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This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/H2364    most recent 00409.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qu, Y.-J. Articles by Morales, M. J. Search for Related Content PubMed PubMed Citation Articles by Qu, Y.-J. Articles by Morales, M. J.

W-7 modulates K_v4.3: pore block and Ca²⁺-calmodulin inhibition

Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York

Submitted 23 April 2005 ; accepted in final form 2 January 2007

Ca⁺-calmodulin (Ca²⁺-CaM)-dependent protein kinase II (Ca²⁺/CaMKII) is an important regulator of cardiac ion channels, and its inhibition may be an approach for treatment of ventricular arrhythmias. Using the two-electrode voltage-clamp technique, we investigated the role of W-7, an inhibitor of Ca²⁺-occupied CaM, and KN-93, an inhibitor of Ca²⁺/CaMKII, on the K_v4.3 channel in Xenopus laevis oocytes. W-7 caused a voltage- and concentration-dependent decrease in peak current, with IC₅₀ of 92.4 µM. The block was voltage dependent, with an effective electrical distance of 0.18 ± 0.05, and use dependence was observed, suggesting that a component of W-7 inhibition of K_v4.3 current was due to open-channel block. W-7 made recovery from open-state inactivation a biexponential process, also suggesting open-channel block. We compared the effects of W-7 with those of KN-93 after washout of 500 µM BAPTA-AM. KN-93 reduced peak current without evidence of voltage or use dependence. Both W-7 and KN-93 accelerated all components of inactivation. We used wild-type and mutated K_v4.3 channels with mutant CaMKII consensus phosphorylation sites to examine the effects of W-7 and KN-93. In contrast to W-7, KN-93 at 35 µM selectively accelerated open-state inactivation in the wild-type vs. the mutant channel. W-7 had a significantly greater effect on recovery from inactivation in wild-type than in mutant channels. We conclude that, at certain concentrations, KN-93 selectively inhibits Ca²⁺/CaMKII activity in Xenopus oocytes and that the effects of W-7 are mediated by direct interaction with the channel pore and inhibition of Ca²⁺-CaM, as well as a change in activity of Ca²⁺-CaM-dependent enzymes, including Ca²⁺/CaMKII.

potassium channel; inactivation gating; KN-93; transient outward potassium current; calmodulin kinase II

This article has been cited by other articles:

				C. Xie, V. E. Bondarenko, M. J. Morales, and H. C. Strauss Closed-state inactivation in Kv4.3 isoforms is differentially modulated by protein kinase C Am J Physiol Cell Physiol, November 1, 2009; 297(5): C1236 - C1248. [Abstract] [Full Text] [PDF]