Published Online
on June 30, 2003

A more recent version of this article appeared on July 15, 2003

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Submitted on February 20, 2003
Revised on May 30, 2003
Accepted on May 30, 2003

Phosphorylation of the I_Ks Channel Complex Inhibits Drug Block. Novel Mechanism Underlying Variable Antiarrhythmic Drug Actions

Tao Yang PhD, Hideaki Kanki MD, PhD, and Dan M. Roden MD^*

From the Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tenn.

^* To whom correspondence should be addressed. E-mail: dan.roden{at}vanderbilt.edu.

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. IC₅₀ for quinidine block of basal I_Ks was 5.8±1.2 µmol/L, versus 19.9±3.2 µmol/L (P<0.01) for PKA-stimulated current. A similar >3-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 40%, and further depolarizations increased the block with a time constant () of 181±27 seconds. By contrast, PKA-stimulated channels displayed a <5% first-pulse block and much slower block development (=405±85 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.

Key words: antiarrhythmia agents • signal transduction • ion channels

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