S49G and R389G polymorphisms of the β₁-adrenergic receptor influence signaling via the cAMP-PKA and ERK pathways

Abstract

Zhang F, Steinberg SF. S49G and R389G polymorphisms of the ␤1-adrenergic receptor influence signaling via the cAMP-PKA and ERK pathways. Physiol Genomics 45: 1186-1192, 2013. First published October 22, 2013 doi:10.1152/physiolgenomics.00087.2013.-Two functionally important ␤ 1-adrenergic receptor (␤1AR) polymorphisms have been identified. The R389G polymorphism influences coupling to the Gs-cAMP pathway. R 389 -␤1ARs display enhanced activation of cAMP/PKA; they provide short-term inotropic support but also cause a predisposition to cardiomyopathic decompensation. A second S49G polymorphism is implicated in the evolution of heart failure, but the mechanism remains uncertain. This study shows that position 49 and 389 polymorphisms function in a coordinate manner to influence agonist-dependent cAMP/PKA and ERK responses. cAMP/PKA and ERK responses are more robust in HEK293 cells that heterologously overexpress G 49 -␤1ARs, compared with S 49 -␤1ARs. However, this phenotype is most obvious on a G 389 -␤1AR background; the more robust agonist-dependent cAMP/PKA and ERK responses in R 389 -␤ 1AR cells effectively obscure the effect of the S49G polymorphism. We also show that isoproterenol (Iso) and carvedilol activate ERK via a similar EGFR-independent mechanism in cells expressing various ␤ 1AR haplotypes. However, Iso activates ERK via an Src-independent pathway, but carvedilol-dependent ERK activation requires Src. Since the S49G polymorphism has been linked to changes in ␤ 1AR trafficking, we examined whether ␤ 1AR polymorphisms influence partitioning to lipid raft membranes. Biochemical fractionation studies show that all four ␤ 1AR variants are recovered in buoyant flotillinenriched membranes; the distinct signaling phenotypes of the different ␤ 1AR variants could not be attributed to any gross differences in basal compartmentalization to lipid raft membranes. The allele-specific differences in ␤ 1AR signaling phenotypes identified in this study could underlie interindividual differences in responsiveness to ␤-blocker therapy and clinical outcome in heart failure. adrenergic receptor; protein kinase A; extracellular signal-regulated kinase; lipid raft ␤ 1 -ADRENERGIC RECEPTORS (␤ 1 ARs) are the principle mediators of catecholamine-dependent changes in the force and rate of cardiac contraction. ␤ 1 ARs adjust cardiac output by activating a Gs-adenylyl cyclase (AC) pathway that increases cAMP, activates protein kinase A (PKA), and phosphorylates substrates involved in excitation-contraction coupling (16). However, heightened ␤ 1 AR drive in the setting of heart failure (HF) activates signaling pathways that promote cardiomyocyte hypertrophy/apoptosis, interstitial fibrosis, disordered energetics, and contractile dysfunction (8,16). ␤AR inhibitors that prevent these maladaptive ␤AR responses have become standard therapy for HF.While there is ample evidence that ␤AR blockers decrease morbidity and mortality in HF, there is considerable interindividual variability in drug responsiveness that is not readily attribu...

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“…Following Iso stimulation, ERK activation was assessed by phospho-ERK (p-ERK) immunoblotting. Consistent with previous studies ( Zhang and Steinberg, 2013 ; Copik et al. , 2015 ), Iso stimulation resulted in a significant increase in ERK activation.…”

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“…Studies have also suggested that Ser49 undergoes less receptor internalization than the glycine variant, also resulting in greater downstream signalling. Data from the last 10–15 years and confirmed again in the past 2 years document that both the Ser49Gly and Arg389Gly variants are functional, although the effect of the Arg389Gly allele is greater and might obscure the functional effect of the codon 49 genotype 42 . The ancestral alleles (Ser49 and Arg389) are both associated with greater agonist-mediated effects than the variant alleles.…”

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“… 5 Several studies support the role of cyclic Adenosine Monophosphate (cAMP) in atherogenesis by modulating the function of vascular endothelium, the production of reactive oxygen species, the recruitment of circulating monocytes to the artery wall and their differentiation into macrophages-foam cells, by controlling the expression of pro-and anti-inflammatory interleukin, and regulating serum level of triglycerides and cholesterol. 6 , 7 cAMP is also a possible target for prevention and treatment of atherosclerosis. 6 The major non-synonymous SNPs of β2AR have been recognized at nucleotides 46 (A>G) (rs1042713) and 79 (C>G) (rs1042714) causing changes in amino acid residues at position 16 (Arg>Gly) and 27 (Gln>Glu) of the amino terminus respectively of the fourth intracellular loop.…”