Referenced in: none

Automatically associated channels: Kv7.1 , Slo1

Title: Phosphorylation of the IKs channel complex inhibits drug block: novel mechanism underlying variable antiarrhythmic drug actions.

Authors: Tao Yang, Hideaki Kanki, Dan M Roden

Journal, date & volume: Circulation, 2003 Jul 15 , 108, 132-4

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/12835205

Abstract
IKs, an important repolarizing current in heart, is an antiarrhythmic drug target and is markedly increased by activation of protein kinase A (PKA; eg, by beta-adrenergic stimulation). Because beta-adrenergic stimulation is a frequent trigger of arrhythmias, we hypothesized that PKA stimulation inhibits drug block.CHO cells were transfected with KCNQ1 cDNA (encoding the pore-forming subunit) with or without the ancillary subunit KCNE1. IC50 for quinidine block of basal IKs was 5.8+/-1.2 micromol/L, versus 19.9+/-3.2 micromol/L (P<0.01) for PKA-stimulated current. A similar >3-fold shift was apparent in the absence of KCNE1 and with the IKs-specific blocker chromanol 293B. The first current recorded after channels were held at rest and exposed to the drug was reduced approximately 40%, and further depolarizations increased the block with a time constant (tau) of 181+/-27 seconds. By contrast, PKA-stimulated channels displayed a <5% first-pulse block and much slower block development (tau=405+/-85 seconds). Alanine substitution at 3 potential PKA target sites (S27, S468, and T470) generated an IKs that did not increase with PKA stimulation; this mutant retained wild-type drug sensitivity that was unaffected by PKA.Activation of this key intracellular signaling pathway blunts drug block. The onset of block and the data with the PKA-resistant mutant support the concept that phosphorylation of the KCNQ1 subunit directly modulates drug access to a binding site on the channel. These data identify a novel mechanism for modulation of drug-channel interactions that may be especially important during beta-adrenergic stimulation.