Troponin I modulation of cardiac performance: Plasticity in the survival switch

Abstract

Signaling complexes targeting the myofilament are essential in modulating cardiac performance. A central target of this signaling is cardiac troponin I (cTnI) phosphorylation. This review focuses on cTnI phosphorylation as a model for myofilament signaling, discussing key gaps and future directions towards understanding complex myofilament modulation of cardiac performance. Human heart cTnI is phosphorylated at 14 sites, giving rise to a complex modulatory network of varied functional responses. For example, while classical Ser23/24 phosphorylation mediates accelerated relaxation, protein kinase C phosphorylation of cTnI serves as a brake on contractile function. Additionally, the functional response of cTnI multi-site phosphorylation cannot necessarily be predicted from the response of individual sites alone. These complexities underscore the need for systematically evaluating single and multi-site phosphorylation on myofilament cellular and in vivo contractile function. Ultimately, a complete understanding of these multi-site responses requires work to establish site occupancy and dominance, kinase/phosphatase signaling balance, and the function of adaptive secondary phosphorylation. As cTnI phosphorylation is essential for modulating cardiac performance, future insight into the complex role of cTnI phosphorylation is important to establish sarcomere signaling in the healthy heart as well as identification of novel myofilament targets in the treatment of disease.

Keywords: Cardiac; Contraction; Phosphorylation; Relaxation; Signaling; Troponin I.

FIGURE 1.

A. Location of known Ser (S), Thr (T), and Tyr (Y) phosphorylated residues on cardiac troponin I (cTnI). B. Location of phosphorylation sites within the troponin complex composed of cTnI, troponin T (TnT) and troponin C (TnC) and in the proposed TnI protein structure in the absence (−Ca²⁺) and presence (+Ca²⁺) bound to TnC. N-TnI refers to the amino-terminus and C-TnI to the carboxy-terminus of TnI. Structures in B are adapted from Takeda et al., 2003 (ref 72).