Targeted protein kinase A and PP-2B regulate insulin secretion through reversible phosphorylation

Endocrinology. 2001 Mar;142(3):1218-27. doi: 10.1210/endo.142.3.8023.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcineurin / physiology*
  • Calcineurin Inhibitors
  • Carrier Proteins / metabolism
  • Carrier Proteins / pharmacology
  • Cell Line
  • Cyclic AMP / physiology
  • Cyclic AMP-Dependent Protein Kinases / physiology*
  • Cyclosporine / pharmacology
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • In Vitro Techniques
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism*
  • Phosphorylation
  • Rats
  • Subcellular Fractions / metabolism
  • Synapsins / metabolism
  • Tacrolimus / pharmacology


  • Calcineurin Inhibitors
  • Carrier Proteins
  • Enzyme Inhibitors
  • Insulin
  • Synapsins
  • Cyclosporine
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Calcineurin
  • Tacrolimus