Differential coupling of glucagon and beta-adrenergic receptors with the small and large forms of the stimulatory G protein.

Glucagon receptors (GRs) and beta-adrenergic receptors (beta-ARs) stimulate adenylate cyclase (AC) via Gs. The present study was performed to determine whether different cAMP-generating receptors share the same pool of Gs. In hepatocytes and liver plasma membranes from partially hepatectomized male rats, glucagon was more potent in stimulating AC than beta-adrenergic agonists, but the effects of glucagon and beta agonists on AC activity were not additive. This suggests that GRs and beta-ARs share the same pathway. Glucagon lowered the affinity of beta agonists for beta-ARs in the presence of GTP gamma S, whereas beta agonists had no effect on glucagon binding to GRs regardless of the presence or the absence of GTP gamma S. Therefore, the pool of Gs coupled to GRs appears to include that coupled to beta-ARs. The alpha subunit of Gs (Gs alpha) exists in small (Gs alpha-S) and large (Gs alpha-L) forms. Recently, with a new method that uses tryptic digestion, the G protein coupled to beta-ARs was identified as Gs-L in partially hepatectomized male rat livers because beta-adrenergic agonists promoted trypsinization of Gs alpha-L but not of Gs alpha-S. By contrast, the present study showed that glucagon enhanced the sensitivity of the two Gs alpha isoforms to trypsin in a concentration-dependent manner, indicating that GRs are coupled to both Gs alpha-S and Gs alpha-L. In conclusion, GRs share a common Gs-L with beta-ARs but are also coupled to another Gs, Gs-S, in partially hepatectomized male rat livers.