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J. Biol. Chem., Vol. 280, Issue 50, 41324-41331, December 16, 2005

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Differential Contribution of Troponin I Phosphorylation Sites to the Endothelin-modulated Contractile Response^*

From the Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109

Cardiac troponin I is a phosphorylation target for endothelin-activated protein kinase C. Earlier work in cardiac myocytes expressing nonphosphorylatable slow skeletal troponin I provided evidence that protein kinase C-mediated cardiac troponin I phosphorylation accelerates relaxation. However, replacement with the slow skeletal isoform also alters the myofilament pH response and the Ca²⁺ transient, which could influence endothelin-mediated relaxation. Here, differences in the Ca²⁺ transient could not explain the divergent relaxation response to endothelin in myocytes expressing cardiac versus slow skeletal troponin I nor could activation of Na⁺/H⁺ exchange. Three separate clusters within cardiac troponin I are phosphorylated by protein kinase C, and we set out to determine the contribution of the Thr¹⁴⁴ and Ser²³/Ser²⁴ clusters to the endothelin-mediated contractile response. Myocyte replacement with a cardiac troponin I containing a Thr¹⁴⁴ substituted with the Pro residue found in slow skeletal troponin I resulted in prolonged relaxation in response to acute endothelin compared with control myocytes. Ser²³/Ser²⁴ also is a target for protein kinase C phosphorylation of purified cardiac troponin I, and although this cluster was not acutely phosphorylated in intact myocytes, significant phosphorylation developed within 1 h after adding endothelin. Replacement of Ser²³/Ser²⁴ with Ala indicated that this cluster contributes significantly to relaxation during more prolonged endothelin stimulation. Overall, results with these mutants provide evidence that Thr¹⁴⁴ plays an important role in the acute acceleration of relaxation, whereas Ser²³/Ser²⁴ contributes to relaxation during more prolonged activation of protein kinase C by endothelin.

Received for publication, June 2, 2005 , and in revised form, October 3, 2005.

^* 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 To whom correspondence should be addressed: Dept. of Surgery, 1150 W. Medical Center Dr., B562 MSRB II 0686, Ann Arbor, MI 48109. Tel.: 734-615-8911; Fax: 734-763-0323; E-mail: wfall{at}umich.edu.

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