Spare Receptors Receptor Reserve fb D Kd D Response is not proportional to fb but dependent on fb Response is function of fb Allosteric Theory of Drug action Inverse Agonist Ligand binding changes receptor energy landscape Inverse agonist for G protein signaling simultaneously can act as an agonist for arrestin signaling Signal transduction pathways in mammalian cells Pharmacological basis of therapeutics 10th edition by Goodman Gilman Four types of receptor Four types of receptor Molecular Structure of four types of Receptor GPCRs are excellent targets for drug discovery 1 The most widely used signaling mechanism and regulate almost all aspects of physiolgical processes 2 GPCRs consists of the largest gene family of our genome 3 Orphan GPCRs and the oligomerization of GPCR provide further opportunities for novel drug development Targets of current drugs Hopkins and Groom Nat Rev 2002 G protein mediated signal transduction Most widely used mechanism of receptor mediated signaling Mechanism of G protein cycle The amount of G GTP determines the strength and duration of the signal GPCR Response is amplified at the membrane Classification of G subunits Gs Gs Golf Adenylyl Cyclase stimutation Gi Gt 1 Gt 2 cGMP Phosphodiesterase stimulation Gi 1 Gi 2 Gi 3 Adenylyl Cyclase inhibition Go A Go B Adenylyl Cyclase inhibition Gz Adenylyl Cyclase inhibition Gq Gq G11 G14 G15 16 Phospholipase C stimulation G12 G12 G13 RhoGEF stimulation Gs stimulates and Gi inhibits cAMP production Rodbell 1980 Soluble second messengers Gq stimulates PLCbeta isozymes Gq Desensitization of beta adrenergic receptor mediated response Desensitization of Receptor mediated response Desensitization of G protein mediated signaling GRK2 Desensitization Cycle Classical Paradigm A and New Paradigm B of GPCR signal transduction Arrestins serve as adaptors scaffolds and actively transmit signals Ligand gated ion channel Growth factor receptor with tyrosine kinase activity
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