Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca 2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction

Philip W. Raake, Xiaoying Zhang, Leif E. Vinge, Henriette Brinks, Erhe Gao, Naser Jaleel, Yingxin Li, Mingxin Tang, Patrick Most, Gerald W. Dorn, Steven R. Houser, Hugo A. Katus, Xiongwen Chen, Walter J. Koch

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Background-G-protein-coupled receptor kinase 2 (GRK2) is a primary regulator of β-adrenergic signaling in the heart. G-protein-coupled receptor kinase 2 ablation impedes heart failure development, but elucidation of the cellular mechanisms has not been achieved, and such elucidation is the aim of this study. Methods and Results-Myocyte contractility, Ca 2+ handling and excitation-contraction coupling were studied in isolated 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 2+ content because of increased sodium-Ca 2+ exchanger activity and inhibited SR Ca 2+ 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 2+ release induced by increased L-type Ca 2+ channel currents. After β-adrenergic stimulation, GRK2KO myocytes revealed significant increases in contractility and Ca 2+ transients, which were not mediated through cardiac L-type Ca 2+ channels but through an increased SR Ca 2+. 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 2+ content was better maintained in post-MI GRK2KO myocytes than in post-MI control myocytes because of better-maintained L-type Ca 2+ channel current density and no increase in sodium-Ca exchanger in GRK2KO myocytes. An L-type Ca 2+ channel blocker, verapamil, reversed some beneficial effects of GRK2KO. Conclusions-These data argue for novel differential regulation of L-type Ca 2+ channel currents and SR load by GRK2. G-protein-coupled receptor kinase 2 ablation represents a novel beneficial Ca 2+ handling phenotype resisting adverse remodeling after MI.

Original languageEnglish
Pages (from-to)2108-2118
Number of pages11
JournalCirculation
Volume125
Issue number17
DOIs
StatePublished - May 1 2012

Keywords

  • Calcium
  • Excitation contraction coupling
  • Experimental models
  • G-Protein coupled receptor kinase 2
  • Heart failure

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