Regulation of glucose-induced [Ca2+]i signals by cannabinoid CB1 and CB2 receptors in pancreatic α- and δ-cells within intact islets of Langerhans

Background and aims: The endocannabinoid system is present in islets of Langerhans as well as in peripheral tissues involved in energy expenditure. The existence of functional CB1 and CB2 receptors has been described in pancreatic beta-cells. However, their expression and role is still greatly unknown in the other two main cell types within the islet, glucagon-secreting alpha-cells and somatostatin-releasing delta-cells, which are also critical in the regulation of glycaemia. Methods: We analyzed by immunocytochemistry whether both, CB1 and CB2 receptors are expressed in mouse alpha- and delta-cells. We also studied the regulation of glucose-induced (Ca2+)(i) in alpha- and delta-cells within freshly isolated intact islets using confocal microscopy. Results: Both CB1 and CB2 receptors are present and functional in alpha and delta-cells. In alpha-cells, the endocannabinoid 2-arachidonylglycerol (2-AG) produces a decrease in the frequency of low glucose-induced (Ca2+](i) oscillations, an action irritated by the CB2 agonist JWH133. However, the selective CB1 receptor-agonist methanandamide (META) increased the frequency of [Ca2+](i) oscillations in 31.2%, decreased them in 22% of the cells tested and had no effect in 47% of the cells. The endocannabinoid anandamide (AEA) also has this dual effect, although the decrease in the frequency of (Ca2+](i) oscillations is the predominant action. In delta-cells, both 2-AG and AEA elicit (Ca2+](i) oscillations in the absence of glucose. The CB2 agonist JWH133 imitates the 2-AG and AEA action. Conclusions: Cannabinoid CB1 and CB2 receptors are present and functional in a and delta-cells, and are involved in the control of glucose-regulated [Ca2+](i) signaling.