Neurotransmitter-induced inhibition of exocytosis in insulin-secreting beta cells by activation of calcineurin.
Neurotransmitters and hormones such as somatostatin, galanin, and adrenalin reduce insulin secretion. Their inhibitory action involves direct interference with the exocytotic machinery. We have examined the molecular processes underlying this effect using high resolution measurements of cell capacitance. Suppression of exocytosis was maximal at concentrations that did not cause complete inhibition of glucose-stimulated electrical activity. This action was dependent on activation of G proteins but was not associated with inhibition of the voltage-dependent Ca2+ currents or adenylate cyclase activity. The molecular processes initiated by the agonists culminate in the activation of the Ca(2+)-dependent protein phosphatase calcineurin, and suppression of the activity of this enzyme abolishes their action on exocytosis. We propose that mechanisms similar to those we report here may contribute to adrenergic and peptidergic inhibition of secretion in other neuroendocrine cells and in nerve terminals.
Renström
E
E
Department of Islet Cell Physiology, Novo Nordisk A/S, Copenhagen, Denmark.
Ding
W G
WG
Bokvist
K
K
Rorsman
P
P
D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin; D002118:Calcium / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003000:Clonidine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003593:Cytoplasm / Q000737:chemistry; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D004837:Epinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects* / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology; D019004:Galanin / Q000494:pharmacology; D006147:Guanine / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D007306:Insecticides / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D009570:Nitriles; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011722:Pyrethrins / Q000494:pharmacology; D013004:Somatostatin / Q000494:pharmacology
D000322:Adrenergic Agonists; D002148:Calmodulin-Binding Proteins; D006727:Hormone Antagonists; D007306:Insecticides; D007328:Insulin; D018377:Neurotransmitter Agents; D009570:Nitriles; D011722:Pyrethrins; C017180:decamethrin; D013004:Somatostatin; D006147:Guanine; D019004:Galanin; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D019204:GTP-Binding Proteins; D003000:Clonidine; D002118:Calcium; D004837:Epinephrine