Document Detail

Protein kinase A-mediated phosphorylation contributes to enhanced contraction observed in mice that overexpress beta-adrenergic receptor kinase-1.
MedLine Citation:
PMID:  16951260     Owner:  NLM     Status:  MEDLINE    
Transgenic mice with cardiac specific overexpression of beta-adrenergic receptor kinase-1 (betaARK-1) exhibit reduced contractility in the presence of adrenergic stimulation. However, whether contractility is altered in the absence of exogenous agonist is not clear. Effects of betaARK-1 overexpression on contraction were examined in mouse ventricular myocytes, studied at 37 degrees C, in the absence of adrenergic stimulation. In myocytes voltage-clamped with microelectrodes (18-26 MOmega; 2.7 M KCl) to minimize intracellular dialysis, contractions were significantly larger in betaARK-1 cells than in wild-type myocytes. In contrast, when cells were dialyzed with patch pipette solution (1-3 MOmega; 0 mM NaCl, 70 mM KCl, 70 mM potassium aspartate, 4 mM MgATP, 1 mM MgCl(2), 2.5 mM KH(2)PO(4), 0.12 mM CaCl(2), 0.5 mM EGTA, and 10 mM HEPES), the extent of cell shortening was similar in wild-type and betaARK-1 myocytes. Furthermore, when cells were dialyzed with solutions that contained phosphodiesterase-sensitive sodium-cAMP (50 microM), the extent of cell shortening was similar in wild-type and betaARK-1 myocytes. However, when patch solutions were supplemented with phosphodiesterase-resistant 8-bromo-cAMP (50 muM), contractions were larger in betaARK-1 than wild-type cells. This difference was eliminated by the protein kinase A inhibitor N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89). Interestingly, Ca(2+) current amplitudes and inactivation rates were similar in betaARK-1 and wild-type cells in all experiments. These results suggest components of the adenylyl cyclase-protein kinase A pathway are sensitized by chronically increased betaARK-1 activity, which may augment contractile function in the absence of exogenous agonist. Thus, changes in contractile function in myocytes from failing hearts may reflect, in part, effects of chronic up-regulation of betaARK-1 on the cAMP-protein kinase A pathway.
Erin E Mueller; Scott A Grandy; Susan E Howlett
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-01
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  319     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-11-19     Completed Date:  2007-01-09     Revised Date:  2012-06-07    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1307-16     Citation Subset:  IM    
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
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MeSH Terms
Adenylate Cyclase / drug effects,  physiology
Calcium Channels, L-Type / drug effects,  physiology
Cardiac Pacing, Artificial
Cell Separation
Cell Size
Cyclic AMP / analogs & derivatives,  pharmacology
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors,  physiology*
Data Interpretation, Statistical
Enzyme Inhibitors / pharmacology
G-Protein-Coupled Receptor Kinase 2
Gene Expression Regulation, Enzymologic / physiology
Heart Ventricles / cytology,  drug effects
Isoquinolines / pharmacology
Myocardial Contraction / genetics*,  physiology*
Myocytes, Cardiac / drug effects
Patch-Clamp Techniques
Signal Transduction / drug effects,  physiology
Sulfonamides / pharmacology
beta-Adrenergic Receptor Kinases / biosynthesis*,  genetics*
Reg. No./Substance:
0/Calcium Channels, L-Type; 0/Enzyme Inhibitors; 0/Isoquinolines; 0/Sulfonamides; 127243-85-0/N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; 60-92-4/Cyclic AMP; EC AMP-Dependent Protein Kinases; EC protein, mouse; EC Receptor Kinase 2; EC Receptor Kinases; EC Cyclase

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