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Potassium channel, voltage gated subfamily E regulatory beta subunit 2
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols KCNE2 ; ATFB4; LQT5; LQT6; MIRP1
External IDs OMIM603796 MGI1891123 HomoloGene71688 GeneCards: KCNE2 Gene
Species Human Mouse
Entrez 9992 246133
Ensembl ENSG00000159197 ENSMUSG00000039672
UniProt Q9Y6J6 Q9D808
RefSeq (mRNA) NM_172201 NM_134110
RefSeq (protein) NP_751951 NP_598871
Location (UCSC) Chr 21:
34.36 – 34.37 Mb
Chr 16:
92.29 – 92.3 Mb
PubMed search [1] [2]
KCNE2 3D animation

Potassium voltage-gated channel subfamily E member 2 also known as MinK-related peptide 1 (MiRP1) is a protein that in humans is encoded by the KCNE2 gene.[1][1] MiRP1 is a voltage-gated potassium channel accessory subunit (beta subunit) associated with Long QT syndrome.[1]

KCNE2 (MiRP1) is a ubiquitously expressed ion channel regulatory subunit that, because of this and its ability to regulate multiple different ion channels, exerts considerable influence on a number of cell types and tissues.[1][2] Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain a single membrane-spanning region, extracellular N-terminal and intracellular C-terminal. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited cardiac arrhythmias. 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.[1]

Tissue distribution[edit]

KCNE2 protein is most readily detected in the choroid plexus epithelium, gastric parietal cells, and thyroid 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.[3]

Epithelial functions and pathophysiology[edit]

Choroid plexus[edit]

KCNE2 protein is most readily detected in the choroid 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 the KCNQ1 α subunit and the sodium-dependent myo-inositol transporter, SMIT1. Kcne2-/- mice exhibit increased seizure susceptibility, reduced immobility time in the tail suspension test, and reduced cerebrospinal fluid myo-inositol content, compared to wild-type littermates. Mega-dosing of myo-inositol reverses all these phenotypes, suggesting a link between myo-inositol and the seizure susceptibility and behavioral alterations in Kcne2-/- mice.[4][5]


KCNE2 is also highly expressed in parietal cells of the gastric epithelium, also at the apical 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. Kcne2-/- mice exhibit achlorhydria, gastric hyperplasia, and mis-trafficking of KCNQ1 to the parietal cell basal membrane. The mis-trafficking occurs because KCNE3 is upregulated in the parietal cells of Kcne2-/- mice, and hijacks KCNQ1, taking it to the basolateral membrane. When both Kcne2 and Kcne3 are germline-deleted in mice, KCNQ1 traffics to the parietal cell apical membrane but the gastric phenotype is even worse than for Kcne2-/- mice, emphasizing that KCNQ1 requires KCNE2 co-assembly for functional attributes other than targeting in parietal cells. Kcne2-/- mice also develop gastritis cystica profunda and gastric neoplasia. Human KCNE2 downregulation is also observed in sites of gastritis cystica profunda and gastric adenocarcinoma.[6][7][8]


KCNE2 forms constitutively active K+ channels with KCNQ1 in the basolateral membrane of thyroid epithelial cells. Kcne2-/- mice exhibit hypothyroidism, particularly apparent during gestation or lactation. KCNQ1-KCNE2 is required for optimal iodide uptake into the thyroid by the basolateral sodium iodide symporter (NIS). Iodide is required for biosynthesis of thyroid hormones. 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 by Kcne2-/- dams are particularly severely affected because rhey receive less milk (hypothyroidism of the dams impairs milk ejection), the milk they receive is deficient in T4, and they themselves cannot adequately transport iodide into the thyroid. Kcne2-/- pups exhibit stunted growth, alopecia, cardiomegaly and reduced cardiac ejection fraction, all of which are alleviated by thyroid hormone supplementation of pups or dams. Surrogating Kcne2-/- pups with Kcne2+/+ dams also alleviates these phenotypes, highlighting the influence of maternal genotype in this case.[9][10]

Cardiac functions and pathophysiology[edit]

Human heart[edit]

KCNE2 was originally discovered to regulate hERG channel function. KCNE2 decreases marcoscopic and unitary current through hERG, and speeds hERG deactivation. hERG generates IKr, the most prominent repolarizing current in human ventricular cardiomyocytes. 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-induced Long QT syndrome (LQTS). LQTS predisposes to potentially lethal ventricular cardiac arrhythmias including torsades de pointe, which can degenerate into ventricular fibrillation and sudden cardiac death.[1]

As observed for hERG mutations, KCNE2 loss-of-function mutations are associated with inherited LQTS, and hERG-KCNE2 channels carrying the mutations show reduced activity compared to wild-type channels. In addition, some KCNE2 mutations and also more common polymorphisms are associated with drug-induced LQTS. 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.[1][11]

KCNE2 may also regulate hyperpolarization-activated, cyclic-nucleotide-gated (HCN) pacemaker channels in human heart and in the hearts of other species. KCNE2 gene variation can disrupt HCN1-KCNE2 channel function and this may potentially contribute to cardiac arrhythmogenesis.[12]

KCNE2 is also associated with familial atrial fibrillation, which may involve excessive KCNQ1-KCNE2 current caused by KCNE2 gain-of-function mutations.[13] [14] KCNE2 may also regulate the Cav1.2 voltage-gated calcium channel.[15]

Mouse heart[edit]

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 as sevoflurane. 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.[16]

Recently, a battery of extracardiac effects were discovered in Kcne2-/- mice that may contribute to cardiac arrhythmogenesis in Kcne2-/- 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 in Kcne2-/- mice in the context of myocardial ischemia and post-ischemic arrhythmogenesis.[17]

See also[edit]


  1. ^ a b c d e f g 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. 
  2. ^ Abbott GW (2012). "KCNE2 and the K (+) channel: the tail wagging the dog". Channels 6 (1): 1–10. doi:10.4161/chan.19126. PMID 22513486. 
  3. ^ Tinel N, Diochot S, Lauritzen I, Barhanin J, Lazdunski M, Borsotto M (Sep 2000). "M-type KCNQ2-KCNQ3 potassium channels are modulated by the KCNE2 subunit". FEBS Letters 480 (2-3): 137–41. PMID 11034315. 
  4. ^ Abbott GW, Tai KK, Neverisky DL, Hansler A, Hu Z, Roepke TK, Lerner DJ, Chen Q, Liu L, Zupan B, Toth M, Haynes R, Huang X, Demirbas D, Buccafusca R, Gross SS, Kanda VA, Berry GT (Mar 2014). "KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability". Science Signaling 7 (315): ra22. doi:10.1126/scisignal.2005025. PMID 24595108. 
  5. ^ Roepke TK, Kanda VA, Purtell K, King EC, Lerner DJ, Abbott GW (Dec 2011). "KCNE2 forms potassium channels with KCNA3 and KCNQ1 in the choroid plexus epithelium". FASEB Journal 25 (12): 4264–73. doi:10.1096/fj.11-187609. PMID 21859894. 
  6. ^ Roepke TK, Anantharam A, Kirchhoff P, Busque SM, Young JB, Geibel JP, Lerner DJ, Abbott GW (Aug 2006). "The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion". The Journal of Biological Chemistry 281 (33): 23740–7. doi:10.1074/jbc.M604155200. PMID 16754665. 
  7. ^ Roepke TK, Purtell K, King EC, La Perle KM, Lerner DJ, Abbott GW (6 July 2010). "Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia". PloS One 5 (7): e11451. doi:10.1371/journal.pone.0011451. PMID 20625512. 
  8. ^ Roepke TK, King EC, Purtell K, Kanda VA, Lerner DJ, Abbott GW (Feb 2011). "Genetic dissection reveals unexpected influence of beta subunits on KCNQ1 K+ channel polarized trafficking in vivo". FASEB Journal 25 (2): 727–36. doi:10.1096/fj.10-173682. PMID 21084694. 
  9. ^ Roepke TK, King EC, Reyna-Neyra A, Paroder M, Purtell K, Koba W, Fine E, Lerner DJ, Carrasco N, Abbott GW (Oct 2009). "Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis". Nature Medicine 15 (10): 1186–94. doi:10.1038/nm.2029. PMID 19767733. 
  10. ^ Purtell K, Paroder-Belenitsky M, Reyna-Neyra A, Nicola JP, Koba W, Fine E, Carrasco N, Abbott GW (Aug 2012). "The KCNQ1-KCNE2 K⁺ channel is required for adequate thyroid I⁻ uptake". FASEB Journal 26 (8): 3252–9. doi:10.1096/fj.12-206110. PMID 22549510. 
  11. ^ Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, Priori SG, Roden DM, George AL, Goldstein SA (Sep 2000). "A common polymorphism associated with antibiotic-induced cardiac arrhythmia". Proceedings of the National Academy of Sciences of the United States of America 97 (19): 10613–8. doi:10.1073/pnas.180223197. PMID 10984545. 
  12. ^ Nawathe PA, Kryukova Y, Oren RV, Milanesi R, Clancy CE, Lu JT, Moss AJ, Difrancesco D, Robinson RB (Sep 2013). "An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia". Journal of Cardiovascular Electrophysiology 24 (9): 1021–7. doi:10.1111/jce.12163. PMID 23631727. 
  13. ^ Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y, Liang B, Lin J, Liu Y, Liu B, Zhou Q, Zhang D, Wang R, Ma N, Su X, Niu K, Pei Y, Xu W, Chen Z, Wan H, Cui J, Barhanin J, Chen Y (Nov 2004). "Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation". American Journal of Human Genetics 75 (5): 899–905. doi:10.1086/425342. PMID 15368194. 
  14. ^ Nielsen JB, Bentzen BH, Olesen MS, David JP, Olesen SP, Haunsø S, Svendsen JH, Schmitt N (2014). "Gain-of-function mutations in potassium channel subunit KCNE2 associated with early-onset lone atrial fibrillation". Biomarkers in Medicine 8 (4): 557–70. doi:10.2217/bmm.13.137. PMID 24796621. 
  15. ^ Liu W, Deng J, Wang G, Zhang C, Luo X, Yan D, Su Q, Liu J (Jul 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. PMID 24681347. 
  16. ^ Roepke TK, Kontogeorgis A, Ovanez C, Xu X, Young JB, Purtell K, Goldstein PA, Christini DJ, Peters NS, Akar FG, Gutstein DE, Lerner DJ, Abbott GW (Oct 2008). "Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I(K,slow1) and I(to,f)". FASEB Journal 22 (10): 3648–60. doi:10.1096/fj.08-110171. PMID 18603586. 
  17. ^ Hu Z, Kant R, Anand M, King EC, Krogh-Madsen T, Christini DJ, Abbott GW (Feb 2014). "Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death". Circulation. Cardiovascular Genetics 7 (1): 33–42. doi:10.1161/CIRCGENETICS.113.000315. PMID 24403551. 

Further reading[edit]

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