Hallucinogen actions present a complicated picture because they (a) cause responses that differ from those of other agonists on specific targets such as 5-HT2 receptor subtypes (5-HT2A, 5- HT2C); (b) modulate multiple signaling pathways in specific neurons; and (c) involve several brain regions in their behavioral effects. In the previous period of this Program Project we have developed a multi-scale approach to this complex problem that connects insights about molecular and cellular signaling events to larger scale processes in the neurons and brain regions involved in the generation of the behaviors. We have also developed the powerful genetic animal models and the protein engineering constructs that can be used to probe the consequences of such specifically designed constructs in vitro and in vivo. The research plan of this PPG renewal application presents such a multi-scale investigation, based on an interdisciplinary protocol of iterative studies in the three Projects. The coordinated and integrated studies span scales of size and organization: from molecular structures of activated forms of the wild type and mutant GPCRs and their interactions in the signaling pathways, that are studied in Project 1; to the quantitative genomics-based approach termed Transcriptome Fingerprinting that reflects differential signaling responses through these receptors, and the identification of neurons and specific molecular mechanisms at the cell signaling level that are involved in hallucinogen-specific responses, pursued in Project 2; and onward to genetically modified mice with brain-region-specific manipulations of the 5-HT2AR and its interactions with other receptors and signaling mediators, in Project 3. New constructs of the receptors and their signaling-associated proteins, engineered in Project 1 from bioinformatics, structure-based analysis and simulations, will be expressed in Project 2 to (i) study of the cellular mechanisms underlying hallucinogen signaling specificity; (ii) test mechanistic hypotheses about receptor dimerization and interactions with scaffolding proteins generated in Project 1; and (iii) select the mechanistically most revealing ones for knock-in/knock-out and region-specific restoration and deletion experiments in Project #3, in order to elucidate the behavioral phenotypes associated with support or disruption of specific mechanisms. Through its integrative construct and focus, this research plan is expected to continue to have significant implications for understanding drug abuse in general, as well as on the design of new GPCR-based therapeutics for drug addiction. ? ? PROGRAM CHARACTERISTICS ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
2P01DA012923-06A1
Application #
7298616
Study Section
Special Emphasis Panel (ZDA1-RXL-E (03))
Program Officer
Hillery, Paul
Project Start
2000-02-01
Project End
2012-06-30
Budget Start
2007-08-01
Budget End
2008-06-30
Support Year
6
Fiscal Year
2007
Total Cost
$1,006,213
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Physiology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Gregorio, G Glenn; Masureel, Matthieu; Hilger, Daniel et al. (2017) Single-molecule analysis of ligand efficacy in ?2AR-G-protein activation. Nature 547:68-73
Sensoy, Ozge; Weinstein, Harel (2015) A mechanistic role of Helix 8 in GPCRs: Computational modeling of the dopamine D2 receptor interaction with the GIPC1-PDZ-domain. Biochim Biophys Acta 1848:976-83
Mondal, Sayan; Khelashvili, George; Johner, Niklaus et al. (2014) How the dynamic properties and functional mechanisms of GPCRs are modulated by their coupling to the membrane environment. Adv Exp Med Biol 796:55-74
Perez-Aguilar, Jose Manuel; Shan, Jufang; LeVine, Michael V et al. (2014) A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2. J Am Chem Soc 136:16044-54
Mondal, Sayan; Khelashvili, George; Weinstein, Harel (2014) Not just an oil slick: how the energetics of protein-membrane interactions impacts the function and organization of transmembrane proteins. Biophys J 106:2305-16
Johner, Niklaus; Mondal, Sayan; Morra, Giulia et al. (2014) Protein and lipid interactions driving molecular mechanisms of in meso crystallization. J Am Chem Soc 136:3271-84
Moreno, Jose L; Holloway, Terrell; Rayannavar, Vinayak et al. (2013) Chronic treatment with LY341495 decreases 5-HT(2A) receptor binding and hallucinogenic effects of LSD in mice. Neurosci Lett 536:69-73
Mondal, Sayan; Johnston, Jennifer M; Wang, Hao et al. (2013) Membrane driven spatial organization of GPCRs. Sci Rep 3:2909
Moreno, José L; Holloway, Terrell; Umali, Adrienne et al. (2013) Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice. Psychopharmacology (Berl) 225:217-26
Moreno, José L; Muguruza, Carolina; Umali, Adrienne et al. (2012) Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A·mGlu2) receptor heteromerization and its psychoactive behavioral function. J Biol Chem 287:44301-19

Showing the most recent 10 out of 75 publications