Glucagon receptor mediates calcium signaling by coupling to G alpha q/11 and G alpha i/o in HEK293 cells.

Glucagon induces intracellular Ca(2+) ([Ca(2+)](i)) elevation by stimulating glucagon receptor (GCGR). Such [Ca(2+)](i) signaling plays important physiological roles, including glycogenolysis and glycolysis in liver cells and the survival of beta-cells. Previous studies indicated that phospholipase C (PLC) might be involved in glucagon-mediated [Ca(2+)](i) response. Other studies also debated whether cAMP accumulation mediated by GCGR/G alpha(s) coupling contributes to [Ca(2+)](i) elevation. But the exact mechanisms remain uncertain. In the present study, we found that glucagon induces [Ca(2+)](i) elevation in HEK293 cells expressing GCGR. Removing extracellular Ca(2+) did not affect glucagon-stimulated [Ca(2+)](i) response. But depleting the intracellular Ca(2+) store by thapsigargin completely inhibited glucagon-induced [Ca(2+)](i) response. Experiments with forskolin and adenylyl cyclase inhibitor revealed that cAMP is not the cause of [Ca(2+)](i) response. Further studies with G alpha(q/11) RNAi and pertussis toxin (PTX) indicated that both G alpha(q/11) and G alpha(i/o) are involved. Combination of G alpha(q/11) RNAi and G alpha(i/o) inhibition almost completely abolished glucagon-induced [Ca(2+)](i) signaling.