Multiplex kinase signaling modifies cardiac function at the level of sarcomeric proteins.

The transient change in tension development and length in a working cardiac myocyte during the heart beat reflects the integrated effects of kinases in signaling cascades regulating mechanisms controlling the dynamics and intensity of a transient increase in cytoplasmic Ca2+ as well as the responsiveness of the sarcomeres to Ca2+. Kinases modifying regulatory membrane proteins represent a major mechanism for controlling the coupling of transmembrane voltage to the release of Ca2+ into the cytoplasm that triggers contraction by binding to TnC2 and for regulating dynamics of the return of Ca2+ to the diastolic state by membrane transporters and exchangers (1). Binding of Ca2+ to TnC triggers a strong reaction of sarcomere thick filament cross-bridges with the thin filament actins and the promotion of force development and shortening (2, 3). Sarcomeres are not passive responders to these transient changes in cytoplasmic Ca2+. Protein-protein interactions downstream of Ca2+-TnC are subject to functionally significant modifications by signaling cascades that modify the number and kinetics of actin-cross-bridge reactions (Fig. 1). FIGURE 1. Kinases affecting sarcomeric proteins. Major substrates for these kinases are illustrated in a region of overlap between thin actin-containing and thick myosin-containing filaments. Also shown is a portion of the network of proteins at the Z-disk, ... I focus here on control mechanisms at the level of the sarcomere and on kinases immediately upstream of sarcomeric protein substrates. Major substrates are (i) thin filament proteins TnI, TnT, and Tm, which are important in transducing the Ca2+-TnC signal (4, 5); (ii) MyBP-C (6) and RLC (7), which control the radial movement of cross-bridges from the thick filament backbone; and (iii) titin, a giant third filament controlling diastolic tension as well as length-dependent radial movement of cross-bridges (8, 9). Detailed discussion of how phosphorylation modifies the function of these proteins has been reviewed elsewhere (2, 4–9). In general, phosphorylation of thin filament proteins controls sarcomere Ca2+ sensitivity, kinetics of Ca2+ binding to TnC (related to dynamics of relaxation), and the number and kinetics of cross-bridges reacting with the thin filament (related to levels and rates of rise and fall of tension). Phosphorylations of MyBP-C and RLC control Ca2+ sensitivity and rates of contraction/relaxation by modifying the local concentration of cross-bridges at the interface with actins. MyBP-C may also interact with and affect thin filament activation. Cardiac but not skeletal isoforms of titin contain phosphorylation sites within a unique sequence, located in the elastic segment. Phosphorylation of a unique cardiac titin reduces passive tension (8). To appreciate the potential role of how kinases modify sarcomeric function, it is important to consider the working cardiac myocyte operating in an environment influenced by immediate prevailing mechanical (load and length), neural, endocrine, autocrine, and paracrine control mechanisms and by the short- and long-term history of this environment. Beat-to-beat control mechanisms, which occur, for example, as hemodynamic load rises with exercise or falls with rest, are related to the immediate prevailing regulatory mechanisms. Mechanisms occurring over the time scale of hours, days, and longer are related to growth and remodeling in response to chronic changes in load or chemical environment as occur with sustained bouts of exercise, hypertension, or ischemia. Kinases and phosphorylations play a significant role in compensation and adaptation to beat-to-beat and chronic changes in hemodynamic load. However, maladaptive kinase activation may induce remodeling and phosphorylations of sarcomeric proteins with cardiovascular disorders, leading to heart failure (10, 11).