title: Targeted protein kinase A and PP-2B regulate insulin secretion through reversible phosphorylation.
abstract: Protein kinases and phosphatases play key roles in integrating signals from various insulin secretagogues. In this study, we show that the activities of the cAMP-dependent protein kinase (PKA) and the calcium/calmodulin-dependent phosphatase, PP-2B are coordinated resulting in the regulation of insulin secretion. Transient inhibition of PP-2B, using the immunosuppressant FK506, increased forskolin stimulated insulin secretion by 2.5-fold +/- 0.3 (n = 6) in rat islets and RINm5F cells. Surprisingly, forskolin treatment resulted in the dephosphorylation of the vesicle-associated protein synapsin 1 and increased PP-2B activity by 2.98 +/- 0.97-fold (n = 4). One potential explanation for the observed coordination of PKA and PP-2B activity is their colocalization through a mutual anchoring protein, AKAP79/150. Accordingly, RINm5F cells expressing AKAP79 exhibited decreased insulin secretion, reduced PP-2B activity and were insensitive to FK506. This suggests that AKAP targeting of PKA and PP-2B maintains a signal transduction complex that may regulate reversible phosphorylation events involved in insulin secretion.
authors.affiliation: Division of Endocrinology , Oregon Health Sciences University, Portland, Oregon 97201, USA. lesterl@ohsu.edu
authors.forename: L B
authors.initials: LB
authors.lastname: Lester
authors.forename: M C
authors.initials: MC
authors.lastname: Faux
authors.forename: J B
authors.initials: JB
authors.lastname: Nauert
authors.forename: J D
authors.initials: JD
authors.lastname: Scott
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D013347:Subcellular Fractions / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007328:Insulin; D016704:Synapsins; D016572:Cyclosporine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D016559:Tacrolimus