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PhD Thesis: Li Zhang

Dissertation Abstract:
Characterization of an Orphan G Protein-Coupled Receptor: Bombesin Receptor Subtype-3

By Li Zhang, PhD
Doctor of Philosophy in Biological Sciences with a concentration in Developmental and Cell Biology/Pharmacology
University of California, Irvine, 2009
Professor Olivier Civelli, Chair

Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled receptor (GPCR) in the mammalian bombesin receptor family. Despite great difficulties imposed by the missing endogenous ligand, this study used three different approaches to investigate the functions of BRS-3: pharmacological characterization of a synthetic BRS-3 agonist (Chapter 1); anatomical characterization of BRS-3 mRNA expression in the rodent central nervous system (Chapter 2); and behavioral characterization of BRS-3 deficient mice (Chapter 3)

Synthetic compound 16a was identified as a potent and selective agonist for BRS-3 and a potential tool to study BRS-3 activation in vitro and possibly in vivo. Compound 16a activation of BRS-3 was found to promote b-arrestin translocation to the cell membrane and no receptor internalization was observed in receptor trafficking studies.

To reveal the anatomical substrates mediating BRS-3’s biological actions, BRS-3 mRNA expression in the rodent CNS was investigated by in situ hybridization. BRS-3 mRNA was found in a wide variety of brain regions, with highest expression in the hypothalamus. Neurochemical characteristics of BRS-3-expressing neurons were investigated by identifying potential neurotransmitters or neuropeptides co-produced with BRS-3. A large number of BRS-3-expressing neurons were found to be glutamatergic and BRS-3 mRNA partially co-localizes with corticotropin-releasing factor (CRF) and growth hormone-releasing hormone (GHRH), suggesting interaction with feeding and growth-related endocrine systems.

The prominent expression of BRS-3 in the hypothalamus supports a possible involvement of BRS-3 signaling in regulating energy homeostasis, while BRS-3 expression in the paraventricular hypothalamic nucleus, amygdala and lateral parabrachial nucleus indicates a role in modulating anxiety and stress. In Chapter 3, BRS-3 deficient mice were used to evaluate the impact of BRS-3 deficiency on high-fat diet induced metabolic changes and on the regulation of anxiety-like and depressive-like behaviors in stressful situations, such as in the light-dark box test, the forced-swim test and the tail suspension test. BRS-3 deficient mice were more susceptible to diet-induced obesity, supporting the hypothesis that BRS-3 may be involved in energy metabolism, especially through the leptin signaling pathway. The attenuated emotional responses of BRS-3 deficient mice in stressful situations suggest that BRS-3 may modulate stress response, potentially through CRF-mediated activation of the HPA axis.