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Structural Basis for Competition between Drug Binding and Kv1.3 Accessory Subunit-Induced N-Type Inactivation of Kv1.5 Channels

From the Nora Eccles Harrison Cardiovascular Research and Training Institute and Department of Physiology, University of Utah, Salt Lake City, Utah (N.D., P.K, T.G., M.C.S.); and Institut für Normale und Pathologische Physiologie, Universität Marburg, Marburg, Germany (V.R.)

Kv subunits are accessory proteins that modify gating of Kv1 channels. Kv1.3 subunits bind to the N termini of Kv1.5 -subunits and induce fast N-type inactivation, slow the rate of deactivation, and alter the voltage dependence and kinetics of channel activation. The N terminus of a Kv subunit and quaternary ammonium compounds bind to the inner pore of Kv1 channels; however, it is unknown to what extent the pore binding sites for drugs and Kv subunits overlap. Here, we used site-directed Ala mutagenesis to scan residues of the Kv1.5 pore to define the binding site for Kv1.3 subunits. Individual mutations of five residues in the S6 domain (Val505, Ile508, Leu510, Val512, and Val516) greatly retarded or prevented Kv1.3 induced inactivation, and reduced effects on Kv1.5 deactivation. Mutation of Thr479 and Thr480 enhanced Kv1.3-induced N-type inactivation. None of the Ala mutations prevented the Kv1.3-induced negative shifts in the voltage dependence of activation or slow C-type inactivation, suggesting that these gating effects are mediated by an interaction other than the one for N-type inactivation. Thr479, Thr480, Val505, Ile508, and Val512, of Kv1.5 channels are also important interaction sites for the anthranilic acid S0100176 (N-benzyl-N-pyridin-3-ylmethyl-2-(toluene-4-sulfonylamino)-benzamide hydrochloride). Leu510 and V516A prevented Kv1.3-induced inactivation but did not alter drug block. Block of Kv1.5 by S0100176 was reduced and voltage-dependent in the presence of Kv1.3 but not in the presence of an N-truncated form of the Kv subunit. Thus, residues in the pore of Kv1.5 required for N-type inactivation overlap with but are not identical to the drug binding site.

Address correspondence to: Michael C. Sanguinetti, Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95 S 2000 E, Salt Lake City, UT 84112. E-mail: sanguinetti{at}cvrti.utah.edu

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