Meta-Biol

• Pathways

Force generation of the heart and calcium homeostasis are coupled in the myocardium. In the sarcoplasmic reticulum (SR), calcium stores provide the majority of calcium used in muscle contraction-relaxation. During relaxation, an ATP-dependent calcium pump (ATP2A2 aka SERCA) in the SR is essential for the recovery of calcium. The reuptake of calcium by ATP2A2 determines the rate of relaxation and the size of the calcium store available for subsequent contractions. In cardiac muscle, a second protein called phospholamban (PLN) acts as a reversible inhibitor of ATP2A2 and thereby modulates contractility in response to physiological factors. Defects in PLN are associated with lethal dilated cardiomyopathy in humans (Ceholski et al. 2012). PLN is a pentameric protein that, when phosphorylated, alleviates ATP2A2 inhibition and may stimulate SR calcium uptake in cardiomyocytes (Kaliman et al. 2005). Phosphorylation of PLN is mediated by myotonin-protein kinase (DMPK), a SR-bound homodimeric enzyme (Bush et al. 2000, Zhang & Epstein 2003).