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1 Physiology and Cell Biology, University of Nevada, School of Medicine, Reno, NV, USA
2 Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
* To whom correspondence should be addressed. E-mail: sdk{at}physiology.unr.edu.
Kv4.3 is one of the major molecular correlates encoding a class of rapidly inactivating K+ currents, including the transient outward current in the heart (ITO) and A-currents (IA) in neuronal, and smooth muscle preparations. Recent studies have shown that ITO in human atrial myocytes and IA in murine colonic myocytes are modulated by CaMKII, however the molecular target of CaMKII in these studies was not elucidated. We performed experiments to investigate if CaMKII could regulate Kv4.3 currents directly. Inclusion of the auto-thiophosphorylated form of Ca2+-calmodulin-dependent protein kinase II in the patch pipette (10 nM) prolonged Kv4.3 currents such that the time to reach 50% inactivation from peak more than doubled with positive shifts in voltage-dependence of both activation and inactivation. In contrast, the rate of recovery from inactivation was accelerated under these conditions. CaMKII inhibitory peptide or KN-93 produced opposite effects to that above, thus the rate of inactivation was increased and recovery from inactivation decreased. A number of mutagenesis experiments were conducted on the three candidate CaMKII consensus sequence sites on the channel. Mutations at S550A, located at the COOH-terminus region of the channel resulted in currents which inactivated more rapidly, but which recovered from inactivation at a slower rate than wild type controls. In addition these currents were unaffected by dialysis with either auto-thiophosphorylated CaMKII or the specific inhibitory peptide of CaMKII suggesting that CaMKII slows the inactivation and accelerates the rate of recovery from inactivation of Kv4.3 currents by a direct effect at S550A, located at the COOH-terminus region of the channel.
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