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Targeted Protein Kinase A and PP-2B Regulate Insulin Secretion through Reversible Phosphorylation¹

Division of Endocrinology (L.B.L., J.B.N.), Oregon Health Sciences University, Portland, Oregon 97201; Ludwig Institute (M.C.F.), Melbourne, Australia; Howard Hughes Medical Institute (J.D.S.), Vollum Institute, Portland, Oregon 97201

Address all correspondence and requests for reprints to: Dr. Linda Lester, Division of Endocrinology L-607, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201. E-mail: lesterl{at}ohsu.edu

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.