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J. Biol. Chem., Vol. 281, Issue 35, 25560-25567, September 1, 2006

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Calmodulin Kinase II Is Involved in Voltage-dependent Facilitation of the L-type Ca_v1.2 Calcium Channel

IDENTIFICATION OF THE PHOSPHORYLATION SITES^*

Tae-Seong Lee, Rosi Karl, Sven Moosmang, Peter Lenhardt, Norbert Klugbauer¹, Franz Hofmann, Thomas Kleppisch, and Andrea Welling²

From the Institut für Pharmakologie und Toxikologie and the Institut für Molekulare Medizin, Technische Universität München, Biedersteiner Strasse 29, 80802 München, Germany

Calcium-dependent facilitation of L-type calcium channels has been reported to depend on the function of calmodulin kinase II. In contrast, the mechanism for voltage-dependent facilitation is not clear. In HEK 293 cells expressing Ca_v1.2, Ca_v2a, and calmodulin kinase II, the calcium current measured at +30 mV was facilitated up to 1.5-fold by a 200-ms-long prepulse to +160 mV. This voltage-dependent facilitation was prevented by the calmodulin kinase II inhibitors KN93 and the autocamtide-2-related peptide. In cells expressing the Ca_v1.2 mutation I1649E, a residue critical for the binding of Ca²⁺-bound calmodulin, facilitation was also abolished. Calmodulin kinase II was coimmunoprecipitated with the Ca_v1.2 channel from murine heart and HEK 293 cells expressing Ca_v1.2 and calmodulinkinase II. The precipitated Ca_v1.2 channel was phosphorylated in the presence of calmodulin and Ca²⁺. Fifteen putative calmodulin kinase II phosphorylation sites were identified mostly in the carboxyl-terminal tail of Ca_v1.2. Neither truncation at amino acid 1728 nor changing the II-III loop serines 808 and 888 to alanines affected facilitation of the calcium current. In contrast, facilitation was decreased by the single mutations S1512A and S1570A and abolished by the double mutation S1512A/S1570A. These serines flank the carboxyl-terminal EF-hand motif. Immunoprecipitation of calmodulin kinase II with the Ca_v1.2 channel was not affected by the mutation S1512A/S1570A. The phosphorylation of the Ca_v1.2 protein was strongly decreased in the S1512A/S1570A double mutant. These results suggest that voltage-dependent facilitation of the Ca_v1.2 channel depends on the phosphorylation of Ser¹⁵¹²/Ser¹⁵⁷⁰ by calmodulin kinase II.

Received for publication, August 5, 2005 , and in revised form, May 22, 2006.

^* This work was supported by grants from Deutsche Forschungsgemeinschaft and Fond der Chemischen Industrie. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Freiburg, Albertstr. 25, 79104 Freiburg, Germany.

² To whom correspondence should be addressed: Institut für Pharmakologie und Toxikologie, TU München, Biedersteiner Str. 29, 80802 München, Germany. Tel.: 49-89-4140-3283; Fax: 49-89-4140-3261; E-mail: Welling{at}ipt.med.tu-muenchen.de.

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