CARDIAC CONTRACTILITY - MODULATION OF MYOFIBRILLAR CALCIUM SENSITIVITY BY BETA-ADRENERGIC STIMULATION

Under conditions of beta-adrenergic receptor stimulation, cardiac perf ormance is enhanced. cAMP-dependent phosphorylation of proteins locate d in the sarcolemma, in the membrane of the sarcoplasmic reticulum (SR ), and in the myofibrils of the cardiomyocytes, mediates the effects o f catecholamines on the heart. Altered Ca2+ handling leads to increase d levels of intracellular free Ca2+. This is mainly responsible for th e enhanced contractility of the myocardium that can be observed follow ing beta-adrenergic receptor stimulation. Phosphorylation of the thin filament regulatory protein troponin I (TnI), on the other hand, decre ases the Ca2+ sensitivity of the myofilaments, which means that the Ca 2+ concentration necessary for the development of half-maximal force i s increased. Cardiac TnI has a 26-33 amino acid N-terminal extension t hat is not present in fast and slow skeletal muscle TnI isoforms. With in this segment, two adjacent serine residues can be phosphorylated by a cAMP-dependent protein kinase. Replacement of endogenous TnI by dif ferent mutants obtained using site-directed mutagenesis of one or both of the serine residues has shown that only the bis-phosphorylated for m decreases the Ca2+ sensitivity. This Ca2+ desensitizing effect, toge ther with an increased rate of Ca2+ uptake into the SR due to phosphor ylation of the SR membrane protein phospholamban, is responsible for t he relaxation-enhancing effect (lusitropic action) of catecholamines. The latter is an important determinant of coronary perfusion and rapid diastolic filling of the ventricles, and is also a prerequisite for t he elevation of heart rate that accompanies beta-adrenergic receptor s timulation.