[beta]1-adrenoceptor Arg389Gly polymorphism and heart disease: marching toward clinical practice integration

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Date: July 2015
From: Pharmacogenomics(Vol. 16, Issue 10)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 2,776 words
Lexile Measure: 2280L

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Author(s): Katie A McCrink aff1 , Anastasios Lymperopoulos [*] aff1

Keywords:

[beta]1 -adrenergic receptor; [beta]-blocker; cardiovascular disease; dobutamine; drug response; GWAS; heart failure; hypertension; polymorphism

The [beta]1 -adrenergic receptor (AR) is a G protein-coupled receptor (GPCR) abundantly expressed in the plasma membranes of human cardiac myocytes. It is the primarily responsible AR for mediating the catecholamine-induced positive inotropy and chronotropy in the heart [1 ]. The human [beta]1 AR gene (Adrb1 ) encodes a 477-amino acid functional protein through a nucleotide sequence that has at least nine nonsynonymous variations reported to date. Out of these, the Gly/Arg polymoprhism at amino acid position 389 (cytosine or guanine at nucleotide 1165 of its coding region) is by far the best-characterized variation to date affecting function and signaling of the encoded receptor [2,3 ]. This amino acid position is located in the intracellular C-terminus of the [beta]1 AR, a region that purportedly participates in the receptor's interactions with the Gs protein, and also gets phosphorylated by GPCR-kinases (GRKs), which induces the subsequent binding of [beta]-arrestins that terminates G-protein signaling (receptor desensitization) [1 ]. Consequently, this C-terminal region is crucial for both activation and termination of the [beta]1 AR-dependent pro-contractile signaling in the heart [1 ]. Indeed, the Arg variant, substantially less prevalent in African Americans than in Caucasians (58 vs 73%, respectively), is presumed to favor/stabilize the active state of the human [beta]1 AR [2 ], rendering the Arg389 [beta]1 AR hyperfunctional compared with the Gly389 receptor. In vitro studies in heterologous cell systems (cell lines with the two variants exogenously overexpressed) have confirmed the higher activity of the Arg389 receptor in terms of second messenger cAMP (cyclic adenosine monophosphate) accumulation, Gs protein coupling efficiency and high affinity ligand binding in the absence of guanine triphosphate (GTP) [2,3 ]. Accordingly, it has also been found to display enhanced homologous (agonist-induced) desensitization versus the Gly variant [4 ]. In physiologically relevant cell systems, in other words, murine cardiomyocytes isolated from cardiac-specific overexpressors of the two variants, increased contractility and receptor desensitization (in old age) were displayed by the Arg variant-overexpressing mice [5 ], and the beating frequency of cardiomyocytes isolated from these mice was also higher than that of Gly [beta]1 AR-overexpressing myocytes [6 ]. However, studies on the native variant receptors in explanted human heart tissue failed to confirm differences in activity/signaling between the two variants, possibly because the human heart tissue studied was not normal (explanted from heart failure patients) [4 ]. Thus, the overall cardiac status may very well affect or mask the functional status of the polymorphic [beta]1 AR [7 ]. Of course, inter-species differences (murine vs human) in cardiomyocyte physiology and cardiac [beta]1 AR biochemistry might be another reason for these discrepancies. Finally, the agonist-activated Arg389 variant was recently shown to undergo GRK-dependent hyperphosphorylation leading to enhanced [beta]-arrestin2 binding (relative to the Gly [beta]1 AR) in heterologous HEK293 cells in vitro , consistent with the elevated homologous desensitization of the...

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Gale Document Number: GALE|A428534835