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Human BRS-3 receptor: Functions/role in cell signaling pathways and glucose metabolism in obese or diabetic myocytes

Ramos-Álvarez, I., Moreno-Villegas, Z., Martín-Duce, A., Sanz, R., Aparicio, C., Portal-Núñez, S., Mantey, S.A., Jensen, R.T., González, N.
Peptides 2014 v.51 pp. 91-99
agonists, bombesin receptors, dose response, glucose, glycogen, glycogen (starch) synthase, homeostasis, humans, ligands, messenger RNA, metabolism, mice, mitogen-activated protein kinase, muscles, myocytes, noninsulin-dependent diabetes mellitus, obesity, patients, phosphatidylinositol 3-kinase, phosphorylation, signal transduction
Several studies showed that the orphan Bombesin Receptor Subtype-3 (BRS-3) – member of the bombesin receptor family – has an important role in glucose homeostasis (v.g.: BRS-3-KO mice developed mild obesity, and decreased levels of BRS-3 mRNA/protein have been described in muscle from obese (OB) and type 2 diabetic (T2D) patients). In this work, to gain insight into BRS-3 receptor cell signaling pathways, and its implication on glucose metabolism, primary cultured myocytes from normal subjects, OB or T2D patients were tested using high affinity ligand – [d-Tyr⁶,β-Ala¹¹,Phe¹³,Nle¹⁴]bombesin6–14. In muscle cells from all metabolic conditions, the compound significantly increased not only MAPKs, p90RSK1, PKB and p70s6K phosphorylation levels, but also PI3K activity; moreover, it produced a dose–response stimulation of glycogen synthase a activity and glycogen synthesis. Myocytes from OB and T2D patients were more sensitive to the ligand than normal, and T2D cells even more than obese myocytes. These results widen the knowledge of human BRS-3 cell signaling pathways induced by a BRS-3 agonist, described its insulin-mimetic effects on glucose metabolism, showed the role of BRS-3 receptor in glucose homeostasis, and also propose the employing of BRS-3/ligand system, as participant in the obese and diabetic therapies.