In classical pharmacology, an agonist activates a? single linear signal transduction pathway, whereas an antagonist blocks the action of the agonist and? possesses no intrinsic activity. A rapidly evolving idea is that a given receptor, through various ligand induced? functional conformations, can engage multiple modalities through interaction with different? signaling partners. Hence, a given ligand can bind a receptor and act as an antagonist for one signaling? pathway while serving as an agonist at another or vice versa. This property is established for several G? protein-coupled receptors ? the most important targets for therapeutic intervention. Importantly, none? of the drugs in clinical use have been developed with these multiple signaling considerations in mind.? Additionally, agonists and antagonists are rarely completely selective and, for a given receptor, may? alter signaling by influencing various receptor-mediated processes such as interaction with G proteins,? desensitization, internalization, down-regulation, and receptor-mediated scaffolding of non-G protein? signaling components. The physiological relevance of these properties is not fully appreciated. Thus,? identifying the FUNCTIONAL SELECTIVITY of compounds may help reveal not only distinct biological? processes, but also specific functional outcomes. Currently, the relevance of functional selectivity to? psychiatry is unknown. This is particularly important for atypical antipsychotics, where dopamine (DA)? D2 and 5-HT2A serotonin receptor antagonism is essentially a prerequisite for all these drugs;? however, their other intrinsic activities are obscure. The overall goal of the proposed research is to? elucidate signal transduction mechanisms that are essential for antipsychotic efficacy in preclinical? genetic and pharmacological mouse models of schizophrenia-like behaviors. The behavioral core will? analyze effects of anti psychotics on locomotion, prepulse inhibition, latent inhibition, and social? behavior in DA transporter knockout, NMDA NR1-subunit knockdown, and C57BL/6 mice treated with? amphetamine or phencyclidine to reproduce schizophrenia-like states. Molecular fingerprinting studies? will be performed to analyze effects of antipsychotic drugs on various signal transduction modalities? that include the PKA and DARPP-32, AktiGSK, PLC, and ERK pathways. Understanding the relevance? of functional selectivity of anti psychotics may provide novel targets with fewer side-effects, greater? therapeutic selectivity, and enhanced efficacy for treating individuals with schizophrenia. ? ?
| McCorvy, John D; Wacker, Daniel; Wang, Sheng et al. (2018) Structural determinants of 5-HT2B receptor activation and biased agonism. Nat Struct Mol Biol 25:787-796 |
| Peng, Yao; McCorvy, John D; Harpsøe, Kasper et al. (2018) 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. Cell 172:719-730.e14 |
| Che, Tao; Majumdar, Susruta; Zaidi, Saheem A et al. (2018) Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor. Cell 172:55-67.e15 |
| Wang, Sheng; Che, Tao; Levit, Anat et al. (2018) Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone. Nature 555:269-273 |
| Rose, Samuel J; Pack, Thomas F; Peterson, Sean M et al. (2018) Engineered D2R Variants Reveal the Balanced and Biased Contributions of G-Protein and ?-Arrestin to Dopamine-Dependent Functions. Neuropsychopharmacology 43:1164-1173 |
| McCorvy, John D; Butler, Kyle V; Kelly, Brendan et al. (2018) Structure-inspired design of ?-arrestin-biased ligands for aminergic GPCRs. Nat Chem Biol 14:126-134 |
| Wacker, Daniel; Wang, Sheng; McCorvy, John D et al. (2017) Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell 168:377-389.e12 |
| Wacker, Daniel; Stevens, Raymond C; Roth, Bryan L (2017) How Ligands Illuminate GPCR Molecular Pharmacology. Cell 170:414-427 |
| Arnsten, Amy F T; Girgis, Ragy R; Gray, David L et al. (2017) Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. Biol Psychiatry 81:67-77 |
| Pappas, Andrea L; Bey, Alexandra L; Wang, Xiaoming et al. (2017) Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers. JCI Insight 2: |
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