, Artigas M, Baldassarre D, Kavousi M . Common genetic determinants of lung function, subclinical atherosclerosis and risk of coronary artery disease. PLoS One. 2014; 9(8):e104082. PMC: 4122436. DOI: 10.1371/journal.pone.0104082. View

Mackinnon R . Determination of the subunit stoichiometry of a voltage-activated potassium channel. Nature. 1991; 350(6315):232-5. DOI: 10.1038/350232a0. View

Zhang M, Jiang M, Tseng G . minK-related peptide 1 associates with Kv4.2 and modulates its gating function: potential role as beta subunit of cardiac transient outward channel?. Circ Res. 2001; 88(10):1012-9. DOI: 10.1161/hh1001.090839. View

Sanguinetti M, Tristani-Firouzi M . hERG potassium channels and cardiac arrhythmia. Nature. 2006; 440(7083):463-9. DOI: 10.1038/nature04710. View

Kundu P, Ciobotaru A, Foroughi S, Toro L, Stefani E, Eghbali M . Hormonal regulation of cardiac KCNE2 gene expression. Mol Cell Endocrinol. 2008; 292(1-2):50-62. PMC: 2893227. DOI: 10.1016/j.mce.2008.06.003. View

Schroeder B, Kubisch C, Stein V, Jentsch T . Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature. 1999; 396(6712):687-90. DOI: 10.1038/25367. View

Kanda V, Purtell K, Abbott G . Protein kinase C downregulates I(Ks) by stimulating KCNQ1-KCNE1 potassium channel endocytosis. Heart Rhythm. 2011; 8(10):1641-7. PMC: 3183296. DOI: 10.1016/j.hrthm.2011.04.034. View

10.

Kanda V, Abbott G . KCNE Regulation of K(+) Channel Trafficking - a Sisyphean Task?. Front Physiol. 2012; 3:231. PMC: 3385356. DOI: 10.3389/fphys.2012.00231. View

11.

Kuwahara N, Kitazawa R, Fujiishi K, Nagai Y, Haraguchi R, Kitazawa S . Gastric adenocarcinoma arising in gastritis cystica profunda presenting with selective loss of KCNE2 expression. World J Gastroenterol. 2013; 19(8):1314-7. PMC: 3587490. DOI: 10.3748/wjg.v19.i8.1314. View

12.

Nadal M, Ozaita A, Amarillo Y, Vega-Saenz de Miera E, Ma Y, Mo W . The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels. Neuron. 2003; 37(3):449-61. DOI: 10.1016/s0896-6273(02)01185-6. View

13.

Kanda V, Lewis A, Xu X, Abbott G . KCNE1 and KCNE2 provide a checkpoint governing voltage-gated potassium channel α-subunit composition. Biophys J. 2011; 101(6):1364-75. PMC: 3177048. DOI: 10.1016/j.bpj.2011.08.014. View

14.

Takumi T, Ohkubo H, Nakanishi S . Cloning of a membrane protein that induces a slow voltage-gated potassium current. Science. 1988; 242(4881):1042-5. DOI: 10.1126/science.3194754. View

15.

Perlstein I, Burton D, Ryan K, Defelice S, Simmers E, Campbell B . Posttranslational control of a cardiac ion channel transgene in vivo: clarithromycin-hMiRP1-Q9E interactions. Hum Gene Ther. 2005; 16(7):906-10. DOI: 10.1089/hum.2005.16.906. View

16.

Bendahhou S, Marionneau C, Haurogne K, Larroque M, Derand R, Szuts V . In vitro molecular interactions and distribution of KCNE family with KCNQ1 in the human heart. Cardiovasc Res. 2005; 67(3):529-38. DOI: 10.1016/j.cardiores.2005.02.014. View

17.

McCrossan Z, Abbott G . The MinK-related peptides. Neuropharmacology. 2004; 47(6):787-821. DOI: 10.1016/j.neuropharm.2004.06.018. View

18.

Bahring R, Milligan C, Vardanyan V, Engeland B, Young B, Dannenberg J . Coupling of voltage-dependent potassium channel inactivation and oxidoreductase active site of Kvbeta subunits. J Biol Chem. 2001; 276(25):22923-9. DOI: 10.1074/jbc.M100483200. View

19.

Wible B, Yang Q, Kuryshev Y, Accili E, Brown A . Cloning and expression of a novel K+ channel regulatory protein, KChAP. J Biol Chem. 1998; 273(19):11745-51. DOI: 10.1074/jbc.273.19.11745. View

20.

Heitzmann D, Grahammer F, von Hahn T, Schmitt-Graff A, Romeo E, Nitschke R . Heteromeric KCNE2/KCNQ1 potassium channels in the luminal membrane of gastric parietal cells. J Physiol. 2004; 561(Pt 2):547-57. PMC: 1665368. DOI: 10.1113/jphysiol.2004.075168. View