SIGNAL-TRANSDUCTION BY THE CLONED GLUCAGON-LIKE PEPTIDE-1 RECEPTOR - COMPARISON WITH SIGNALING BY THE ENDOGENOUS RECEPTORS OF BETA-CELL LINES

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone that pot entiates glucose-induced insulin secretion by pancreatic beta cells. T he mechanisms of interaction between GLP-1 and glucose signaling pathw ays are not well understood. Here we studied the coupling of the clone d GLP-1 receptor, expressed in fibroblasts or in COS cells, to intrace llular second messengers and compared this signaling with that of the endogenous receptor expressed in insulinoma cell lines. Binding of GLP -1 to the cloned receptor stimulated formation of cAMP with the same d ose dependence and similar kinetics, compared with the endogenous rece ptor of insulinoma cells. Compared with forskolin-induced cAMP accumul ation, that induced by GLP-1 proceeded with the same initial kinetics but rapidly reached a plateau, suggesting fast desensitization of the receptor. Coupling to the phospholipase C pathway was assessed by meas uring inositol phosphate production and variations in the intracellula r calcium concentration. No GLP-1-induced production of inositol phosp hates could be measured in the different cell types studied. A rise in the intracellular calcium concentration was nevertheless observed in transfected COS cells but was much smaller than that observed in respo nse to norepinephrine in cells also expressing the alpha(1 beta)-adren ergic receptor. Importantly, no such increase in the intracellular cal cium concentration could be observed in transfected fibroblasts or ins ulinoma cells, which, however, responded well to thrombin or carbachol , respectively. Together, our data show that interaction between GLP-1 and glucose signaling pathways in beta cells may be mediated uniquely by an increase in the intracellular cAMP concentration, with the cons equent activation of protein kinase A and phosphorylation of elements of the glucose-sensing apparatus or of the insulin granule exocytic ma chinery.