Voltage-gated potassium (Kv) 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.
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 Kv channel subtypes. KCNE5 co-assembles with KCNQ1, a Kv 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.
KCNE5 also inhibits activity of channels formed with KCNQ1 and KCNE1. While reportedly not affecting KCNQ2, KCNQ2/3 or KCNQ5 channel activity, KCNE5 inhibits KCNQ4 in CHO cells but not in oocytes.
Although it has no known effects on hERG (Kv11.1) or Kv1.x family channel activity, KCNE5 inhibits Kv2.1 activity 50% and accelerates activation, slows deactivation and accelerates the recovery from closed state inactivation of channels formed by Kv2.1 and the 'silent' alpha subunit, Kv6.4.
KCNE5 was previously reported to not regulate Kv4.2 or Kv4.3, but has been found to accelerate, and left-shift the voltage dependence of, inactivation of Kv4.3-KChIP2 channel complexes.
The KCNE family subunits are type I membrane proteins with an extracellular N-terminus and intracellular C-terminus. 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 Kv channel beta subunits, regulating the functional properties of Kv 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.
Human KCNE5 transcripts are most highly expressed in cardiac and skeletal muscle, spinal cord and brain, and it is also detectable in placenta. In mice, Kcne5 transcript was detected in embryonic cranial nerve migrating crest cells, ganglia, somites and myoepicaridal layer.
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.
KCNE5 is expressed in the human placenta and its expression increases in preeclampsia, although causality has not been established for this phenomenon.
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 Kv 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, although these findings were at odds with those of other studies.
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 Kv4.3-KChIP2, giving a possible mechanism for Brugada syndrome, i.e., increased ventricular Ito density.
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.
^ abcdePiccini 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. PMID10493825.
^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. PMID16914890.
^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. PMID16876774.
^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. PMID10219239.
^ abMistry 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. PMID21730298.
^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. PMID16054468.
^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. PMID22402074.
^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. PMID21493962.
^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. PMID21985337.
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. PMID15193977.
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. PMID16054468.
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. PMID8125298.
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. PMID9373149.