Disease relevance of ERG

• The function of voltage-gated human ether-à-go-go related gene (hERG) K(+) channels is critical for both normal cardiac repolarization and suppression of arrhythmias initiated by premature excitation [1].
• The enhanced risk of Torsades de Pointes associated with hypokalaemia in aLQTS may be due to reduction of other (non-hERG) potassium currents, further reducing the repolarization reserve, and not due to direct modulation of hERG block by [K(+)](o) [2].
• 1. Drug-induced block of the rapidly activating delayed rectifier K(+) current (I(Kr)), encoded by human ether-a-go-go-related gene (hERG), has been linked to acquired long QT syndrome (aLQTS) [2].
• As in silico predictive models are increasingly accepted, from reactivity and genetic toxicity to models for hERG inhibition, kinase crossreactivity and cytochrome P450 reactivity, increasing amounts of high-quality data will be needed to 'feed' the models [3].

High impact information on ERG

• Alternate transcripts of the human ether-à-go-go-related gene (hERG1) encode two subunits, hERG 1a and 1b, which form potassium channels regulating cardiac repolarization, neuronal firing frequency, and neoplastic cell growth [4].
• Development, interpretation and temporal evaluation of a global QSAR of hERG electrophysiology screening data [5].
• This increases the relative occupancy of the open state and contributes to the marked temperature sensitivity of hERG current magnitude observed during action potential voltage clamps [1].
• Here, we describe a novel, naturally occurring hERG channel activator, mallotoxin (MTX) [6].
• Mallotoxin Is a Novel Human Ether-a-go-go-Related Gene (hERG) Potassium Channel Activator [6].

Biological context of ERG

• A 'global' model of hERG K(+) channel was built to satisfy three basic criteria for QSAR models in drug discovery: (1) assessment of the applicability domain, (2) assuring that model decisions can be interpreted by medicinal chemists and (3) assessment of model performance after the model was built [5].
• Null mutations were generated in the erg-3 gene of Neurospora crassa by repeat-induced point mutation (RIP) [7].
• The erg-3 mutant could be complemented by transformation with recombinant genes that encode proteins chimeric for amino acid sequences from the transmembrane (TM) domain of human lamin B receptor (LBR) [7].
• For hERG potassium channel currents, the IC50 value was 0.62 +/- 0.30 microM [8].

Anatomical context of ERG

• 3. These results demonstrate that [K(+)](o) does not directly modulate drug block of hERG channels expressed in an HEK-293 cell line [2].

Associations of ERG with chemical compounds

• The erg-3 (sterol delta14,15-reductase) gene of Neurospora crassa: generation of null mutants by repeat-induced point mutation and complementation by proteins chimeric for human lamin B receptor sequences [7].
• 5. Compound 8i showed good selectivity for blockade of Kv1.5 vs hERG and L-type calcium channels [9].
• 2. The effects of selected [K(+)](o) (1-20 mmol/L) on hERG block with four structurally diverse compounds (dofetilide, mesoridazine, quinidine and terfenadine) from different therapeutic classes were evaluated [2].
• Preliminary results suggest that a macromolecular signalling complex indeed occurs between integrins and the hERG1 protein and that hERG channel activity can modulate integrin downstream signalling [10].

Other interactions of ERG

• Genes encoding chimeras of Neurospora crassa erg-3 and human TM7SF2 proteins fail to complement Neurospora and yeast sterol C-14 reductase mutants [11].

Analytical, diagnostic and therapeutic context of ERG

• The effects of MTX on hERG channels were investigated using the patch-clamp technique [6].

References