Calcineurin Regulates Homologous Desensitization of Natriuretic Peptide Receptor-A and Inhibits ANP-Induced Testosterone Production in MA-10 Cells 英文参考文献.docVIP

CalcineurinRegulatesHomologousDesensitizationof NatriureticPeptideReceptor-AandInhibitsANP-Induced TestosteroneProductioninMA-10Cells MichelleB.Henesy1,AndreaL.Britain1,BingZhu1,2,LaurenAmable3,RichardE.Honkanen3, JackieD.Corbin4,SharronH.Francis4,ThomasC.Rich1,2* 1DepartmentofPharmacology,UniversityofSouthAlabamaCollegeofMedicine,Mobile,Alabama,UnitedStatesofAmerica,2CenterforLungBiology,Universityof South Alabama College of Medicine, Mobile, Alabama, United States of America, 3Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama, United States of America, 4Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville,Tennessee,UnitedStatesofAmerica Abstract Receptordesensitizationisaubiquitousregulatorymechanismthatdefinestheactivatablepoolofreceptors,andthus,the ability of cells to respond to environmental stimuli. In recent years, the molecular mechanisms controlling the desensitizationofavarietyofreceptorshavebeenestablished.However,littleisknownaboutthemolecularmechanisms that underlie desensitization of natriuretic peptide receptors, including natriuretic peptide receptor-A (NPR-A). Here we reportthatcalcineurin (proteinphosphatase2B,PP2B,PPP3C)regulateshomologousdesensitizationofNPR-Ainmurine Leydig tumor (MA-10) cells. We demonstrate that both pharmacological inhibition of calcineurin activity and siRNA- mediated suppression of calcineurin expression potentiate atrial natriuretic peptide (ANP)-induced cGMP synthesis. Treatment of MA-10 cells with inhibitors of other phosphoprotein phosphatases had little or no effect on ANP-induced cGMPaccumulation.Inaddition,overexpressionofcalcineurinbluntsANP-inducedcGMPsynthesis.Wealsopresentdata indicating that the inhibition of calcineurin potentiates ANP-induced testosterone production. To better understand the contributionofcalcineurinintheregulationofNPR-Aactivity,weexaminedthekineticsofANP-inducedcGMPsignals.