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Role of the acidic N' region of cardiac troponin I in regulating myocardial function

Sakthivel Sadayappan^*, Natosha Finley, Jack W. Howarth, Hanna Osinska^*, Raisa Klevitsky^*, John N. Lorenz, Paul R. Rosevear and Jeffrey Robbins^*,1

^* Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA;

Molecular Genetics, Biochemistry and Microbiology; and

Molecular and Cellular Physiology, Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA

¹Correspondence: Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, MLC 7020, 3333 Burnet Ave., Cincinnati, OH 45229-3039, USA. E-mail: jeff.robbins{at}cchmc.org

Cardiac troponin I (cTnI) phosphorylation modulates myocardial contractility and relaxation during β-adrenergic stimulation. cTnI differs from the skeletal isoform in that it has a cardiac specific N' extension of 32 residues (N' extension). The role of the acidic N' region in modulating cardiac contractility has not been fully defined. To test the hypothesis that the acidic N' region of cTnI helps regulate myocardial function, we generated cardiac-specific transgenic mice in which residues 2–11 (cTnI^2–11) were deleted. The hearts displayed significantly decreased contraction and relaxation under basal and β-adrenergic stress compared to nontransgenic hearts, with a reduction in maximal Ca²⁺-dependent force and maximal Ca²⁺-activated Mg²⁺-ATPase activity. However, Ca²⁺ sensitivity of force development and cTnI-Ser^23/24 phosphorylation were not affected. Chemical shift mapping shows that both cTnI and cTnI^2–11 interact with the N lobe of cardiac troponin C (cTnC) and that phosphorylation at Ser^23/24 weakens these interactions. These observations suggest that residues 2–11 of cTnI, comprising the acidic N' region, do not play a direct role in the calcium-induced transition in the cardiac regulatory or N lobe of cTnC. We hypothesized that phosphorylation at Ser^23/24 induces a large conformational change positioning the conserved acidic N region to compete with actin for the inhibitory region of cTnI. Consistent with this hypothesis, deletion of the conserved acidic N' region results in a decrease in myocardial contractility in the cTnI^2–11 mice demonstrating the importance of acidic N' region in regulating myocardial contractility and mediating the response of the heart to β-AR stimulation.—Sadayappan, S., Finley, N., Howarth, J. W., Osinska, H., Klevitsky, R., Lorenz, J. N., Rosevear, P. R., Robbins, J. Role of the acidic N' region of cardiac troponin I in regulating myocardial function.

Key Words: muscle • transgenic mouse model • contractility • heart