Heart Failure Cardiac G-Protein–Coupled Receptor Kinase 2 Ablation Induces a Novel Ca Handling Phenotype Resistant to Adverse Alterations and Remodeling After Myocardial Infarction

cardiomyocytes from wild-type and GRK2 knockout (GRK2KO) mice without (sham) or with myocardial infarction (MI). In cardiac myocytes isolated from unstressed wild-type and GRK2KO hearts, myocyte contractions and Ca transients were similar, but GRK2KO myocytes had lower sarcoplasmic reticulum (SR) Ca content because of increased sodium-Ca exchanger activity and inhibited SR Ca ATPase by local protein kinase A–mediated activation of phosphodiesterase 4 resulting in hypophosphorylated phospholamban. This Ca handling phenotype is explained by a higher fractional SR Ca release induced by increased L-type Ca channel currents. After -adrenergic stimulation, GRK2KO myocytes revealed significant increases in contractility and Ca transients, which were not mediated through cardiac L-type Ca channels but through an increased SR Ca . Interestingly, post-MI GRK2KO mice showed better cardiac function than post-MI control mice, which is explained by an improved Ca handling phenotype. The SR Ca content was better maintained in post-MI GRK2KO myocytes than in post-MI control myocytes because of better-maintained L-type Ca channel current density and no increase in sodium-Ca exchanger in GRK2KO myocytes. An L-type Ca channel blocker, verapamil, reversed some beneficial effects of GRK2KO. Conclusions—These data argue for novel differential regulation of L-type Ca channel currents and SR load by GRK2. G-protein–coupled receptor kinase 2 ablation represents a novel beneficial Ca handling phenotype resisting adverse