title: A selective human bombesin receptor subtype-3 peptide agonist mediates CREB phosphorylation and transactivation.
abstract: The native ligand for the G protein-coupled bombesin receptor subtype-3 (BRS-3) has currently not been identified. Studies in mice showed robust BRS-3 expression in the hypothalamic satiety centers, and genetic receptor inactivation resulted in obesity, diabetes, and hypertension. BRS-3 was also detected in normal human pancreatic islet cells suggesting a critical role of BRS-3 in regulating energy metabolism and satiety via central and peripheral mechanisms of action. The cyclic AMP response element binding protein (CREB) is a main regulator of pancreatic β-cell gene expression required for glucose homeostasis and islet cell survival, and hypothalamic regulation of satiety. Therefore, in this study we examined whether agonist-dependent hBRS-3 stimulation mediates CREB activation. A selective hBRS-3 peptide agonist and two non-selective hBRS-3 peptide agonists were used to activate ectopically expressed hBRS-3. Stimulation with hBRS-3 peptide agonists resulted in transient calcium mobilization, whereby the selective peptide agonist acted exclusively via hBRS-3 but not through the gastrin-releasing peptide receptor (GRP-R). A selective high-affinity GRP-R antagonist did not inhibit hBRS-3-mediated calcium signals. We also found time-dependent CREB phosphorylation in response to the selective hBRS-3 activation, which was abrogated by pretreatment with protein kinase A and protein kinase C inhibitors. Human BRS-3 agonists also stimulated CREB transactivation and resulted in modest increases of CRE-dependent gene transcription. These changes were significantly reduced after pretreatment with inhibitors of PKA, PKC, and MEK-1. Thus, our results suggest that hBRS-3 agonist-dependent signaling mediates CREB phosphorylation and transactivation through partially PKA, PKC, and MEK-1 pathways.
authors: Department of Physiology, Xiangya Medicine School, Central South University, Changsha, Hunan, 410078, People's Republic of China.
authors: Xiaoqun
authors: X
authors: Qin
authors: Xiangping
authors: X
authors: Qu
authors: David
authors: D
authors: Coy
authors: H Christian
authors: HC
authors: Weber
mesh_terms: D000818:Animals; D041702:BALB 3T3 Cells; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D018004:Receptors, Bombesin / Q000819:agonists* / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D010455:Peptides; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3; D048369:MAP Kinase Kinase 1