title: Inhibition of glucose-stimulated insulin secretion by Ro 31-8220, a protein kinase C inhibitor.
abstract: The involvement of the family of protein kinase C (PKC) isoenzymes in the secretory response of rat islets of Langerhans to glucose, the major insulin secretagogue, was investigated using the PKC inhibitor Ro 31-8220, a derivative of staurosporine. Ro 31-8220 was a more selective PKC inhibitor than staurosporine in islets, having minimal effects on protein kinases activated by cyclic AMP or by Ca(2+) and calmodulin. The secretory response to 4βPMA, an activator of phorbol ester-sensitive isoforms of PKC, was abolished by Ro 31-8220. Basal insulin secretion (2MM: glucose) was not affected by Ro 31-8220, but 20MM: glucose-induced insulin release was inhibited in a dose-dependent manner, maximally by ∼50% at 10 µM: Ro 31-8220. Higher concentrations of Ro 31-8220 (507gmM: ) did not further inhibit the secretory response to glucose and also caused ∼50% inhibition of insulin secretion stimulated by 10MM: glyceraldehyde. Ca(2+)-stimulated insulin secretion from electrically permeabilised islets was not inhibited by Ro 31-8220. Calphostin C, which inhibits some isoforms of PKC by interacting with the diacylglycerol binding site, unexpectedly caused a large (∼10-fold) increase in secretion at 2MM: glucose, so could not be used in islets to further investigate the involvement of phorbol ester-sensitive PKC isoforms in the insulin secretory process. One possible explanation for our results using Ro 31-8220 is that phorbol ester-insensitive isoforms of PKC (ζ and/orι) are involved in glucose-stimulated insulin secretion from rat islets.
authors.affiliation: Biomedical Sciences Division, King's College London, Campden Hill Road, W8 7AH, London, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Persaud
authors.forename: P M
authors.initials: PM
authors.lastname: Jones