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Cardiac hypertrophy and altered -adrenergic signaling in transgenic mice that express the amino terminus of -ARK1

¹Department of Surgery and ²Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

Submitted 4 February 2003 ; accepted in final form 15 July 2003

The G protein-coupled receptor (GPCR) kinase -adrenergic receptor (-AR) kinase-1 (-ARK1) is elevated during heart failure; however, its role is not fully understood. -ARK1 contains several domains that are 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 -ARK1 that is comprised of amino acid residues 50–145 (-ARKnt) in the heart to determine whether this domain has any functional significance in vivo. Surprisingly, the -ARKnt transgenic mice presented with cardiac hypertrophy. Our data suggest that the phenotype was driven via an enhanced -AR system, as -ARKnt mice had elevated cardiac -AR density. Moreover, administration of a -AR antagonist reversed hypertrophy in these mice. Interestingly, signaling through the -AR in response to agonist stimulation was not enhanced in these mice. Thus the amino terminus of -ARK1 appears to be critical for normal -AR regulation in vivo, which further supports the hypothesis that -ARK1 plays a key role in normal and compromised cardiac GPCR signaling.

G protein-coupled receptors; isoproterenol; -adrenergic receptor kinase-1

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