Clonidine-displacing substance reduces glucagon secretion from mouse pancreatic alpha-cells by K-ATP-channel-independent inhibition of exocytosis

Clonidine-displacing substance (CDS) is a potent stimulator of insulin rele ase from pancreatic beta -cells and has been suggested to constitute the en dogenous ligand for the islet imidazoline-binding site. Here we have explor ed the effects of CDS on glucagon release from mouse pancreatic a-cells. CD S (5 U/ml) produced a 35% inhibition (P < 0.05) of glucagon release from in tact islets. This effect was dose-dependent and half-maximal inhibition by CDS was observed at 0.03 U/ml. Inhibition of glucagon release was not assoc iated with a change in whole-cell ATP-sensitive K+-channel activity in sing le a-cells. However, during intracellular application through the recording pipette, CDS produced a 36% (P < 0.05) decrease in the rate of exocytosis, measured as changes in cell capacitance. The inhibitory effect of CDS on e xocytosis resulted from activation of the protein phosphatase calcineurin a nd was abolished by cyclosporin A. These data provide further evidence for a role of CDS as an endogenous ligand controlling islet hormone secretion. (C) 2001 Academic Press.