Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known asMinK-related peptide 1 (MiRP1), is aprotein that in humans is encoded by theKCNE2gene onchromosome 21.[5][6] MiRP1 is avoltage-gated potassium channel accessory subunit (beta subunit) associated withLong QT syndrome.[5] It is ubiquitously expressed in many tissues and cell types.[7] Because of this and its ability to regulate multiple differention channels, KCNE2 exerts considerable influence on a number of cell types and tissues.[5][8] Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain a single membrane-spanning region, extracellularN-terminal and intracellularC-terminal. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inheritedcardiac arrhythmias. TheKCNE2 gene also contains one of 27SNPs associated with increased risk ofcoronary artery disease.[9] More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored.
Steve Goldstein (then at Yale University) used a BLAST search strategy, focusing on KCNE1 sequence stretches known to be important for function, to identify related expressed sequence tags (ESTs) in the NCBI database. Using sequences from these ESTs, KCNE2, 3 and 4 were cloned.[5]
KCNE2 protein is most readily detected in thechoroid plexus epithelium, gastricparietal cells, andthyroid epithelial cells. KCNE2 is also expressed in atrial and ventricular cardiomyocytes, the pancreas, pituitary gland, and lung epithelium. In situ hybridization data suggest that KCNE2 transcript may also be expressed in various neuronal populations.[10]
TheKCNE2 gene resides on chromosome 21 at the band 21q22.11 and contains 2exons.[6] Since humanKCNE2 is located ~79kb fromKCNE1 and in the opposite direction, KCNE2 is proposed to originate from agene duplication event.[11]
This protein belongs to the potassium channel KCNE family and is one five singletransmembrane domainvoltage-gated potassium (Kv) channel ancillary subunits.[12][13] KCNE2 is composed of three major domains: theN-terminal domain, the transmembrane domain, and theC-terminal domain. The N-terminal domain protrudes out of theextracellular side of thecell membrane and is, thus,soluble in the aqueous environment. Meanwhile, the transmembrane and C-terminal domains arelipid-soluble to enable the protein to incorporate into the cell membrane.[13] The C-terminal faces theintracellular side of the membrane and may share a putativePKCphosphorylation site with other KCNE proteins.
KCNE2 protein is most readily detected in thechoroid plexus epithelium, at the apical side. KCNE2 forms complexes there with the voltage-gated potassium channel α subunit,Kv1.3. In addition, KCNE2 forms reciprocally regulating tripartite complexes in the choroid plexus epithelium with theKCNQ1 α subunit and the sodium-dependentmyo-inositol transporter,SMIT1.Kcne2-/- mice exhibit increased seizure susceptibility, reduced immobility time in the tail suspension test, and reduced cerebrospinal fluidmyo-inositol content, compared to wild-type littermates. Mega-dosing ofmyo-inositol reverses all these phenotypes, suggesting a link betweenmyo-inositol and the seizure susceptibility and behavioral alterations inKcne2-/- mice.[14][15]
KCNE2 is also highly expressed in parietal cells of thegastric epithelium, also at theapical side. In these cells,KCNQ1-KCNE2 K+ channels, which are constitutively active, provide a conduit to return K+ ions back to the stomach lumen. The K+ ions enter the parietal cell through the gastric H+/K+-ATPase, which swaps them for protons as it acidifies the stomach. While KCNQ1 channels are inhibited by low extracellular pH, KCNQ1-KCNE2 channels activity is augmented by extracellular protons, an ideal characteristic for their role in parietal cells.[16][17][18]
KCNE2 forms constitutively active K+ channels with KCNQ1 in the basolateral membrane of thyroid epithelial cells.Kcne2-/- mice exhibithypothyroidism, particularly apparent duringgestation orlactation. KCNQ1-KCNE2 is required for optimal iodide uptake into the thyroid by thebasolateral sodium iodide symporter (NIS). Iodide is required for biosynthesis ofthyroid hormones.[19][20]
KCNE2 was originally discovered to regulatehERG channel function. KCNE2 decreases macroscopic and unitary current through hERG, and speeds hERG deactivation. hERG generates IKr, the most prominent repolarizing current in humanventricularcardiomyocytes. hERG, and IKr, are highly susceptible to block by a range of structurally diverse pharmacological agents. This property means that many drugs or potential drugs have the capacity to impair human ventricular repolarization, leading to drug-inducedlong QT syndrome.[5] KCNE2 may also regulate hyperpolarization-activated,cyclic-nucleotide-gated (HCN) pacemaker channels in human heart and in the hearts of other species, as well as the Cav1.2 voltage-gated calcium channel.[21][22]
In mice, mERG and KCNQ1, another Kv α subunit regulated by KCNE2, are neither influential nor highly expressed in adult ventricles. However,Kcne2-/- mice exhibit QT prolongation at baseline at 7 months of age, or earlier if provoked with a QT-prolonging agent such assevoflurane. This is because KCNE2 is a promiscuous regulatory subunit that forms complexes with Kv1.5 and with Kv4.2 in adult mouse ventricular myocytes. KCNE2 increases currents though Kv4.2 channels and slows their inactivation. KCNE2 is required for Kv1.5 to localize to the intercalated discs of mouse ventricular myocytes.Kcne2 deletion in mice reduces the native currents generated in ventricular myocytes by Kv4.2 and Kv1.5, namely Ito and IKslow, respectively.[23]
Kcne2-/- mice exhibitachlorhydria, gastrichyperplasia, and mis-trafficking of KCNQ1 to the parietal cell basal membrane. The mis-trafficking occurs becauseKCNE3 is upregulated in the parietal cells ofKcne2-/- mice, and hijacks KCNQ1, taking it to thebasolateral membrane. When bothKcne2 andKcne3 are germline-deleted in mice, KCNQ1 traffics to the parietal cell apical membrane but the gastric phenotype is even worse than forKcne2-/- mice, emphasizing that KCNQ1 requires KCNE2 co-assembly for functional attributes other than targeting in parietal cells.Kcne2-/- mice also developgastritis cystica profunda and gastricneoplasia. Human KCNE2 downregulation is also observed in sites of gastritis cystica profunda andgastric adenocarcinoma.[16][17][18]
Positron emission tomography data show that with KCNE2, 124I uptake by the thyroid is impaired.Kcne2 deletion does not impair organification of iodide once it has been taken up by NIS. Pups raised byKcne2-/- dams are particularly severely affected becauset they receive less milk (hypothyroidism of the dams impairs milk ejection), the milk they receive is deficient inT4, and they themselves cannot adequately transport iodide into the thyroid.Kcne2-/- pups exhibit stunted growth,alopecia,cardiomegaly and reduced cardiacejection fraction, all of which are alleviated by thyroid hormone supplementation of pups or dams. SurrogatingKcne2-/- pups withKcne2+/+ dams also alleviates these phenotypes, highlighting the influence of maternal genotype in this case.[19][20]
As observed for hERG mutations, KCNE2 loss-of-function mutations are associated with inherited long QT syndrome, and hERG-KCNE2 channels carrying the mutations show reduced activity compared to wild-type channels. In addition, some KCNE2 mutations and also more commonpolymorphisms are associated with drug-induced long QT syndrome. In several cases, specific KCNE2 sequence variants increase the susceptibility to hERG-KCNE2 channel inhibition by the drug that precipitated the QT prolongation in the patient from which the gene variant was isolated.[5][24] Long QT syndrome predisposes to potentially lethal ventricularcardiac arrhythmias includingtorsades de pointe, which can degenerate intoventricular fibrillation andsudden cardiac death.[5] Moreover, KCNE2 gene variation can disrupt HCN1-KCNE2 channel function and this may potentially contribute to cardiac arrhythmogenesis.[21] KCNE2 is also associated with familial atrial fibrillation, which may involve excessive KCNQ1-KCNE2 current caused by KCNE2 gain-of-function mutations.[25][26]
Recently, a battery of extracardiac effects were discovered inKcne2-/- mice that may contribute to cardiac arrhythmogenesis inKcne2-/- mice and could potentially contribute to human cardiac arrhythmias if similar effects are observed in human populations.Kcne2 deletion in mice causes anemia, glucose intolerance, dyslipidemia, hyperkalemia and elevated serum angiotensin II. Some or all of these might contribute to predisposition to sudden cardiac death inKcne2-/- mice in the context of myocardial ischemia and post-ischemic arrhythmogenesis.[27]
A multi-locus genetic risk score study based on a combination of 27 loci, including theKCNE2 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit fromstatin therapy. The study was based on a communitycohort study (the Malmo Diet and Cancer study) and four additionalrandomized controlled trials ofprimary prevention cohorts (JUPITER and ASCOT) andsecondary prevention cohorts (CARE and PROVE IT-TIMI 22).[9]
^Liu W, Deng J, Wang G, Zhang C, Luo X, Yan D, Su Q, Liu J (July 2014). "KCNE2 modulates cardiac L-type Ca(2+) channel".Journal of Molecular and Cellular Cardiology.72:208–18.doi:10.1016/j.yjmcc.2014.03.013.PMID24681347.S2CID7271200.
Nyholt DR, LaForge KS, Kallela M, Alakurtti K, Anttila V, Färkkilä M, Hämaläinen E, Kaprio J, Kaunisto MA, Heath AC, Montgomery GW, Göbel H, Todt U, Ferrari MD, Launer LJ, Frants RR, Terwindt GM, de Vries B, Verschuren WM, Brand J, Freilinger T, Pfaffenrath V, Straube A, Ballinger DG, Zhan Y, Daly MJ, Cox DR, Dichgans M, van den Maagdenberg AM, Kubisch C, Martin NG, Wessman M, Peltonen L, Palotie A (November 2008)."A high-density association screen of 155 ion transport genes for involvement with common migraine".Human Molecular Genetics.17 (21):3318–31.doi:10.1093/hmg/ddn227.PMC2566523.PMID18676988.
Chevalier P, Bellocq C, Millat G, Piqueras E, Potet F, Schott JJ, Baró I, Lemarec H, Barhanin J, Rousson R, Rodriguez-Lafrasse C (February 2007). "Torsades de pointes complicating atrioventricular block: evidence for a genetic predisposition".Heart Rhythm.4 (2):170–4.doi:10.1016/j.hrthm.2006.10.004.PMID17275752.
Liu XS, Zhang M, Jiang M, Wu DM, Tseng GN (April 2007). "Probing the interaction between KCNE2 and KCNQ1 in their transmembrane regions".The Journal of Membrane Biology.216 (2–3):117–27.doi:10.1007/s00232-007-9047-7.PMID17676362.S2CID12153552.
Berge KE, Haugaa KH, Früh A, Anfinsen OG, Gjesdal K, Siem G, Oyen N, Greve G, Carlsson A, Rognum TO, Hallerud M, Kongsgård E, Amlie JP, Leren TP (2008). "Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers".Scandinavian Journal of Clinical and Laboratory Investigation.68 (5):362–8.doi:10.1080/00365510701765643.PMID18752142.S2CID25777418.
Chung SK, MacCormick JM, McCulley CH, Crawford J, Eddy CA, Mitchell EA, Shelling AN, French JK, Skinner JR, Rees MI (October 2007). "Long QT and Brugada syndrome gene mutations in New Zealand".Heart Rhythm.4 (10):1306–14.doi:10.1016/j.hrthm.2007.06.022.PMID17905336.
Tester DJ, Cronk LB, Carr JL, Schulz V, Salisbury BA, Judson RS, Ackerman MJ (July 2006). "Allelic dropout in long QT syndrome genetic testing: a possible mechanism underlying false-negative results".Heart Rhythm.3 (7):815–21.doi:10.1016/j.hrthm.2006.03.016.PMID16818214.
