Protein phosphorylation and beta-cell function.
The central role of reversible protein phosphorylation in regulation of beta-cell function is reviewed and the properties of the protein kinases so far defined in beta cells are summarised. The key effect of Ca2+ to initiate insulin secretion involves activation of a Ca2+/calmodulin-dependent protein kinase. Potentiation of secretion by agents activating protein kinase A or C appears to involve an increase in the sensitivity of the secretory system to intracellular Ca2+. The effects of MgATP on the binding of [3H]-glibenclamide to the beta-cell sulphonylurea receptor suggest that the properties of this receptor, which controls the activity of ATP-sensitive K-channels, are modulated by phosphorylation. The identity of the kinases and phosphatases responsible is not known but the presence in beta-cell membranes of various kinases not dependent on Ca2+ or cyclic AMP, and including tyrosine kinase, is documented, together with the presence of both Ca(2+)-dependent and Ca(2+)-independent protein phosphatases. Protein phosphorylation is also involved in regulation of beta-cell Ca2+ fluxes and evidence is presented that protein kinase C activation inhibits Ca2+ signalling by reducing influx of Ca2+ into the beta cell. The identity of the Ca2+/calmodulin-dependent protein kinase activity in beta cells is discussed. Comparison of its properties towards substrates and inhibitors with those of brain Ca2+/calmodulin-dependent protein kinase II suggests that the beta-cell enzyme may be similar or identical to the brain enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
Ashcroft
S J
SJ
Nuffield Department of Clinical Biochemistry, John Radcliffe Hospital, Oxford, UK.
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001363:Awards and Prizes; D001921:Brain / Q000201:enzymology; D002118:Calcium / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000266:history; D005060:Europe; D005905:Glyburide / Q000378:metabolism; D049673:History, 20th Century; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology*; D008954:Models, Biological; D010766:Phosphorylation; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D012955:Societies, Medical; D064233:Sulfonylurea Receptors; D006113:United Kingdom
D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D011493:Protein Kinase C; D011188:Potassium; D005905:Glyburide; D002118:Calcium