Disease relevance of KCNE2

• Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation [1].
• We identified a novel missense mutation, V65 M, in the KCNE2 gene of a 17-year-old female with syncope and LQTS [2].
• Mechanisms whereby mutations of KCNE2 produce fatal cardiac arrhythmias characteristic of long-QT syndrome remain unclear [3].
• Here, we disrupted the murine kcne2 gene and found that kcne2 (-/-) mice have a severe gastric phenotype with profoundly reduced parietal cell proton secretion, abnormal parietal cell morphology, achlorhydria, hypergastrinemia, and striking gastric glandular hyperplasia arising from an increase in the number of non-acid secretory cells [4].
• A potassium channel protein KCNE2, identified as a down-regulated gene in gastric cancer, was chosen for further study [5].

High impact information on KCNE2

• MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia [6].
• Three missense mutations associated with long QT syndrome and ventricular fibrillation are identified in the gene for MiRP1 [6].
• Six genotypes (LQT1 to LQT6) have been identified, and attempts are being made to correlate different mutations with clinical signs and specific therapy [7].
• So far, KCNE2 (MirP1) has only been shown to modulate HERG current [8].
• Transduction of protein phosphorylation into physiologically necessary channel function represents a previously uncharacterized role for the KCNE1 auxiliary subunit, which can be disrupted in LQT-5 [9].

Chemical compound and disease context of KCNE2

• The present study investigates a novel gene therapy approach for atrial arrhythmias, using a clarithromycin-responsive ion channel subunit mutation, hMiRP1-Q9E, cloned into an expression plasmid; wild-type expression plasmids encoding human minK-related protein 1 (hMiRP1) were also used as controls [10].

Biological context of KCNE2

• Furthermore, four novel single-nucleotide polymorphisms (SNPs) and one amino acid polymorphism (R1047L) were identified in KCNH2, and one novel SNP and one previously known amino acid polymorphism (T8A) were found in KCNE2 [11].
• METHODS: We developed a robust single-strand conformation polymorphism-heteroduplex screening analysis, with identical thermocycling conditions for all PCR reactions, covering all of the coding exons in KCNH2 and KCNE2 [11].
• Identification and functional characterization of a novel KCNE2 (MiRP1) mutation that alters HERG channel kinetics [2].
• In this study, the frequency of mutations in KCNE2 of 150 unrelated LQTS patients without known genotype and of 100 controls was analyzed using single-strand conformation polymorphism analysis and direct sequencing [2].
• In this study, we characterize functional interactions between HERG and KCNE2 with a view to defining underlying mechanisms for action potential prolongation and long-QT syndrome [3].

Anatomical context of KCNE2

• The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion [4].
• To determine whether KCNE2 can also modulate the slow component of native I(f/h/q) currents, we co-expressed KCNE2 with HCN4 in Xenopus oocytes and in Chinese hamster ovary (CHO) cells and analysed the resulting currents using two-electrode voltage-clamp and patch-clamp techniques, respectively [12].
• Consistent with this is the recent description of KCNE2, which is highly expressed in the sinoatrial node, as a beta-subunit of rapidly activating HCN1 and HCN2 channels [12].
• The results suggest that KCNQ1, probably with KCNE2 or KCNE3 as its accessory unit, provides a significant fraction of IKvol in rat hepatocytes [13].
• Similar to KCNQ1, KCNE2 was present in gastric glands in only a subset of cells that probably represent parietal cells [14].

Associations of KCNE2 with chemical compounds

• An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the beta subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current, was found in 2 of the 28 probands [1].
• Mutation of arginine to histidine (R --> H) to yield R83H-MiRP2 is associated with periodic paralysis; the analogs K69H-MinK and K75H-MiRP1 were also studied [15].
• Here, we examine KCNE2 in 98 patients with drug-induced LQTS, identifying three individuals with sporadic mutations and a patient with sulfamethoxazole-associated LQTS who carried a single-nucleotide polymorphism (SNP) found in approximately 1.6% of the general population [16].
• The KCNQ1/KCNE1/KCNE2 current had a more depolarized activation voltage, a faster deactivation kinetics, and a less sensitivity to activation by mefenamic acid [17].
• One KCNE2 mutation (R77W) identified in a patient treated with flecainide did not alter I(Kr) [18].

Physical interactions of KCNE2

• The summation of cAMP-mediated effects is a net diminution of the effective current, but when HERG is complexed with with the K(+) channel accessory proteins MiRP1 or minK, the stimulatory effects of cAMP are favored [19].

Co-localisations of KCNE2

• Expression studies in Chinese hamster ovary cells revealed that mutant and wild-type MiRP1 co-localized with HERG subunits and formed functional channels [2].
• KCNE2 is colocalized with KCNQ1 and KCNE1 in cardiac myocytes and may function as a negative modulator of I(Ks) current amplitude in the heart [20].

Regulatory relationships of KCNE2

• In both cell types, co-expressed KCNE2 enhanced HCN4-generated current amplitudes, slowed the activation kinetics and shifted the voltage for half-maximal activation of currents to more negative voltages [12].
• When HERG was co-expressed with the accessory subunit KCNE2, an IC50 value of 52 microM was determined [21].

Other interactions of KCNE2

• KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel [8].
• Missense forme frust mutations were identified in four aLQTS patients: D85N in KCNE1 (two cases), T8A in KCNE2, and P347S in KCNH2 [22].
• We demonstrate that KCNE2 associates with KCNQ2 and/or KCNQ3 subunits [23].
• However, the identification of common nonsynonymous single nucleotide polymorphisms (nSNPs; i.e., amino-acid coding variants) with functional phenotypes in the SCN5A Na(+) channel and MiRP1 K(+) channel beta-subunit have challenged this viewpoint [24].
• No significant EPI-MID differences were observed in the expression of the other channel proteins studied (Kir2.1, alpha1C, HERG and MiRP1) [25].

Analytical, diagnostic and therapeutic context of KCNE2

• Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot (immunoblot) techniques, we studied the reactivity of specific antibodies to the 37-kilodalton (kDa) major iron-regulated protein (MIRP) of gonococci grown under iron-limiting conditions [26].
• Electroimmunoblotting experiments confirmed that outer-membrane protein III (PIII) and the major iron-regulated protein (MIRP), two conserved gonococcal proteins, were cleaved by cathepsin G [27].

References