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Talk Abstract
K+-channels as molecular targets for antiarrhythmic drugs. Molecular mechanisms of drug action

Dirk J. Snyders, Vanderbilt Univ. School of Medicine

Therapy of cardiac arrhythmias remains a challenge due to issues of efficiency, specificity and/or side effects. We will discuss antiarrhythmic drug action in relation to the molecular biology of cardiac ion channels, specifically potassium channels. Class III antiarrhythmic drugs increase cardiac refractoriness by prolonging the plateau duration of the action potential. While this can be achieved by increasing inward currents or blocking outward currents, most clinically used drugs act as K+ channel blockers. Over the past decade a large number of Kv channel $\alpha$ and $\beta$ subunits have been cloned. The basic properties (voltage-gating and selective pore permeation) reside in the $\alpha$ subunits; and can be modulated by accessory $\beta$-subunits. The molecular architecture of the native channel complexes is not fully understood, but the emerging pattern is that the different cardiac K+ currents controlling the plateau phase are each encoded by subunits belonging to distinct subfamilies (I TO: Kv4.2/3; IKur: Kv1.5; IKr: HERG; IKs: KvLQT1 + minK).

In principle, channel function can be altered by interfering with either permeation or gating. The cloned subunits have enabled us to identify binding sites and molecular determinants fro drug action. Quinidine and other local anesthetic type drugs have been shown to act as open channel blockers. That is, they bind in the intracellular mouth of the (hydrophilic) permeation pathway, but binding is apparently stabilized by hydrophobic interactions. An obvious question is how much specificity can be expected with such rather generic mechanism. Fortunately, a reasonable degree of subfamily specificity has been demonstrated for several drugs, and small changes in side chains of amino acids in the proposed binding site can abolish stereoselective block. These findings support the view that more specific channel blocking drugs can be developed based on the emerging molecular information. However, an new challenge is posed by recent studies that have revealed down-regulation of some currents in cardiac disease (including long QT disease). Since block of near-absent currents is unlikely to be of therapeutic value, novel agents that up-regulate ion channels (agonists) could have a future role in the treatment of certain arrhythmias.

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