Opioid and cannabinoid receptor function is modulated by multiple cellular mechanisms; both receptors are critical to a number of physiological processes in health as well as in central nervous system disorders including the development of tolerance, dependence and addiction to drugs of abuse. This application focuses on the modulation of receptor function by direct protein-protein interaction i.e. dimerization. We and others have previously shown that opioid receptors dimerize with each other as well as with other G protein-coupled receptors such as cannabinoid receptors. In order to explore the molecular consequences of heterodimerization in vivo and its relevance to analgesia and addiction, we have initiated studies to characterize the mechanisms that contribute to the regulation of these heteromers. During the previous funding period we have made considerable progress with the characterization of opioid receptor heteromers in endogenous tissue. For this, we generated heteromer-selective antibodies and using them demonstrated that the heteromer levels are significantly upregulated in select brain regions under distinct pathological states. We also showed that these heteromers exhibit distinct signaling. Relatively little is known about the mechanisms regulating opioid receptor heteromer abundance or the functional relevance of heteromer signaling. In this application studies to investigate the mechanisms of regulation of opioid and cannabinoid receptor heteromers and to characterize heteromer-specific signaling are proposed.
Specific aims are:
Aim 1, to explore mechanisms of regulation of G protein-coupled receptor heteromer levels, and Aim 2, to generate, characterize, and validate tools that disrupt heteromers and use them to study heteromer-specific signaling. We describe studies using a combination of state-of-the-art technologies as well as unique reagents to address an emerging concept of disease-state specific heteromer upregulation. This, combined with heteromer-mediated distinct signaling, makes the heteromer an ideal disease-specific drug target. Studies proposed here, in addition to providing fundamental information about heteromer biology, form a foundation for the identification of small drug-like molecules specifically targeting the heteromer. Hence, the studies in this application are novel, pioneering and clinically relevant, and are likely to help i the identification of novel targets and therapeutics for the treatment of a number of brain diseases including drug addiction.

Public Health Relevance

The exposure of opioid or cannabinoid receptors to drugs of abuse (morphine or tetrahydrocannabinol, respectively) initiates a number of biological responses including analgesia and development of tolerance/ addiction. The objective of studies in this grant application is to explore novel mechanisms such as receptor- receptor interactions in order to gain basic information about the early events that modulate receptor function. Furthermore, this information forms a foundation for studies identifying novel therapeutic targets for the treatment of pain and drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37DA008863-21S1
Application #
9045047
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Wu, Da-Yu
Project Start
1995-03-15
Project End
2017-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
21
Fiscal Year
2015
Total Cost
$114,855
Indirect Cost
$47,094
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Heimann, Andrea S; Gupta, Achla; Gomes, Ivone et al. (2018) Correction: Generation of G protein-coupled receptor antibodies differentially sensitive to conformational states. PLoS One 13:e0193322
Fricker, Lloyd D; Devi, Lakshmi A (2018) Orphan neuropeptides and receptors: Novel therapeutic targets. Pharmacol Ther 185:26-33
Lueptow, Lindsay M; Devi, Lakshmi A; Fakira, Amanda K (2018) Targeting the Recently Deorphanized Receptor GPR83 for the Treatment of Immunological, Neuroendocrine and Neuropsychiatric Disorders. Prog Mol Biol Transl Sci 159:1-25
Margolis, Elyssa B; Fujita, Wakako; Devi, Lakshmi A et al. (2017) Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor. Neuropharmacology 123:420-432
Reckziegel, PatrĂ­cia; Festuccia, William T; Britto, Luiz R G et al. (2017) A novel peptide that improves metabolic parameters without adverse central nervous system effects. Sci Rep 7:14781
Heimann, Andrea S; Gupta, Achla; Gomes, Ivone et al. (2017) Generation of G protein-coupled receptor antibodies differentially sensitive to conformational states. PLoS One 12:e0187306
Bobeck, Erin N; Gomes, Ivone; Pena, Darlene et al. (2017) The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning. Neuropsychopharmacology 42:2527-2536
Gomes, Ivone; Sierra, Salvador; Devi, Lakshmi A (2016) Detection of Receptor Heteromerization Using In Situ Proximity Ligation Assay. Curr Protoc Pharmacol 75:2.16.1-2.16.31
Gomes, Ivone; Bobeck, Erin N; Margolis, Elyssa B et al. (2016) Identification of GPR83 as the receptor for the neuroendocrine peptide PEN. Sci Signal 9:ra43
Wardman, Jonathan H; Gomes, Ivone; Bobeck, Erin N et al. (2016) Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake. Sci Signal 9:ra55

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