Allosteric Modulation of the Activity of the Glucagon-like Peptide-1 (GLP-1) Metabolite GLP-1 9–36 Amide at the GLP-1 Receptor 英文参考文献.docVIP

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Allosteric Modulation of the Activity of the Glucagon-like Peptide-1 (GLP-1) Metabolite GLP-1 9–36 Amide at the GLP-1 Receptor 英文参考文献.doc

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Allosteric Modulation of the Activity of the Glucagon-like Peptide-1 (GLP-1) Metabolite GLP-1 9–36 Amide at the GLP-1 Receptor 英文参考文献

AllostericModulationoftheActivityoftheGlucagon-like Peptide-1(GLP-1)MetaboliteGLP-19–36Amideatthe GLP-1Receptor NaichangLi1,2,JingLu1,GaryB.Willars1* 1DepartmentofCellPhysiologyandPharmacology,UniversityofLeicester,Leicester,UnitedKingdom,2DepartmentofBiochemistry,TianjinMedicalUniversity,Tianjin, China Abstract Glucagon-likepeptide-1(GLP-1)releasedfromintestinalLcellsinresponsetonutrientshasmanyphysiologicaleffectsbut particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R). GLP-1 7–36 amide, the predominantcirculatingactiveformofGLP-1,israpidlytruncatedbydipeptidylpeptidase-4toGLP-19–36amide,whichis generallyconsideredinactive.Givenitsphysiologicalroles,theGLP-1Ristargetedfortreatmentoftype2diabetes.Recently ‘compound2’hasbeendescribedasbothanagonistandpositiveallostericmodulatorofGLP-17–36amideaffinity,butnot potency, at the GLP-1R. Importantly, we demonstrated previously that exendin 9–39, generally considered a GLP-1R antagonist, enhances compound 2 efficacy (or vice versa) at the GLP-1R. Given that GLP-1 9–36 amide is the major circulating form of GLP-1 post-prandially and is a low affinity weak partial agonist or antagonist at the GLP-1R, we investigatedinteractionbetweenthismetaboliteandcompound2inacelllinewithrecombinantexpressionofthehuman GLP-1R and the rat insulinoma cell line, INS-1E, with native expression of the GLP-1R. We show compound 2 markedly enhancesefficacyandpotencyofGLP-19–36amideforkeycellularresponsesincludingAMPgeneration,Ca2+signalingand extracellular signal-regulated kinase. Thus, metabolites of peptide hormones including GLP-1 that are often considered inactivemayprovideameansofmanipulatingkeyaspectsofreceptorfunctionandanoveltherapeuticstrategy. Citation:LiN,LuJ,WillarsGB(2012)AllostericModulationoftheActivityoftheGlucagon-likePeptide-1(GLP-1)MetaboliteGLP-19–36AmideattheGLP-1 Receptor.PLoSONE7(10):e47936.doi:10.1371/journal.pone.0047936 Editor:AlexanderG.Obukhov,IndianaUniversitySchoolofMedicine,Un