S100A1: A Regulator of Striated Muscle Sarcoplasmic Reticulum Ca²⁺ Handling, Sarcomeric, and Mitochondrial Function

Figure 3

Proposed model for S100A1 inotropic actions in cardiomyocytes. (a) During excitation-contraction coupling, the action potential-dependent opening of the L-type Ca²⁺ channel (LTCC) results in a transsarcolemmal Ca²⁺ entry which triggers sarcoplasmic reticulum (SR) Ca²⁺ release via Ryanodine Receptor 2 (RyR2) that in turn activates myofilament cross-bridge cycling and mechanical contraction. During diastole, the SR Ca²⁺ reuptake is conducted by the SR Ca²⁺ ATPase (SERCA), whereas the sodium-calcium exchanger (NCX) extrudes Ca²⁺ from the cardiomyocyte to keep steady-state conditions. (b) S100A1 interacts with both RyR2 and the SERCA-Phospholamban (PLB)-complex and is present at myofilaments and mitochondria. Increased S100A1 protein levels result in an enhanced systolic SR Ca²⁺ release via RyR2 without influencing LTCC activity. Augmented SR Ca²⁺ release is balanced by an intensified SERCA activity leading to an improved Ca²⁺ cycling and a raised force generation. Additionally, the S100A1/F1-ATPase interference in mitochondria is associated with an enhanced generation of cytoplasmic ATP in cardiomyocytes. Moreover, S100A1 inhibits the actin-titin interactions in the sarcomere, resulting in a reduced precontractile passive tension [24].

(a)

(b)