The overall purpose of this research proposal is to identify the molecular basis underlying the functions of the CB2 cannabinoid receptor. One of the major problems for cannabinoids as therapeutic agents is their severe psychoactive side-effect. The recent cloning of CB2, a subtype of cannabinoid receptors, brought us new hope for a better medical use of cannabinoids. CB2 is distributed primarily in the peripheral tissues, whereas CB1 I distributed primary in the central nervous system. CB2 has only 44 percent amino acid identity with CB1. Recently several CB2-selective cannabinoid ligands have been discovered; the signal transduction pathway for CB2 is being identified; and the pharmacological properties of CB2 in a rat mast cell line, RBL-2H3 cells, have been shown to be different from those of the cloned human CB2. The hypotheses of this proposal include: 1. The ligand binding and signal transduction characteristics of CB2 are determined by its unique structural features. 2. The differences between RBL-2H3 cell cannabinoid receptors and human CB2 may be explained by either the structural differences between rat and human CB2, or the novel receptor subtypes that may exist in RBL-2H3 cells. The following specific aims will attempt to test these hypotheses:
Specific Aim 1 : To determine the amino acids of CB2 that are important for ligand binding.
Specific Aim 2 : To determine the amino acids of CB2 that are important for receptor activation.
Specific Aim 3 : To characterize cannabinoid receptor subtypes in a rat mast cell line (RBL-2H3). A combination of molecular cloning, mutagenesis, heterologous expression, and pharmacological assays will be utilized to test the hypotheses of this proposal. Molecular modeling studies will be performed collaboratively. These studies should help us to understand in more molecular detail the ligand binding and activation of cannabinoid receptor subtypes, particularly about CB2, which is a very important receptor for the immune-modulatory effects of marijuana and cannabinoids. Ultimately, this may facilitate the development of novel cannabinoid mimetics with improved therapeutic properties and minimized psychoactive side effects.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Human Development Research Subcommittee (NIDA)
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Hillery, Paul
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Texas A&M University
Schools of Medicine
College Station
United States
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Brown, Kevin J; Laun, Alyssa S; Song, Zhao-Hui (2017) Cannabidiol, a novel inverse agonist for GPR12. Biochem Biophys Res Commun 493:451-454
Kumar, Pritesh; Carrasquer, Carl A; Carter, Arren et al. (2014) A categorical structure-activity relationship analysis of GPR119 ligands. SAR QSAR Environ Res 25:891-903
Kumar, Pritesh; Song, Zhao-Hui (2014) CB2 cannabinoid receptor is a novel target for third-generation selective estrogen receptor modulators bazedoxifene and lasofoxifene. Biochem Biophys Res Commun 443:144-9
Mnpotra, Jagjeet S; Qiao, Zhuanhong; Cai, Jian et al. (2014) Structural basis of G protein-coupled receptor-Gi protein interaction: formation of the cannabinoid CB2 receptor-Gi protein complex. J Biol Chem 289:20259-72
Kumar, Pritesh; Kumar, Akhilesh; Song, Zhao-Hui (2014) Structure-activity relationships of fatty acid amide ligands in activating and desensitizing G protein-coupled receptor 119. Eur J Pharmacol 723:465-72
Kumar, Pritesh; Song, Zhao-Hui (2013) Identification of raloxifene as a novel CB2 inverse agonist. Biochem Biophys Res Commun 435:76-81
Qiao, Zhuanhong; Kumar, Akhilesh; Kumar, Pritesh et al. (2012) Involvement of a non-CB1/CB2 cannabinoid receptor in the aqueous humor outflow-enhancing effects of abnormal-cannabidiol. Exp Eye Res 100:59-64
Kumar, Akhilesh; Qiao, Zhuanhong; Kumar, Pritesh et al. (2012) Effects of palmitoylethanolamide on aqueous humor outflow. Invest Ophthalmol Vis Sci 53:4416-25
Carrasquer, Alex; Nebane, Nstang M; Williams, Walter M et al. (2010) Functional consequences of nonsynonymous single nucleotide polymorphisms in the CB2 cannabinoid receptor. Pharmacogenet Genomics 20:157-66