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 agonis t-dependent phosphorylation and desensitization of G protein-coupled r eceptors, We have cloned and disrupted the beta ARK1 gene in mice by h omologous 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 myocardi um 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 t o heart failure as they exhibit a >70% decrease in cardiac ejection fr action determined by direct in utero intravital microscopy. These resu lts along with the virtual absence of endogenous GRK activity in beta ARK1(-/-) embryos demonstrate that beta ARK1 appears to be the predomi nant GRK in early embryogenesis and that it plays a fundamental role i n cardiac development.