Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function

The beta-adrenergic receptor kinase 1 (beta ARK1) is a member of the G protein-coupled receptor kinase (GRK) family that mediates the agonist-dependent phosphorylation and desensitization of G protein-coupled receptors, We have cloned and disrupted the beta ARK1 gene in mice by homologous recombination, No homozygote beta ARK1(-/-) embryos survive beyond gestational day 15.5. Prior to gestational day 15.5, beta ARK1(-/-) embryos display pronounced hypoplasia of the ventricular myocardium essentially identical to the ''thin myocardium syndrome'' observed upon gene inactivation of several transcription factors (RXR alpha, N-myc, TEF-1, WT-1). Lethality in beta ARK1(-/-) embryos is likely due to heart failure as they exhibit a >70% decrease in cardiac ejection fraction determined by direct in utero intravital microscopy. These results along with the virtual absence of endogenous GRK activity in beta ARK1(-/-) embryos demonstrate that beta ARK1 appears to be the predominant GRK in early embryogenesis and that it plays a fundamental role in cardiac development.