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 release from pancreatic beta-cells and has been suggested to constitute the endogenous ligand for the islet imidazoline-binding site. Here we have explored the effects of CDS on glucagon release from mouse pancreatic alpha-cells. CDS (5 U/ml) produced a 35% inhibition (P < 0.05) of glucagon release from intact 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 associated with a change in whole-cell ATP-sensitive K(+)-channel activity in single alpha-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 exocytosis resulted from activation of the protein phosphatase calcineurin and was abolished by cyclosporin A. These data provide further evidence for a role of CDS as an endogenous ligand controlling islet hormone secretion.
Høy
M
M
Laboratory of Islet Cell Physiology, Building 1KM.06, Novo Nordisk A/S, Novo Alle, DK-2880 Bagsvaerd, Denmark. mkh@novonordisk.com
Chan
S L
SL
Weng
X G
XG
Gromada
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004594:Electrophysiology; D005089:Exocytosis / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005934:Glucagon / Q000378:metabolism*; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D018408:Patch-Clamp Techniques; D015221:Potassium Channels
D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D005934:Glucagon; C055140:clonidine-displacing substance; D003000:Clonidine; D002118:Calcium