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

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

^*Howard Hughes Medical Institute Laboratories, and Departments of ^†Cell Biology, ^‡‡Medicine and Biochemistry, ^¶Radiology, and ^‡Surgery, Duke University Medical Center, Durham, NC 27710; ^§Department of Medicine, University of California at San Diego, La Jolla, CA 92093; ^‖Department of Pharmacological and Pharmaceutical Sciences, University of Houston, TX 77204; and ^**Birth Defects Center, University of North Carolina, Chapel Hill, NC 27599

Abstract

The β-adrenergic receptor kinase 1 (βARK1) 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 βARK1 gene in mice by homologous recombination. No homozygote βARK1^−/− embryos survive beyond gestational day 15.5. Prior to gestational day 15.5, βARK1^−/− embryos display pronounced hypoplasia of the ventricular myocardium essentially identical to the “thin myocardium syndrome” observed upon gene inactivation of several transcription factors (RXRα, N-myc, TEF-1, WT-1). Lethality in βARK1^−/− 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 βARK1^−/− embryos demonstrate that βARK1 appears to be the predominant GRK in early embryogenesis and that it plays a fundamental role in cardiac development.

Footnotes

↵ †† To whom reprint requests should be addressed at: Howard Hughes Medical Institute, Duke University Medical Center, Box 3287, Durham, NC 27710. e-mail: caron002{at}mc.duke.edu.
↵ §§ Present address: Institut National de la Santé et de la Recherche Médicale U-288, Centre Pitié-Salpetrière, 75013 Paris, France.
Gordon G. Hammes, Duke University Medical Center, Durham, NC
Abbreviations: βARK, β-adrenergic receptor kinase; GRK, G protein-coupled receptor kinase; E, gestational day; LV, left ventricle.