title: Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction.
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.
  
  
  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(2+) 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(2+) 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(2+) 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(2+) 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.
authors.affiliation: Department of Internal Medicine III, Cardiology, University of Heidelberg, Germany. philip.raake@med.uni-heidelberg.de
authors.forename: Philip W
authors.initials: PW
authors.lastname: Raake
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.forename: Leif E
authors.initials: LE
authors.lastname: Vinge
authors.forename: Henriette
authors.initials: H
authors.lastname: Brinks
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Naser
authors.initials: N
authors.lastname: Jaleel
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Li
authors.forename: Mingxin
authors.initials: M
authors.lastname: Tang
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D056966:Excitation Contraction Coupling / Q000502:physiology*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000150:complications* / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000502:physiology*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011943:Receptors, Adrenergic, beta; D019831:Sodium-Calcium Exchanger; D014700:Verapamil; D017868:Cyclic AMP-Dependent Protein Kinases; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium