GLUCAGON-LIKE PEPTIDE-I INCREASES CYTOPLASMIC CALCIUM IN INSULIN-SECRETING BETA-TC3-CELLS BY ENHANCEMENT OF INTRACELLULAR CALCIUM MOBILIZATION

In the insulin-secreting beta-cell line beta TC3, stimulation with 11. 2 mmol/l glucose caused a rise in the intracellular free Ca2+ concentr ation ([Ca2+](i)) in only 18% of the tested cells. The number of gluco se-responsive cells increased after pretreatment of the cells with glu cagon-Like peptide I (GLP-I)(7-36)amide and at 10(-11) mol/l; 84% of t he cells responded to glucose with a rise in [Ca2+](i). GLP-I(7-36)ami de induces a rapid increase in [Ca2+](i) only in cells exposed to elev ated glucose concentrations (greater than or equal to 5.6 mmol/l 1). T he action of GLP-I(7-36)amide and forskolin involved a 10-fold increas e in cytoplasmic cAMP concentration and was mediated by activation of protein kinase A. It was not associated with an effect on the membrane potential but required some (small) initial entry of Ca2+ through vol tage-dependent L-type Ca2+ channels, which then produced a further inc rease in [Ca2+](i) by mobilization from intracellular stores. The latt er effect reflected Ca2+-induced Ca2+ release and was blocked by ryano dine. Similar increases in [Ca2+](i) were also observed in voltage-cla mped cells, although there was neither activation of a background (Ca2 +-permeable) inward current nor enhancement of the voltage-dependent L -type Ca2+ current. These observations are consistent with GLP-I(736) amide inducing glucose sensitivity by promoting mobilization of Ca2+ f rom intracellular stores. We propose that this novel action of GLP-I(7 36)amide represents an important factor contributing to its insulinotr opic action.