Phosphorylation of the IKs Channel Complex Inhibits Drug Block: Novel Mechanism Underlying Variable Antiarrhythmic Drug Actions

T. Yang
2003 Circulation  
Background-I Ks , an important repolarizing current in heart, is an antiarrhythmic drug target and is markedly increased by activation of protein kinase A (PKA; eg, by ␤-adrenergic stimulation). Because ␤-adrenergic stimulation is a frequent trigger of arrhythmias, we hypothesized that PKA stimulation inhibits drug block. Methods and Results-CHO cells were transfected with KCNQ1 cDNA (encoding the pore-forming subunit) with or without the ancillary subunit KCNE1. IC 50 for quinidine block of
more » ... al I Ks was 5.8Ϯ1.2 mol/L, versus 19.9Ϯ3.2 mol/L (PϽ0.01) for PKA-stimulated current. A similar Ͼ3-fold shift was apparent in the absence of KCNE1 and with the I Ks -specific blocker chromanol 293B. The first current recorded after channels were held at rest and exposed to the drug was reduced Ϸ40%, and further depolarizations increased the block with a time constant () of 181Ϯ27 seconds. By contrast, PKA-stimulated channels displayed a Ͻ5% first-pulse block and much slower block development (ϭ405Ϯ85 seconds). Alanine substitution at 3 potential PKA target sites (S27, S468, and T470) generated an I Ks that did not increase with PKA stimulation; this mutant retained wild-type drug sensitivity that was unaffected by PKA. Conclusions-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 ␤-adrenergic stimulation. (Circulation. 2003;108:132-134.)
doi:10.1161/01.cir.0000082708.86266.b8 pmid:12835205 fatcat:uu7osprebvgorbybcwv7xwxefu