Abstract 887: Cardiac-Specific Ablation of GRK2 Re-Defines its Roles in Heart Development and Beta-Adrenergic Signaling
Introduction: G-protein receptor kinase 2 (GRK2) is one of seven mammalian GRKs that phosphorylate ligand-bound seven transmembrane receptors, causing receptor uncoupling from G-proteins and potentially activating non-G-protein signaling pathways. Previous conventional deletion of GRK2 caused embryonic lethality associated with cardiac malformations, suggesting a role in cardiac development, but preventing a determination of its function in the adult heart. We hypothesized that germ-line and tissue-specific GRK2 knockout would result in dissimilar phenotypes.
Methods: We created GRK2-loxP-targeted mice and used Cre-recombination to generate germ-line and cardiac-specific knockouts, and studied cardiac structure, gene expression and function.
Results: GRK2 deletion in the pre-implantation embryo with EIIa-Cre (germ-line null) resulted in developmental retardation and embryonic lethality between embryonic day (E) 10.5 and 11.5. At E9.5 cardiac myocyte specification and cardiac looping were evident, but ventricular development was delayed and myocardium was hypoplastic. Specific deletion of GRK2 in the embryonic heart with Nkx2.5-Cre produced viable mice with normal basal cardiac structure and function, and without pathological gene expression. In these animals, contractile sensitivity to the beta-adrenergic receptor (beta-AR) agonist, isoproterenol, was enhanced, desensitization was impaired, and late p38 phosphorylation was diminished.
Conclusion: These findings show that GRK2 is not essential for cardiac development after initial cardiac myocyte specification. In the adult heart, cardiac GRK2 is a major factor controlling homologous desensitization of beta-AR-mediated inotropy, and is required for induction of late p38 signaling by beta-ARs.