Disease relevance of Kcnh2

• Knockout of ERG1 B predisposes mice to episodic sinus bradycardia [1].
• Mutations in human ERG1 lead to defects in cardiac repolarization, referred to as the long QT syndrome [1].
• We created a mouse model with a prolonged Q-T interval and spontaneous arrhythmias by overexpressing the NH(2) terminus and first transmembrane segment (Kv1.1N206Tag) of a delayed rectifier potassium channel (LQT(+/-) mouse) [2].
• The aim of this study was to explore and characterize the effect of the histidine-specific reagent diethylpyrocarbonate (DEPC) on the ERG (ether-à-go-go related gene) channels of whole-cell voltage-clamped NG108-15 neuroblastoma x glioma hybrid cells [3].
• Here we review the phenotype of a mouse model for the recessive form of LQT known as Jervell and Lange-Nielsen syndrome [4].

High impact information on Kcnh2

• In adult ERG1 B(-/-) myocytes no I(Kr) was detected [1].
• Through homologous recombination in mouse embryonic stem cells the ERG1 B potassium channel transcript was eliminated while the ERG1 A transcript was maintained [1].
• When expressed in Xenopus oocytes, the kinetics of activation and deactivation of the MERG B current were best fit by a biexponential function, with the fast components dominant over the slow components [5].
• To better define the role of Erg in the heart, we cloned Merg1 from mouse genomic and cardiac cDNA libraries [6].
• The MERG B current was blocked by the selective IKr blocker, dofetilide, with an IC50 of 54 nmol/L [5].

Biological context of Kcnh2

• In this study, we report a detailed analysis of Kcnq1, Kcnh2, and Kcne3 protein expression during mouse embryogenesis [7].
• Action potential duration (APD) was prolonged to the same extent and was more highly variable in myocytes derived from LQT(+/-) and LQT(+/+) mice than in myocytes derived from wild-type (WT) FVB mice [2].
• BSAP, the Erg transcription factor and unidentified factors interacting with a GC rich binding site denoted PyG [8].
• Except for KCNE1, Northern blots (KCNQ1, MERG, Kv1.5, connexins 40 and 43, TREK1, and TASK1) did not detect sex differences [9].

Anatomical context of Kcnh2

• Expression pattern of the ether-a-go-go-related (ERG) family proteins in the adult mouse central nervous system: evidence for coassembly of different subunits [10].
• We isolated three cardiac isoforms of Merg1: Merg1a is homologous to HERG and is expressed in heart, brain, and testes, Merg1a' lacks the first 59 amino acids of Merg1a and is not expressed abundantly, and Merg1b has a markedly shorter divergent N-terminal cytoplasmic domain and is expressed specifically in the heart [6].
• Single myocytes from portal vein displayed membrane staining with an ERG1-specific antibody [11].
• Here we show that expression of the mouse ether-a-go-go related gene (Merg1a) K+ channel is up-regulated in skeletal muscle of mice experiencing atrophy as a result of both malignant tumor expression and disuse [12].
• We provide evidence from PCR analysis and expression studies to indicate that these two components are mediated by two distinct molecular species of K(+) channel: the fast component resembles that in sympathetic ganglia and is probably carried by KCNQ2/3 channels, whereas the slow component appears to be carried by merg1a channels [13].

Associations of Kcnh2 with chemical compounds

• Melk2 currents are insensitive to E-4031, a class III antiarrhythmic compound that blocks the Human Ether-à-go-go-Related Gene (HERG) channel and its counterpart in native tissues, IKr [14].
• Under ketamine anesthesia, the Q-T interval of both LQT(+/+) and LQT(+/-) mice was comparably prolonged versus that of WT mice [2].
• Bradykinin (100 nM) inhibited 76% of the KCNQ component of current compared with 12% of the merg component [15].
• Acetylcholine (100 microM) inhibited 89% of the KCNQ component of current compared to 34% of the merg component [15].
• After 15 min of intracellular dialysis with the cADPR antagonist 8-amino-cADP ribose (100 microM), the inhibition reduced to 40% and 19% and after 30 min it was further reduced to 8% and 5% for the KCNQ currents and merg currents respectively [15].

Other interactions of Kcnh2

• The biophysical properties of channels from the Eag and Erg subfamilies have been described, and based on their characteristic features and expression patterns, Erg channels have been associated with native currents in the heart [14].
• ERG channels are encoded by different genes: the erg1 gene, which can generate two alternative transcripts (erg1a and erg1b), erg2 and erg3 [10].
• Our results demonstrate that Kcnq1 and Kcnh2 are widely distributed [7].
• Protein distribution of Kcnq1, Kcnh2, and Kcne3 potassium channel subunits during mouse embryonic development [7].

References