TRANSLATIONAL PHYSIOLOGY S49G and R389G polymorphisms of the 1-adrenergic receptor influence signaling via the cAMP-PKA and ERK pathways

Zhang F, Steinberg SF. S49G and R389G polymorphisms of the 1adrenergic 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. R1ARs 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 G1ARs, compared with S1ARs. However, this phenotype is most obvious on a G1AR background; the more robust agonist-dependent cAMP/PKA and ERK responses in R1AR 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.