Differential contribution of troponin I phosphorylation sites to the endothelin modulated contractile response

doi:10.1074/jbc.M506043200

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Papers In Press, published online ahead of print October 18, 2005
J. Biol. Chem, 10.1074/jbc.M506043200
Submitted on June 2, 2005
Revised on October 3, 2005
Accepted on October 18, 2005

Differential contribution of troponin I phosphorylation sites to the endothelin modulated contractile response

Margaret V. Westfall, Adonia M. Lee, and Dustin A. Robinson

Department of Surgery, University of Michigan, Ann Arbor, MI 48109-0686

Corresponding Author: wfall{at}umich.edu

Cardiac troponin I is a phosphorylation target for endothelin activated protein kinase C. Earlier work in cardiac myocytes expressing non-phosphorylatable 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 then set out to determine the contribution of the Thr144 and Ser23/24 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 to control myocytes. Ser23/24 also is a target for protein kinase C phosphorylation of purified cardiac troponin I, and while this cluster was not acutely phosphorylated in intact myocytes, significant phosphorylation developed within 1 hr after adding endothelin. Replacement of Ser23/24 with Ala indicated 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, while Ser23/24 contributes to relaxation during more prolonged activation of protein kinase C by endothelin.

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