Spare Receptors (Receptor Reserve)fb[D]Kd + [D]=Response is not proportional to fb but dependent on fb. Response is function of fb.Inverse AgonistAllosteric Theory of Drug action Ligand binding changes receptor energy landscape.Inverse agonist for G protein signaling simultaneously can actas an agonist for β-arrestin signaling.Signal transduction pathways in mammalian cellsPharmacological basis of therapeutics 10th editionby Goodman & GilmanFour types of receptorFour types of receptorMolecular Structure of four types of ReceptorGPCRs are excellent targets for drug discovery1. The most widely used signaling mechanism and regulate almost all aspects ofphysiolgical processes.2. GPCRs consists of the largest gene family of our genome.3. Orphan GPCRs and the oligomerization of GPCR provide further opportunities fornovel drug development.Targets of current drugsHopkins and Groom, Nat Rev.(2002) G protein-mediated signal transduction(Most widely used mechanism of receptor-mediated signaling)Mechanism of G protein cycleThe amount of GαGTP determines the strength and duration of the signalGPCR Response is amplified at the membraneGs Gsα Adenylyl Cyclase (stimutation)GolfαGi Gtα1 cGMP Phosphodiesterase (stimulation)Gtα2Giα1 Adenylyl Cyclase (inhibition)Giα2Giα3GoαA Adenylyl Cyclase (inhibition) (?)GoαBGzα Adenylyl Cyclase (inhibition) Gq Gqα Phospholipase C β (stimulation)G11αG14αG15/16α G12 G12α RhoGEF (stimulation)G13αClassification of Gα subunitsGs stimulates and Gi inhibits cAMP productionRodbell (1980)Soluble second messengersGqGq stimulates PLCbeta isozymesDesensitization of beta-adrenergic receptor-mediated response.Desensitization of Receptor-mediated responseDesensitization of G protein-mediated signalingGRK2 Desensitization Cycle?Classical Paradigm (A) and New Paradigm (B) of GPCR signal transduction.β-Arrestins serve as adaptors, scaffolds, and actively transmit signalsLigand gated ion channelGrowth factor receptor with tyrosine kinase
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