Cardiac contractility: modulation of myofibrillar calcium sensitivity by beta-adrenergic stimulation.
Under conditions of beta-adrenergic receptor stimulation, cardiac performance is enhanced. cAMP-dependent phosphorylation of proteins located in the sarcolemma, in the membrane of the sarcoplasmic reticulum (SR), and in the myofibrils of the cardiomyocytes, mediates the effects of catecholamines on the heart. Altered Ca2+ handling leads to increased levels of intracellular free Ca2+. This is mainly responsible for the enhanced contractility of the myocardium that can be observed following beta-adrenergic receptor stimulation. Phosphorylation of the thin filament regulatory protein troponin I (TnI), on the other hand, decreases the Ca2+ sensitivity of the myofilaments, which means that the Ca2+ concentration necessary for the development of half-maximal force is increased. Cardiac TnI has a 26-33 amino acid N-terminal extension that is not present in fast and slow skeletal muscle TnI isoforms. Within this segment, two adjacent serine residues can be phosphorylated by a cAMP-dependent protein kinase. Replacement of endogenous TnI by different mutants obtained using site-directed mutagenesis of one or both of the serine residues has shown that only the bis-phosphorylated form decreases the Ca2+ sensitivity. This Ca2+ desensitizing effect, together with an increased rate of Ca2+ uptake into the SR due to phosphorylation of the SR membrane protein phospholamban, is responsible for the 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 the elevation of heart rate that accompanies beta-adrenergic receptor stimulation.
Kögler
H
H
Department of Physiology II, University of Heidelberg, Germany.
Rüegg
J C
JC
D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D002395:Catecholamines / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D006801:Humans; D009200:Myocardial Contraction / Q000502:physiology*; D009210:Myofibrils / Q000378:metabolism*; D010766:Phosphorylation; D011486:Protein C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D019210:Troponin I / Q000378:metabolism
D015220:Calcium Channels; D002395:Catecholamines; D011486:Protein C; D011943:Receptors, Adrenergic, beta; D019210:Troponin I; D000242:Cyclic AMP; D011494:Protein Kinases