Brain functions are regulated by the interactions of neurotransmitters and neuropeptides with their specific receptors. Dysfunction in these interactions is the cause of many neurological and psychiatric disorders. Today, over 100 different neurotransmitters and neuropeptides have been identified. However, genomic sequence analyses show that about 50% of the molecules that mediate brain functions are still unknown. Finding and characterizing these molecules should significantly extend our understanding of brain function. We have developed a strategy, called the orphan receptor strategy, which allows us to discover novel neurotransmitters and neuropeptides. This strategy uses orphan G protein-coupled receptors (GPCRs) as """"""""bait"""""""" to isolate their natural ligands. We analyzed two orphan GPCRs and identified the neuropeptides that are their natural ligands: melanin-concentrating hormone (MCH) and urotensin II (UII). We have studied these systems anatomically, pharmacologically and biologically. We have isolated a MCH receptor antagonist and have found that it can inhibit the hedonic aspect of food intake, e now propose to analyze the effects of this antagonist on rewarding responses. We have also studied two recently found equentially-similar neuropeptides, NPB and NPW, that bind to the orphan GPCR, GPR7. Since little is known about the function of this novel neuropeptide system, we propose to help identify its central roles by first study NPB sites of action in the CNS. We have already obtained preliminary anatomical and behavioral data that show that NPB may act as an anxiolytic agent. Because anxiety is a response to stress, this could set the NPB/NPW system as an important medical target. We propose to further study this role by analyzing NPB effect in different anxiety-related assays. We also propose to extend these studies to mice devoid of GPR7 receptor and analyze their innate level of anxiety. Finally we propose to isolate GPR7 antagonists, by applying the methodology that we used to identify MCH antagonists, and use these antagonists to further understand the function of the NPB/NPW system in anxiety and possibly other behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH060231-08
Application #
7217521
Study Section
Special Emphasis Panel (ZRG1-MDCN-L (02))
Program Officer
Winsky, Lois M
Project Start
1999-09-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
8
Fiscal Year
2007
Total Cost
$316,374
Indirect Cost
Name
University of California Irvine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Zhang, Yan; Long, Zhen; Guo, Zhimou et al. (2016) Hydroxycinnamic acid amides from Scopolia tangutica inhibit the activity of M1 muscarinic acetylcholine receptor in vitro. Fitoterapia 108:9-12
Zhang, Yan; Wang, Chaoran; Guo, Zhimou et al. (2014) Discovery of N-methyltetrahydroprotoberberines with ?-opioid receptor agonists-opioid receptor agonist activities from corydalis yanhusuo W. T. Wang by using two-dimensional liquid chromatography. J Ethnopharmacol 155:1597-602
Zhang, Yan; Wang, Chaoran; Wang, Lien et al. (2014) A novel analgesic isolated from a traditional Chinese medicine. Curr Biol 24:117-23
Parks, Gregory S; Wang, Lien; Wang, Zhiwei et al. (2014) Identification of neuropeptide receptors expressed by melanin-concentrating hormone neurons. J Comp Neurol 522:3817-33
Zhang, Li; Parks, Gregory S; Wang, Zhiwei et al. (2013) Anatomical characterization of bombesin receptor subtype-3 mRNA expression in the rodent central nervous system. J Comp Neurol 521:1020-39
Civelli, Olivier; Reinscheid, Rainer K; Zhang, Yan et al. (2013) G protein-coupled receptor deorphanizations. Annu Rev Pharmacol Toxicol 53:127-46
Chung, Shinjae; Liao, Xiao-Hui; Di Cosmo, Caterina et al. (2012) Disruption of the melanin-concentrating hormone receptor 1 (MCH1R) affects thyroid function. Endocrinology 153:6145-54
Civelli, Olivier (2012) Orphan GPCRs and neuromodulation. Neuron 76:12-21
Zhang, Yan; Wang, Zhiwei; Cox, D Phillip et al. (2012) Study on the activation of the opioid receptors by a set of morphine derivatives in a well-defined assay system. Neurochem Res 37:410-6
Zhang, Yan; Xu, Junyan; Wang, Zhiwei et al. (2012) BmK-YA, an enkephalin-like peptide in scorpion venom. PLoS One 7:e40417

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