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.
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Related Subject Headings
- beta-Adrenergic Receptor Kinases
- Signal Transduction
- Receptors, Adrenergic, beta
- RGS Proteins
- Protein Structure, Tertiary
- Mice, Transgenic
- Mice
- Heart
- Gene Expression Regulation, Enzymologic
- Down-Regulation
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- beta-Adrenergic Receptor Kinases
- Signal Transduction
- Receptors, Adrenergic, beta
- RGS Proteins
- Protein Structure, Tertiary
- Mice, Transgenic
- Mice
- Heart
- Gene Expression Regulation, Enzymologic
- Down-Regulation