Carbachol stimulation of phospholipase A2 and insulin secretion in pancreatic islets.
Arachidonic acid has been implicated as a second messenger in insulin secretion by islets of Langerhans. D-Glucose, the major physiological stimulus, increases unesterified arachidonate accumulation in islets. We now show, for the first time, that the muscarinic agonist carbachol, at concentrations which stimulate insulin secretion, causes a rapid and nearly 3-fold increase in arachidonic acid accumulation in islets. The combination of glucose and carbachol has an additive effect on unesterified arachidonate release. There is a large component of secretagogue-induced arachidonate accumulation that is independent of extracellular Ca2+. Carbachol stimulation of arachidonic acid release is mediated by activation of phospholipase A2, as demonstrated by early increases in endogenous lysophosphatidylcholine. In addition to phospholipase A2 activation, carbachol-induced arachidonic acid accumulation also appears to involve diacylglycerol hydrolysis, since the diacylglycerol lipase inhibitor RG80267 partly inhibited arachidonic acid accumulation. In contrast, glucose-induced arachidonic acid accumulation appears to reflect diacylglycerol hydrolysis entirely. Our observations indicate that phospholipase A2 has an important role in muscarinic-induced insulin secretion.
Konrad
R J
RJ
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
Jolly
Y C
YC
Major
C
C
Wolf
B A
BA
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002118:Calcium / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology*; D003512:Cyclohexanones / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008297:Male; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems; D015398:Signal Transduction
D003512:Cyclohexanones; D004075:Diglycerides; D007328:Insulin; D008244:Lysophosphatidylcholines; D016718:Arachidonic Acid; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; D002217:Carbachol; D010741:Phospholipases A; D008071:Lipoprotein Lipase; D054467:Phospholipases A2; D005947:Glucose; D002118:Calcium