Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function
- Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12974-9. doi: 10.1073/pnas.93.23.12974.
- 1. Howard Hughes Medical Institute Laboratories, Duke University Medical Center, Durham, NC 27710, USA.
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.