Metabolites of an Epac-Selective cAMP Analog Induce Cortisol Synthesis by Adrenocortical Cells through a cAMP-Independent Pathway 英文参考文献.docVIP

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Metabolites of an Epac-Selective cAMP Analog Induce Cortisol Synthesis by Adrenocortical Cells through a cAMP-Independent Pathway 英文参考文献.doc

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Metabolites of an Epac-Selective cAMP Analog Induce Cortisol Synthesis by Adrenocortical Cells through a cAMP-Independent Pathway 英文参考文献

MetabolitesofanEpac-SelectivecAMPAnalogInduce CortisolSynthesisbyAdrenocorticalCellsthrougha cAMP-IndependentPathway JudithA.Enyeart,JohnJ.Enyeart* DepartmentofNeuroscience,TheOhioStateUniversity,CollegeofMedicineandPublicHealth,Columbus,Ohio,UnitedStatesofAmerica Abstract Adrenal zona fasciculata (AZF) cells express a cAMP-activated guanine nucleotide exchange protein (Epac2) that may functioninACTH-stimulatedcortisolsynthesis.ExperimentsweredonetodeterminewhethercAMPanalogsthatselectively activateEpacscouldinducecortisolsynthesisandtheexpressionofgenescodingforsteroidogenicproteinsinbovineAZF cells. Treatment of AZF cells with the Epac-selective cAMP analog (ESCA) 8CPT-29-OMe-cAMP induced large (.100 fold), concentration-dependent, delayed increases in cortisol synthesis and the expression of mRNAs coding for the steroid hydroxylasesCYP11a1,CYP17,CYP21,andthesteroidacuteregulatoryprotein(StAR).However,anon-hydrolyzableanalog ofthisESCA,Sp-8CPT-29-OMe-cAMP,failedtostimulatecortisolproductionevenatconcentrationsthatactivatedRap1,a downstream effector of Epac2. Accordingly, putative metabolites of 8CPT-29-OMe-cAMP, including 8CPT-29-OMe-59AMP, 8CPT-29-OMe-adenosine,and8CPT-adenineallinducedcortisolsynthesisandsteroidhydroxylasemRNAexpressionwitha temporalpattern,potency,andeffectivenesssimilartotheparentcompound.Atconcentrationsthatmarkedlystimulated cortisolproduction,noneofthesemetabolitessignificantlyactivatedcAMP-dependentproteinkinase(PKA).Theseresults showthatoneormoremetabolitesoftheESCA8CPT-29-OMe-cAMPinducecortico-steroidogenesisbyactivatingapanelof genesthatcodeforsteroidogenicproteins.Theremarkableincreasesincortisolsynthesisobservedinthisstudyappearto bemediatedbyanovelcAMP-,Epac-andPKA-independentsignalingpathway. Citation: Enyeart JA, Enyeart JJ (2009) Metabolites of an Epac-Selective cAMP Analog Induce Cortisol Synthesis by Adrenocortical Cells through a cAMP- IndependentPathway.PLoSONE4(6):e6088.doi:10.1371/journal.pone.0006088 Editor:DamienKeating,Fl