G-proteincoupledreceptors(GPCRs)areoneofthelargestgenefamiliesofsignalingproteins.Residingintheplasmamembranewithseventransmembranedomains,GPCRsrespondtoextracellularstimulithatincludecatecholamineneurotransmitters,neuropeptides,largerproteinhormones,lipids,nucleotidesandotherBIOLOGicalmolecules.WhenaGPCRbindsitsextracellularligand,itinteractswithaG-proteintotransduceasignalacrossthemembraneintothecellularinterior.G-proteinsareaheterotrimericcomplexcontainingaGasubunitwithGTPaseactivity,aswellasbandgsubunits.Gacanexistinanactivestateandaninactivestate.GaintheoffstatehasGDPboundanddoesnotactivatedownstreamsignalingmolecules.WhenaGPCRisactivatedbyligand,itstimulatesGasubunitstobindGTPinsteadofGDPandbecomeactive,dissociatingfromthereceptorandfromtheb/gsubunitstoactivatedownstreamsignalingfactorsliketheenzymeadenylylcyclasethatsynthesizescyclic-AMP(cAMP)fromATP.GaturnsitselfbackoffagainwithitsintrinsicGTPaseactivity,hydrolyzingGTPtoGDPtobecomeinactiveagain.ActivatedGproteinsinteractwithdownstreamsignalingfactorstoaltertheproductionofsecondmessengersignalingmoleculeslikeinositolphosphates,calciumandcAMP.GPCRsthatactivatetheGiclassofGasubunitsinhibitcAMPproductionandGPCRsthatactivatetheGsclassofGasubunitsactivatecAMPproduction.cAMPinturnactivatesthecAMP-dependentproteinkinase,proteinkinaseA(PKA).PKAisatetramercomposedofcatalyticsubunitsandregulatorysubunitsthatrepressthecatalyticunitswhentheyareboundtogether.TheregulatorysubunitsbindcAMPwhenitispresentandreleasethecatalyticunits,releasingtheirinhibitionofthecatalyticsubunitsaswell.ThecatalyticsubunitsofPKAwhentheyarereleasedandactivephosphorylatetargetsubstrateproteinsonserineandthreonineresidues,alteringtheactivityofthemodifiedproteinandcreatingacellularresponsetotheextracellularstimulusactingontheGPCR.ThePKAactivationpathwayisanexampleofasignaltransductioncascade,inwhichtyingseveralsignalingeventstogetheramplifiestheoriginalsignalinthecell.ForeachGPCRmoleculethatisactivated,manyG-proteinscanbeactivated,andeachactiveGproteincansynthesizemanycAMPmolecules,continuingthecascadetoPKAandfurtherdownstream.OneoftherolesofPKAthatwasfirststudiedwastheregulationofglycogenmetabolism.Whenepinephrinebindstoitsreceptorinliver,itactivatescAMPproductionandPKAactivation.OnesubstrateofPKAisphosphorylasekinase,whichisactivatedphosphorylationandispartofthesignalingcascadethatmobilizesglycogenintoglucosetoprovideenergythatfuelstheresponsetoepinephrine.AnothersubstrateofPKAisglycogensynthase,whichisturnedoffbyPKAphosphorylation.PKAalsoparticipatesinmanyothersignalingpathways,integratingthekeysignalingintermediarycAMPwithawiderangeofbiologicalresponses

Contributor:GlennCroston,PhD.

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