title: Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE2.
abstract: The major physiological inhibitors of insulin secretion, norepinephrine, somatostatin, galanin, and prostaglandin E2, act via specific receptors that activate pertussis toxin (PTX)-sensitive G proteins. Four inhibitory mechanisms are known: 1) activation of ATP-sensitive K channels and repolarization of the beta-cell; 2) inhibition of L-type Ca2+ channels; 3) decreased activity of adenylyl cyclase; and 4) inhibition of exocytosis at a "distal" site in stimulus-secretion coupling. We have examined the underlying mechanisms of inhibition at this distal site. In rat pancreatic islets, 2-bromopalmitate, cerulenin, and polyunsaturated fatty acids, all of which suppress protein acyltransferase activity, blocked the distal inhibitory effects of norepinephrine in a concentration-dependent manner. In contrast, control compounds such as palmitate, 16-hydroxypalmitate, and etomoxir, which do not block protein acylation, had no effect. Furthermore, 2-bromopalmitate also blocked the distal inhibitory actions of somatostatin, galanin, and prostaglandin E2. Importantly, neither 2-bromopalmitate nor cerulenin affected the action of norepinephrine to decrease cAMP production. We also examined the effects of norepinephrine, 2-bromopalmitate, and cerulenin on palmitate metabolism. Palmitate oxidation and its incorporation into lipids seemed not to contribute to the effects of 2-bromopalmitate and cerulenin on norepinephrine action. These data suggest that protein acylation mediates the distal inhibitory effect on insulin secretion. We propose that the inhibitors of insulin secretion, acting via PTX-sensitive G proteins, activate a specific protein acyltransferase, causing the acylation of a protein or proteins critical to exocytosis. This particular acylation and subsequent disruption of the essential and precise interactions involved in core complex formation would block exocytosis.
authors.affiliation: Dept. of Molecular Medicine, College of Veterinary Medicine, Cornell Univ., Ithaca, NY 14853-6401, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Cheng
authors.forename: Susanne G
authors.initials: SG
authors.lastname: Straub
authors.forename: Geoffrey W G
authors.initials: GW
authors.lastname: Sharp
mesh_terms: D000215:Acylation; D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002569:Cerulenin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D019004:Galanin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007004:Hypoglycemic Agents; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050356:Lipid Metabolism; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010168:Palmitates / Q000494:pharmacology; D019308:Palmitic Acid / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005231:Fatty Acids, Unsaturated; D007004:Hypoglycemic Agents; D007328:Insulin; D010168:Palmitates; D011506:Proteins; D002569:Cerulenin; C022776:2-bromopalmitate; D019308:Palmitic Acid; D013004:Somatostatin; D019004:Galanin; D000242:Cyclic AMP; D000217:Acyltransferases; D019204:GTP-Binding Proteins; D015232:Dinoprostone; C054207:etomoxir; D009638:Norepinephrine