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.

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(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: Philip W Raake, Xiaoying Zhang, Leif E Vinge, Henriette Brinks, Erhe Gao, Naser Jaleel, Yingxin Li, Mingxin Tang, Patrick Most, Gerald W Dorn 2nd, Steven R Houser, Hugo A Katus, Xiongwen Chen, Walter J Koch
• Journal: Circulation (Circulation) Vol. 125 Issue 17 Pg. 2108-18 (May 01 2012) ISSN: 1524-4539 [Electronic] United States
• PMID: 22496128 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Agonists
• Calcium Channel Blockers
• Calcium Channels, L-Type
• Receptors, Adrenergic, beta
• Sodium-Calcium Exchanger
• Verapamil
• Cyclic AMP-Dependent Protein Kinases
• GRK2 protein, mouse
• G-Protein-Coupled Receptor Kinase 2
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Calcium

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Calcium (metabolism)
• Calcium Channel Blockers (pharmacology)
• Calcium Channels, L-Type (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Excitation Contraction Coupling (physiology)
• G-Protein-Coupled Receptor Kinase 2 (deficiency, genetics, physiology)
• Heart Failure (etiology, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Contraction
• Myocardial Infarction (complications, enzymology)
• Myocytes, Cardiac (metabolism)
• Phenotype
• Protein Structure, Tertiary
• Receptors, Adrenergic, beta (physiology)
• Sarcoplasmic Reticulum (metabolism)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (metabolism)
• Sodium-Calcium Exchanger (metabolism)
• Ventricular Remodeling (physiology)
• Verapamil (pharmacology)