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(Circulation Research. 2007;100:1486.)
© 2007 American Heart Association, Inc.

Cellular Biology

The Troponin C G159D Mutation Blunts Myofilament Desensitization Induced by Troponin I Ser23/24 Phosphorylation

Brandon J. Biesiadecki, Tomoyoshi Kobayashi, John S. Walker, R. John Solaro, Pieter P. de Tombe

From the Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago.

Correspondence to Pieter P. de Tombe, Department of Physiology and Biophysics, University of Illinois, 835 S Wolcott Ave (M/C 901), Chicago, IL 60612. E-mail PdeTombe{at}uic.edu

Striated muscle contraction is regulated by the binding of Ca²⁺ to the N-terminal regulatory lobe of the cardiac troponin C (cTnC) subunit in the troponin complex. In the heart, ß-adrenergic stimulation induces protein kinase A phosphorylation of cardiac troponin I (cTnI) at Ser23/24 to alter the interaction of cTnI with cTnC in the troponin complex and is critical to the regulation of cardiac contractility. We investigated the effect of the dilated cardiomyopathy linked cTnC Gly159 to Asp (cTnC-G159D) mutation on the development of Ca²⁺-dependent tension and ATPase rate in whole troponin-exchanged skinned rat trabeculae. Even though this mutation is located in the C-terminal lobe of cTnC, the G159D mutation was demonstrated to depress ATPase activation and filament sliding in vitro. The effects of this mutation within the cardiac myofilament are unknown. Our results demonstrate that the cTnC-G159D mutation by itself does not alter the myofilament response to Ca²⁺ in the cardiac muscle lattice. However, in the presence of cTnI phosphorylated at Ser23/24, which reduced Ca²⁺ sensitivity and enhanced cross-bridge cycling in controls, cTnC-G159D specifically blunted the phosphorylation induced decrease in Ca²⁺-sensitive tension development without altering cross-bridge cycling. Measurements in purified troponin confirmed that this cTnC-G159D blunting of myofilament desensitization results from altered Ca²⁺-binding to cTnC. Our results provide novel evidence that modification of the cTnC-cTnI interaction has distinct effects on troponin Ca²⁺-binding and cross-bridge kinetics to suggest a novel role for thin filament mutations in the modulation of myofilament function through ß-adrenergic signaling as well as the development of cardiomyopathy.

Key Words: skinned muscle • rat • human • tension cost • cross-bridge cycling • cardiomyopathy

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