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• W2117707907 abstract "The blockade of heptahelical receptor coupling to heterotrimeric G proteins by the expression of peptides derived from G protein Gα subunits represents a novel means of simultaneously inhibiting signals arising from multiple receptors that share a common G protein pool. Here we examined the mechanism of action and functional consequences of expression of an 83-amino acid polypeptide derived from the carboxyl terminus of Gαs(GsCT). In membranes prepared from GsCT-expressing cells, the peptide blocked high affinity agonist binding to β2adrenergic receptors (AR) and inhibited β2AR-induced [35S]GTPγS loading of Gαs. GsCT expression inhibited β2AR- and dopamine D1Areceptor-mediated cAMP production, without affecting the cellular response to cholera toxin or forskolin, indicating that the peptide inhibited receptor-Gs coupling without impairing G protein or adenylyl cyclase function. [35S]GTPγS loading of Gαq/11 by α1BARs and Gαi by α2AARs and Gq/11- or Gi-mediated phosphatidylinositol hydrolysis was unaffected, indicating that the inhibitory effects of GsCT were selective for Gs. We next employed the GsCT construct to examine the complex role of Gs in regulation of the ERK mitogen-activated protein kinase cascade, where activation of the cAMP-dependent protein kinase (PKA) pathway reportedly produces both stimulatory and inhibitory effects on heptahelical receptor-mediated ERK activation. For the β2AR in HEK-293 cells, where PKA activity is required for ERK activation, expression of GsCT caused a net inhibition of ERK activation. In contrast, α2AAR-mediated ERK activation in COS-7 cells was enhanced by GsCT expression, consistent with the relief of a downstream inhibitory effect of PKA. ERK activation by the Gq/11-coupled α1BAR was unaffected by GsCT. These findings suggest that peptide G protein inhibitors can provide insights into the complex interplay between G protein pools in cellular regulation." @default.
• W2117707907 created "2016-06-24" @default.
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• W2117707907 date "2002-08-01" @default.
• W2117707907 modified "2023-10-09" @default.
• W2117707907 title "Selective Inhibition of Heterotrimeric GsSignaling" @default.
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• W2117707907 doi "https://doi.org/10.1074/jbc.m204753200" @default.
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