KCNE2

Potassium channel, voltage gated subfamily E regulatory beta subunit 2
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2M0Q
Identifiers
Symbols	KCNE2 ; ATFB4; LQT5; LQT6; MIRP1
External IDs	OMIM: 603796 MGI: 1891123 HomoloGene: 71688 GeneCards: KCNE2 Gene
Gene ontology Molecular function • inward rectifier potassium channel activity • delayed rectifier potassium channel activity • potassium channel regulator activity • protein homodimerization activity • ion channel binding • voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization Cellular component • lysosome • plasma membrane • voltage-gated potassium channel complex • cell surface Biological process • aging • potassium ion import • cellular response to drug • tongue development • regulation of membrane repolarization • regulation of ventricular cardiac muscle cell membrane repolarization • potassium ion export • potassium ion transmembrane transport • cardiac muscle cell action potential involved in contraction • ventricular cardiac muscle cell action potential • membrane repolarization • membrane repolarization during action potential • regulation of heart rate by cardiac conduction • regulation of potassium ion transmembrane transport • positive regulation of voltage-gated calcium channel activity • positive regulation of proteasomal protein catabolic process • regulation of inward rectifier potassium channel activity • regulation of cyclic nucleotide-gated ion channel activity • regulation of delayed rectifier potassium channel activity • negative regulation of delayed rectifier potassium channel activity Sources: Amigo / QuickGO
Orthologs
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. MiRP1 is a voltage-gated potassium channel accessory subunit (beta subunit) associated with Long QT syndrome.

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. 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.

Discovery

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.

Tissue distribution

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.

Epithelial functions and pathophysiology

Choroid plexus

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.

Gastric

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.

Thyroid

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.

Cardiac functions and pathophysiology

Human heart

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.

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.

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.

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

Mouse heart

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 I_to and I_Kslow, respectively.

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.

See also

• Voltage-gated potassium channel
• KCNE1
• KCNE3
• KCNQ1

Further reading

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External links

• GeneReviews/NIH/NCBI/UW entry on Romano-Ward Syndrome
• KCNE2 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• KCNE2 human gene location in the UCSC Genome Browser.
• KCNE2 human gene details in the UCSC Genome Browser.