Melanocortin 4 receptor activation induces brain-derived neurotrophic factor expression in rat astrocytes through cyclic AMP-protein kinase A pathway |
| |
Authors: | Caruso Carla Carniglia Lila Durand Daniela Gonzalez Patricia V Scimonelli Teresa N Lasaga Mercedes |
| |
Affiliation: | a Research Institute for Reproduction, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina b IFEC-CONICET, Department of Pharmacology, School of Chemistry, National University of Córdoba, Córdoba, Argentina |
| |
Abstract: | Melanocortin 4 receptors (MC4R) are mainly expressed in the brain. We previously showed that the anti-inflammatory action of α-melanocyte-stimulating hormone (α-MSH) in rat hypothalamus and in cultured astrocytes involved MC4R activation. However, MC4R mechanisms of action remain undetermined. Since brain-derived neurotrophic factor (BDNF) may be mediating MC4R hypothalamic anorexigenic actions, we determined melanocortin effects on BDNF expression in rat cultured astrocytes and certain mechanisms involved in MC4R signaling. α-MSH and its analogue NDP-MSH, induced production of cAMP in astrocytes. This effect was completely blocked by the MC4R antagonist, HS024. We found that NDP-MSH increased BDNF mRNA and protein levels in astrocytes. The effect of NDP-MSH on BDNF expression was abolished by the adenylate cyclase inhibitor SQ22536, and decreased by the PKA inhibitor Rp-cAMP. Since melanocortins are immunomodulators, we investigated their actions with bacterial lipopolysaccharide (LPS) and interferon-γ (IFN-γ) stimulus. Although both α-MSH and LPS + IFN-γ increased cAMP responding element binding protein (CREB) activation, LPS + IFN-γ did not modify BDNF expression. On the other hand, α-MSH did not modify basal or LPS + IFN-γ-induced nuclear factor-κB activation. Our results show for the first time that MC4R activation in astrocytes induces BDNF expression through cAMP-PKA-CREB pathway without involving NF-κB. |
| |
Keywords: | α-MSH, α-melanocyte-stimulating hormone AC, adenylate cyclase BDNF, brain-derived neurotrophic factor cAMP, cyclic AMP CRE, cAMP responsive element CREB, cAMP responsive element binding protein db-cAMP, N6,2&prime -O-dibutyryladenosine 3&prime ,5&prime -cyclic monophosphate sodium HPRT, Hypoxanthine-guanine phosphoribosyltransferase FBS, fetal bovine serum MEM-S, supplemented MEM IκB, nuclear factor κB inhibitor IFN, interferon LPS, lipopolysaccharide MAPK, mitogen activated protein kinase MCR, melanocortin receptor NDP-MSH, [Nle(4), smallcaps" >d-phe(7)]melanocyte-stimulating hormone NF-κB, nuclear factor κB PKA, protein kinase A Rp-cAMP, Rp-adenosine 3&prime ,5&prime -cyclic monophosphorothioate triethylammonium TNF, tumor necrosis factor |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|