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: Xiaoqun Qin, Xiangping Qu, David Coy, H Christian Weber
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) Vol. 46 Issue 1 Pg. 88-99 (Jan 2012) ISSN: 1559-1166 [Electronic] United States
• PMID: 22127929 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CREB1 protein, human
• Cyclic AMP Response Element-Binding Protein
• Peptides
• Receptors, Bombesin
• bombesin receptor subtype 3
• MAP Kinase Kinase 1

Topics

• Animals
• BALB 3T3 Cells
• Cell Line, Tumor
• Cyclic AMP Response Element-Binding Protein (genetics, metabolism)
• Humans
• MAP Kinase Kinase 1 (physiology)
• MAP Kinase Signaling System (physiology)
• Mice
• Mice, Inbred BALB C
• Peptides (physiology)
• Phosphorylation (physiology)
• Receptors, Bombesin (agonists, physiology)
• Transcriptional Activation (drug effects, physiology)