KCNE1
Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the KCNE1 gene.[3][4]
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.[5]
KCNE1 is one of five members of the KCNE family of Kv channel ancillary or β subunits. It is also known as minK (minimal potassium channel subunit).
Function
KCNE1 is primarily known for modulating the cardiac and epithelial Kv channel alfa subunit, KCNQ1. KCNQ1 and KCNE1 form a complex in human ventricular cardiomyocytes that generates the slowly activating K+ current, IKs. Together with the rapidly activating K+ current (IKr), IKs is important for human ventricular repolarization.[6][7] KCNQ1 is also essential for the normal function of many different epithelial tissues, but in these non-excitable cells it is thought to be predominantly regulated by KCNE2 or KCNE3.[8]
KCNE1 slows the activation of KCNQ1 5-10 fold, increases its unitary conductance 4-fold, eliminates its inactivation, and alters the manner in which KCNQ1 is regulated by other proteins, lipids and small molecules. The association of KCNE1 with KCNQ1 was discovered 8 years after Takumi and colleagues reported the isolation of a fraction of RNA from rat kidney that, when injected into Xenopus oocytes, produced an unusually slow-activating, voltage-dependent, potassium-selective current. Takumi et al discovered the KCNE1 gene[9] and it was correctly predicted to encode a single-transmembrane domain protein with an extracellular N-terminal domain and a cytosolic C-terminal domain. The ability of KCNE1 to generate this current was confusing because of its simple primary structure and topology, contrasting with the 6-transmembrane domain topology of other known Kv α subunits such as Shaker from Drosophila, cloned 2 years earlier. The mystery was solved when KCNQ1 was cloned and found to co-assemble with KCNE1, and it was shown that Xenopus laevis oocytes endogenously express KCNQ1, which is upregulated by exogenous expression of KCNE1 to generate the characteristic slowly activating current.,[6][7] KCNQ1 is also essential for the normal function of many different epithelial tissues, but in these non-excitable cells it is thought to be predominantly regulated by KCNE2 or KCNE3.[8]
KCNE1 is also reported to regulate two other KCNQ family α subunits, KCNQ4 and KCNQ5. KCNE1 increased both their peak currents in oocyte expression studies, and slowed the activation of the latter.,[10][11]
KCNE1 also regulates hERG, which is the Kv α subunit that generates ventricular IKr. KCNE1 doubled hERG current when the two were expressed in mammalian cells, although the mechanism for this remains unknown.[12]
Although KCNE1 had no effect when co-expressed with the Kv1.1 α subunit in Chinese Hamster ovary (CHO) cells, KCNE1 traps the N-type (rapidly inactivating) Kv1.4 α subunit in the ER/Golgi when co-expressed with it. KCNE1 (and KCNE2) also has this effect on the two other canonical N-type Kv α subunits, Kv3.3 and Kv3.4. This appears to be a mechanism for ensuring that homomeric N-type channels do not reach the cell surface, as this mode of suppression by KCNE1 or KCNE2 is relieved by co-expression of same-subfamily delayed rectifier (slowly inactivating) α subunits. Thus, Kv1.1 rescued Kv1.4, Kv3.1 rescued Kv3.4; in each of these cases the resultant channels at the membrane were heteromers (e.g., Kv3.1-Kv3.4) and displayed intermediate inactivation kinetics to those of either α subunit alone.,[13][14]
KCNE1 also regulates the gating kinetics of Kv2.1, Kv3.1 and Kv3.2, in each case slowing their activation and deactivation, and accelerating inactivation of the latter two.,[15][16] No effects were observed upon oocyte co-expression of KCNE1 and Kv4.2,[17] but KCNE1 was found to slow the gating and increase macroscopic current of Kv4.3 in HEK cells.[18] In contrast, channels formed by Kv4.3 and the cytosolic ancillary subunit KChIP2 exhibited faster activation and altered inactivation when co-expressed with KCNE1 in CHO cells.[19] Finally, KCNE1 inhibited Kv12.2 in Xenopus oocytes.[20]
Structure
The large majority of studies into the structural basis for KCNE1 modulation of Kv channels focus on its interaction with
The transmembrane segment of KCNE1 is α-helical when in a membrane environment.,[26][27] The transmembrane segment of KCNE1 has been suggested to interact with the KCNQ1 pore domain (S5/S6) and with the S4 domain of the KCNQ1 (KvLQT1) channel.[21] KCNE1 may bind to the outer part of the KCNQ1 pore domain, and slide from this position into the “activation cleft” which leads to greater current amplitudes[23]
KCNE1 slows KCNQ1 activation several-fold, and there are ongoing discussions about the precise mechanisms underlying this. In a study in which KCNQ1 voltage sensor movement was monitored by site-directed fluorimetry and also by measuring the charge displacement associated with movement of charges within the S4 segment of the voltage sensor (gating current), KCNE1 was found to slow S4 movement so much that the gating current was no longer measurable. Fluorimetry measurements indicated that KCNQ1-KCNE1 channel S4 movement was 30-fold slower than that of the well-studied Drosophila Shaker Kv channel.[28] Nakajo and Kubo found that KCNE1 either slowed KCNQ1 S4 movement upon membrane depolarization, or altered S4 equilibrium at a given membrane potential.[29] The Kass lab deduced that while homomeric KCNQ1 channels can open after the movement of a single S4 segment, KCNQ1-KCNE1 channels can only open after all four S4 segments have been activated.[30] The intracellular C-terminal domain of KCNE1 is thought to sit on the KCNQ1 S4-S5 linker, a segment of KCNQ1 crucial for communicating S4 status to the pore and thus control activation.[31]
Tissue distribution
KCNE1 is expressed in human heart (atria and ventricles), whereas in adult mouse heart its expression appears limited to the atria and/or conduction system.[32] KCNE1 is also expressed in human and musine inner ear[33] and kidneys.[34] KCNE1 has been detected in mouse brain[35] but this finding is a subject of ongoing debate.
Clinical significance
Inherited or sporadic KCNE gene mutations can cause
While loss-of-function mutations in KCNE1 cause Long QT syndrome, gain-of-function KCNE1 mutations are associated with early-onset atrial fibrillation.[36] A common KCNE1 polymorphism, S38G, is associated with altered predisposition to lone atrial fibrillation[37] and postoperative atrial fibrillation.[38] Atrial KCNE1 expression was downregulated in a porcine model of post-operative atrial fibrillation following lung lobectomy.[39]
Recently an analysis of 32 KCNE1 variants shows that putative/confirmed loss-of-function KCNE1 variants predispose to QT-prolongation, however the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for JLNS2 patients.[40]
See also
Notes
Wikidata Q37028794 . |
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000180509 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 8432548.
- ^ "Entrez Gene: KCNE1 potassium voltage-gated channel, Isk-related family, member 1".
- ISSN 0958-0670.
- ^ S2CID 4277239.
- ^ S2CID 4366973.
- ^ PMID 26123744.
- PMID 3194754.
- PMID 16914890.
- PMID 19910673.
- S2CID 4395891.
- PMID 21943416.
- PMID 21943417.
- PMID 12954870.
- PMID 14679187.
- PMID 11375270.
- S2CID 41910930.
- PMID 16876774.
- PMID 19623261.
- ^ PMID 9625865.
- S2CID 4415584.
- ^ PMID 19008479.
- PMID 21691061.
- PMID 24591645.
- PMID 9230130.
- PMID 17892302.
- PMID 23359697.
- PMID 17698596.
- PMID 21149716.
- PMID 18611041.
- PMID 15947250.
- S2CID 34273800.
- S2CID 25369134.
- PMID 20368164.
- PMID 22471742.
- PMID 25366730.
- PMID 24439990.
- PMID 22641150.
- PMID 31941373.
Further reading
- Murai T, Kakizuka A, Takumi T, Ohkubo H, Nakanishi S (May 1989). "Molecular cloning and sequence analysis of human genomic DNA encoding a novel membrane protein which exhibits a slowly activating potassium channel activity". Biochemical and Biophysical Research Communications. 161 (1): 176–81. PMID 2730656.
- Malo MS, Srivastava K, Ingram VM (Jul 1995). "Gene assignment by polymerase chain reaction: localization of the human potassium channel IsK gene to the Down's syndrome region of chromosome 21q22.1-q22.2". Gene. 159 (2): 273–5. PMID 7622063.
- Lai LP, Deng CL, Moss AJ, Kass RS, Liang CS (Dec 1994). "Polymorphism of the gene encoding a human minimal potassium ion channel (minK)". Gene. 151 (1–2): 339–40. PMID 7828904.
- Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, Fauré S, Gary F, Coumel P, Petit C, Schwartz K, Guicheney P (Feb 1997). "A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome". Nature Genetics. 15 (2): 186–9. S2CID 22782386.
- Chouabe C, Neyroud N, Guicheney P, Lazdunski M, Romey G, Barhanin J (Sep 1997). "Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias". The EMBO Journal. 16 (17): 5472–9. PMID 9312006.
- Tyson J, Tranebjaerg L, Bellman S, Wren C, Taylor JF, Bathen J, Aslaksen B, Sørland SJ, Lund O, Malcolm S, Pembrey M, Bhattacharya S, Bitner-Glindzicz M (Nov 1997). "IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome". Human Molecular Genetics. 6 (12): 2179–85. PMID 9328483.
- Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, Rubie C, Hördt M, Towbin JA, Borggrefe M, Assmann G, Qu X, Somberg JC, Breithardt G, Oberti C, Funke H (Nov 1997). "KCNE1 mutations cause jervell and Lange-Nielsen syndrome". Nature Genetics. 17 (3): 267–8. S2CID 26448022.
- Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT (Nov 1997). "Mutations in the hminK gene cause long QT syndrome and suppress IKs function". Nature Genetics. 17 (3): 338–40. S2CID 27715956.
- Duggal P, Vesely MR, Wattanasirichaigoon D, Villafane J, Kaushik V, Beggs AH (Jan 1998). "Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome". Circulation. 97 (2): 142–6. PMID 9445165.
- Bianchi L, Shen Z, Dennis AT, Priori SG, Napolitano C, Ronchetti E, Bryskin R, Schwartz PJ, Brown AM (Aug 1999). "Cellular dysfunction of LQT5-minK mutants: abnormalities of IKs, IKr and trafficking in long QT syndrome". Human Molecular Genetics. 8 (8): 1499–507. PMID 10400998.
- Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT (Sep 2000). "Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2". Circulation. 102 (10): 1178–85. PMID 10973849.
- Melman YF, Domènech A, de la Luna S, McDonald TV (Mar 2001). "Structural determinants of KvLQT1 control by the KCNE family of proteins". The Journal of Biological Chemistry. 276 (9): 6439–44. PMID 11104781.
- Schulze-Bahr E, Schwarz M, Hauenschild S, Wedekind H, Funke H, Haverkamp W, Breithardt G, Pongs O, Isbrandt D, Hoffman S (Sep 2001). "A novel long-QT 5 gene mutation in the C-terminus (V109I) is associated with a mild phenotype". Journal of Molecular Medicine. 79 (9): 504–9. S2CID 44620852.
- Furukawa T, Ono Y, Tsuchiya H, Katayama Y, Bang ML, Labeit D, Labeit S, Inagaki N, Gregorio CC (Nov 2001). "Specific interaction of the potassium channel beta-subunit minK with the sarcomeric protein T-cap suggests a T-tubule-myofibril linking system". Journal of Molecular Biology. 313 (4): 775–84. PMID 11697903.
External links
- GeneReviews/NIH/NCBI/UW entry on Romano-Ward Syndrome
- KCNE1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)