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.
Jaber
M
M
Howard Hughes Medical Institute Laboratories, Duke University Medical Center, Durham, NC 27710, USA.
Koch
W J
WJ
Rockman
H
H
Smith
B
B
Bond
R A
RA
Sulik
K K
KK
Ross
J
J
Lefkowitz
R J
RJ
Caron
M G
MG
Giros
B
B
D000818:Animals; D002678:Chimera; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D005314:Embryonic and Fetal Development; D005091:Exons; D005260:Female; D005313:Fetal Death; D005318:Fetal Heart / Q000502:physiology*; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics / Q000473:pathology; D006720:Homozygote; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011995:Recombination, Genetic; D051552:beta-Adrenergic Receptor Kinases
D017931:DNA Primers; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases