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Am J Physiol Heart Circ Physiol (July 17, 2003). doi:10.1152/ajpheart.00112.2003
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Submitted on February 4, 2003
Accepted on July 15, 2003

Cardiac Hypertrophy and Altered {beta}-adrenergic Signaling in Transgenic Mice Expressing the Amino Terminus of {beta}ARK1

Janelle R. Keys1, Emily A. Greene1, Chris J. Cooper1, Sathyamangla V. Naga Prasad2, Howard A. Rockman2, and Walter J. Koch1*

1 Department of Surgery, Duke University Medical Center, Durham, NC, USA
2 Department of Medicine (Cardiology), Duke University Medical Center, Durham, NC, USA

* To whom correspondence should be addressed. E-mail: koch0002{at}mc.duke.edu.

The G protein-coupled receptor (GPCR) kinase, {beta}-adrenergic receptor ({beta}AR) kinase ({beta}ARK1) is elevated in heart failure, however its role is not fully understood. {beta}ARK1 contains several domains capable of protein-protein interactions that may play critical roles in the regulation of GPCR signaling. In this study, we developed a novel line of transgenic mice that express an amino-terminal peptide of {beta}ARK1, comprised of amino acid residues 50-145 ({beta}ARKnt), in the heart, to determine if this domain has any functional significance in vivo. Surprisingly, the {beta}ARKnt transgenic mice presented with cardiac hypertrophy. Our data suggest that the phenotype was driven via an enhanced {beta}AR system, as {beta}ARKnt mice had elevated cardiac {beta}AR density. Moreover, administration of a {beta}AR antagonist reversed hypertrophy in these mice. Interestingly, signaling through the {beta}AR in response to agonist stimulation was not enhanced in these mice. Thus, the amino terminus of {beta}ARK1 appears critical for normal {beta}AR regulation in vivo, and further supports the hypothesis that {beta}ARK1 plays a key role in normal and compromised cardiac GPCR signaling.




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