PFOS Lecture 18 Receptor Theory I & II

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1、RECEPTORTHEORY(I&II)FOUNDATIONSTUDIESCOURSEMEDICALYEAR1Prof.HangYungAlasterLauSchoolofBiomedicalSciencesNov2013AGONISTSANDANTAGONISTSAnagonistasanactivatorofcell-surfacereceptorsleadingtoaresponseofthecellAnantagonistasablockerofthesereceptors,andhenceoftheactionoftheagonistMovingon,the

2、reareseveraltheoriesofhowreceptorsystemsfunction-eachmustexplainanimportantexperimentalobservationNotallagonistselicitthemaximumresponseofthebiologicalsystemTheexperimentalsituation100ResponseAgonistA(%)50AgonistB0-9-8-7-6-5[Agonist](logM)Letusassumethatresponseisthecontractionofsmoothm

3、uscleExplanation1:tworeceptorsystemsStrongAgonistARContractionWeakAgonistBR’ContractionThetworeceptorsactivatedifferenttransductionsystems,withdifferentabilitiestoactivatethecontractilesystemofthecellExplanation2:twoopposingreceptorsystemsOpposinginputsRAgonistB-veR’ContractionAgonistAA

4、gonistBsimultaneouslyactivatestworeceptorsystemsthatopposeeachother:anexampleoffunctionalantagonism.However,abell-shapedconcentration-responsecurveisoftenseenExplanation3:ThisismorecomplicatedAgonistshavetwobasicproperties:thefirstisaffinity-definedasthetendencyoftheagonisttocombinewith

5、thereceptork1A+RA-Rk2AtequilibriumForwardrate=k1[A][R]=Backwardrate=k2[AR]Equilibriumk2[A][R]dissociationconstant(Kd)==k1[AR]WhenKdissmallinsize,affinityishighTherelationshipbetweenreceptoroccupancyandagonistconcentration[A]y=[A]+Kd[A]andKdhavethedimensionsofconcentration,thereforerecep

6、toroccupancy(y)hasnodimensionsWhen[A]=Kd,y=0.50Inotherwords,ataligandconcentrationequivalenttotheKd,theligandoccupies50%ofthereceptorpoolTheagonistconcentration-occupancycurve1.0Receptorrectangularoccupancyhyperbola0.5Kd=1x10-7M0012345x10-6[Agonist](M)Whatfactorscontributetoaffinity?Dif

7、fusionrateofagonistWithinanagonistseries,andsuccessofcollisionkdoesnotvarygreatly1k1A+RA-Rk2Incontrast,kvaries2considerablyfortheseriesStabilityofagonist-receptorcomplexHighandlowaffinityagonistsAgonistAngiotensinIIAcetylcholineFunctionPowerfulvaso-Transmitterattheconstrictorho