Submitted on April 17, 2008
Revised on July 15, 2008
Accepted on July 25, 2008
Differential Coupling of Arg- and Gly389 Polymorphic Forms of the 
1-adrenergic Receptor Leads to Pathogenic Cardiac Gene Regulatory Programs
Steven M Swift1, Brigitte R Gaume1, Kersten M Small2, Bruce J Aronow3, and Stephen Bryant Liggett1*
1 University of Maryland School of Medicine
2 Merck Research Laboratories
3 Cincinnati Children's Hospital Research Foundation
* To whom correspondence should be addressed. E-mail: sligg001{at}umaryland.edu.
The 
1-adrenergic receptor (1AR; ADRB1) polymorphism Arg389Gly is located in an intracellular loop and is associated with distinct human and mouse cardiovascular phenotypes. To test the hypothesis that 1-Arg389 and 1-Gly389 alleles could differentially couple to pathways beyond that of classic Gs-adenylyl cyclase (AC)/cAMP signaling, we performed comparative gene expression profile analyses on hearts from wildtype and transgenic mice that expressed either human 1-Arg389 or 1-Gly389 receptors, or AC5, sampling at an early age prior to the onset of pathologic features. All three models up-regulated the expression of genes associated with RNA metabolism and translation, and down-regulated genes associated with mitochondria and energy metabolism, consistent with shared cAMP-driven increase in cardiac contractility, protein synthesis, and compensatory down-regulation of mitochondrial energy production. Both 1AR alleles activated additional genes associated with kinase-dependent pathways. Uniquely, 1-Arg389 hearts exhibited upregulated expression of genes associated with inflammation, programmed cell death, and extracellular matrix. These observations expand the scope of 7-transmembrane domain receptor signaling propagation beyond known cognate G-protein couplings. Moreover, they implicate alterations of a repertoire of processes evoked by a single amino acid variation in the cardiac 1AR that might be exploited for genotype-specific heart failure diagnostics and therapeutics.
