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PMID: 8917529 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 93 ·No. 23 ·1996-11-12 ·Pages 12974-9

Jaber M, Koch WJ, Rockman H, Smith B, Bond RA, Sulik KK, Ross J, Lefkowitz RJ, Caron MG, Giros B

Abstract

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.

MeSH Terms
Animals Chimera Cyclic AMP-Dependent Protein Kinases/biosynthesis,genetics,metabolism DNA Primers Embryonic and Fetal Development Exons Female Fetal Death Fetal Heart/physiology Heart Defects, Congenital/embryology,genetics,pathology Homozygote Mice Mice, Transgenic Myocardium/enzymology Polymerase Chain Reaction Pregnancy Recombination, Genetic beta-Adrenergic Receptor Kinases
Chemicals
DNA Primers Cyclic AMP-Dependent Protein Kinases beta-Adrenergic Receptor Kinases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Jaber M
Howard Hughes Medical Institute Laboratories, Duke University Medical Center, Durham, NC 27710, USA.
Koch W J
Rockman H
Smith B
Bond R A
Sulik K K
Ross J
Lefkowitz R J
Caron M G
Giros B
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.93.23.12974
Published
1996-11-12
Pages
12974-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC24031
Subset
IM
Grants
NHLBI NIH HHS · R01 HL016037 · United States
NINDS NIH HHS · R01 NS019576 · United States
NHLBI NIH HHS · HL 16037 · United States
NINDS NIH HHS · NS 19576 · United States
External Links
PubMed source DOI: 10.1073/pnas.93.23.12974 PMC Full Text View journal details
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