Cardiac hypertrophy and altered beta-adrenergic signaling in transgenic mice that express the amino terminus of beta-ARK1.
The G protein-coupled receptor (GPCR) kinase beta-adrenergic receptor (beta-AR) kinase-1 (beta-ARK1) is elevated during heart failure; however, its role is not fully understood. Beta-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 beta-ARK1 that is comprised of amino acid residues 50-145 (beta-ARKnt) in the heart to determine whether 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 to be critical for normal beta-AR regulation in vivo, which further supports the hypothesis that beta-ARK1 plays a key role in normal and compromised cardiac GPCR signaling.
Keys
Janelle R
JR
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Greene
Emily A
EA
Cooper
Chris J
CJ
Naga Prasad
Sathyamangla V
SV
Rockman
Howard A
HA
Koch
Walter J
WJ
D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006321:Heart / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D020710:RGS Proteins / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051552:beta-Adrenergic Receptor Kinases
D020710:RGS Proteins; D011943:Receptors, Adrenergic, beta; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases