Document Detail

Control of myocardial contractile function by the level of beta-adrenergic receptor kinase 1 in gene-targeted mice.
MedLine Citation:
PMID:  9660778     Owner:  NLM     Status:  MEDLINE    
We studied the effect of alterations in the level of myocardial beta-adrenergic receptor kinase betaARK1) in two types of genetically altered mice. The first group is heterozygous for betaARK1 gene ablation, betaARK1(+/-), and the second is not only heterozygous for betaARK1 gene ablation but is also transgenic for cardiac-specific overexpression of a betaARK1 COOH-terminal inhibitor peptide, betaARK1(+/-)betaARKct. In contrast to the embryonic lethal phenotype of the homozygous betaARK1 knockout (Jaber, M., Koch, W. J., Rockman, H. A., Smith, B., Bond, R. A., Sulik, K., Ross, J., Jr., Lefkowitz, R. J., Caron, M. G., and Giros, B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 12974-12979), betaARK1(+/-) mice develop normally. Cardiac catheterization was performed in mice and showed a stepwise increase in contractile function in the betaARK1(+/-) and betaARK1(+/-)betaARKct mice with the greatest level observed in the betaARK1(+/-)betaARKct animals. Contractile parameters were measured in adult myocytes isolated from both groups of gene-targeted animals. A significantly greater increase in percent cell shortening and rate of cell shortening following isoproterenol stimulation was observed in the betaARK1(+/-) and betaARK1(+/-)betaARKct myocytes compared with wild-type cells, indicating a progressive increase in intrinsic contractility. These data demonstrate that contractile function can be modulated by the level of betaARK1 activity. This has important implications in disease states such as heart failure (in which betaARK1 activity is increased) and suggests that betaARK1 should be considered as a therapeutic target in this situation. Even partial inhibition of betaARK1 activity enhances beta-adrenergic receptor signaling leading to improved functional catecholamine responsiveness.
H A Rockman; D J Choi; S A Akhter; M Jaber; B Giros; R J Lefkowitz; M G Caron; W J Koch
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  273     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1998 Jul 
Date Detail:
Created Date:  1998-08-13     Completed Date:  1998-08-13     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  18180-4     Citation Subset:  IM    
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
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MeSH Terms
Adrenergic beta-Agonists / pharmacology
Cyclic AMP-Dependent Protein Kinases / metabolism*
Heart / drug effects
Heart Rate / drug effects
Isoproterenol / pharmacology
Mice, Transgenic
Myocardial Contraction*
Myocardium / enzymology
Rhodopsin / metabolism
beta-Adrenergic Receptor Kinases
Grant Support
Reg. No./Substance:
0/Adrenergic beta-Agonists; 7683-59-2/Isoproterenol; 9009-81-8/Rhodopsin; EC AMP-Dependent Protein Kinases; EC Receptor Kinases

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