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This Article Full Text Full Text (PDF) All Versions of this Article: 285/2/E287    most recent 00535.2002v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Cheng, H. Articles by Sharp, G. W. G. Search for Related Content PubMed PubMed Citation Articles by Cheng, H. Articles by Sharp, G. W. G.

Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE₂

Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853

Submitted 10 December 2002 ; accepted in final form 1 April 2003

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 -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.

rat pancreatic islets; -cell; signaling; pertussis toxin; G proteins

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				H. Cheng, S. G. Straub, and G. W. G. Sharp Inhibitory role of Src family tyrosine kinases on Ca2+-dependent insulin release Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E845 - E852. [Abstract] [Full Text] [PDF]

				G. Las, N. Mayorek, K. Dickstein, and J. Bar-Tana Modulation of Insulin Secretion by Fatty Acyl Analogs Diabetes, December 1, 2006; 55(12): 3478 - 3485. [Abstract] [Full Text] [PDF]