cAMP-Mediated Actions in Adrenocortical Cells Activated by 3',5'-Cyclic Adenosine 5'-Monophosphate (cAMP) 2 (EPAC2) in Functional Roles of Protein Kinase A (PKA) and Exchange Protein Directly

Department of Biomedicine (L.A., M.R., M.B., A.E.L.) and Institute of Medicine (G.M.), University ofBergen, N-5009 Bergen, Norway; and Hormone Laboratory (G.M.), Haukeland University Hospital,N-5021 Bergen, NorwayIn the adrenal cortex, the biosynthesis of steroid hormones is controlled by the pituitary-derivedhormone ACTH. The functions of ACTH are principally relayed by activating cAMP-dependentsignalingpathwaysleadingtotheinductionofgenesencodingenzymesinvolvedintheconversionofcholesteroltosteroidhormones.Previously,proteinkinaseA(PKA)wasthoughttobetheonlydirect effector of cAMP. However, the discovery of the cAMP sensors, exchange proteins directlyactivatedbycAMP(EPAC1and2),hasledtoareevaluationofthisassumption.Inthepresentstudy,wedemonstratetheoccurrenceoftheEPAC2splicingvariantEPAC2Binadrenocorticalcancercells.Immunocytochemistry demonstrated that EPAC2B is localized predominantly in the nucleus.EPAC2B is functional because it activates Rap1 in these cells. Using the cAMP analogs 8-