Signal transduction in insulin secretion: comparison between fuel stimuli and receptor agonists.
The initial events in signal transduction in insulin-secreting cells are summarized in FIGURE 8. Both nutrient stimuli, such as glucose and amino acids and the muscarinic agonist carbachol (carbamylcholine) raise [Ca2+]i. Although the rise in [Ca2+]i precedes the stimulation of insulin release, it is not a moment-to-moment regulator of release. The metabolizable fuel stimuli cause Ca2+ influx through voltage-dependent Ca2+ channels following depolarization of the membrane potential. In contrast, carbachol, which does not depolarize, elicits Ptd Ins 4,5-P2 hydrolysis, a reaction catalyzed by phospholipase C. The generation of Ins 1,4,5-P3 in this instance is Ca2+ independent, but appears to involve a GTP-binding protein. However, this protein is not a substrate for pertussis toxin. The levels of Ins 1,4,5-P3, which releases Ca2+ from an ATP-dependent Ca2+ pool of the endoplasmic reticulum, are increased prior to the rise in [Ca2+]i. The mitochondria may take up Ca2+ after large increases in [Ca2+]i. A previously proposed second messenger, arachidonic acid, is much less selective than Ins 1,4,5-P3 in that it releases Ca2+ from mitochondria as well as from the endoplasmic reticulum in a slow and irreversible manner. As Ins 1,4,5-P3 is also generated during glucose stimulation of islets, albeit in a Ca2+-dependent manner, this metabolite could mediate not only the action of carbachol but also contribute to amplifying the [Ca2+]i rise in response to glucose.
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D005985:Glyceraldehyde / Q000494:pharmacology; D006706:Homeostasis; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000096:biosynthesis / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials
D000596:Amino Acids; D001095:Arachidonic Acids; D007295:Inositol Phosphates; D007328:Insulin; D016718:Arachidonic Acid; D005985:Glyceraldehyde; D015544:Inositol 1,4,5-Trisphosphate; D002217:Carbachol; D005947:Glucose; D002118:Calcium