Regulation of Kv4.3 currents by Ca2+/calmodulin-dependent protein kinase II

Gerard Sergeant, Susumu Ohya, James Reihill, Brian Perrino, Gregory Amberg, Yuji Imaizumi, Burton Horowitz, Kenton Sanders, Sang Don Koh

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Abstract

The voltage-dependent K+ channel 4.3 (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 Ca2+/calmodulin-dependent protein kinase II (CaMKII); however, the molecular target of CaMKII in these studies has not been elucidated. We performed experiments to investigate whether CaMKII could regulate Kv4.3 currents directly. Inclusion of the autothiophosphorylated form of CaMKII in the patch pipette (10 nM) prolonged Kv4.3 currents such that the time required 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 effects opposite 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-terminal region of the channel, resulted in currents that inactivated more rapidly but recovered from inactivation at a slower rate than that of wild-type controls. In addition, these currents were unaffected by dialysis with either autothiophosphorylated 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-terminal region of the channel.
Original languageEnglish
Pages (from-to)C304
Number of pages9
JournalAmerican Journal of Physiology - Cell Physiology
Volume288
Issue number2
Publication statusPublished - 10 Jan 2005

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    Sergeant, G., Ohya, S., Reihill, J., Perrino, B., Amberg, G., Imaizumi, Y., Horowitz, B., Sanders, K., & Koh, S. D. (2005). Regulation of Kv4.3 currents by Ca2+/calmodulin-dependent protein kinase II. American Journal of Physiology - Cell Physiology, 288(2), C304.