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      Mitogen- and stress-activated protein kinase-1 activation is involved in melanocortin-induced BDNF expression in Neuro2a neuronal cells

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          Abstract

          Melanocortins are neuropeptides exerting versatile functions in the nervous system. Melanocortin 4 receptor (MC4R) is primarily expressed in the brain and is thought to be a major mediator for melanocortin. Brain-derived neurotrophic factor (BDNF) may be a crucial downstream molecule of MC4R activation, to yield neurite outgrowth, neuroregenerative, anorexigenic and other actions. In this study, we stimulated Neuro2a murine neuronal cells with an α-melanocyte stimulating hormone (α-MSH) analog, [Nle(4), D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH). In Neuro2a cells, NDP-MSH promoted neurite outgrowth. Upon NDP-MSH administration, BDNF expression was greatly enhanced. Furthermore, this effect was effectively reversed by the MC4R antagonist, JKC-363. We found that NDP-MSH treatment activated the ERK cascade and its downstream kinase MSK1 (mitogen- and stress-activated protein kinase-1). Antagonism of the MSK1 cascade by a specific inhibitor or overexpression of a defective MSK1 mutant interrupted the phosphorylation of the transcription factor cAMP-response element binding protein (CREB), blocking BDNF upregulation. In addition, MSK1 activation triggered an epigenetic alteration in histone H3 (Ser10), facilitating the expression of the BDNF gene. Taken together, our results showed that MSK1 kinase positively activates MC4R-induced BDNF expression via modulating the phosphorylation of CREB and histone H3 in Neuro2a neuronal cells.

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          Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor.

          The melanocortin-4 receptor (MC4R) is critically involved in regulating energy balance, and obesity has been observed in mice with mutations in the gene for brain-derived neurotrophic factor (BDNF). Here we report that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH) where its expression is regulated by nutritional state and by MC4R signaling. In addition, similar to MC4R mutants, mouse mutants that expresses the BDNF receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets. Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higher-fat diets in mice with deficient MC4R signaling. These results show that MC4R signaling controls BDNF expression in the VMH and support the hypothesis that BDNF is an important effector through which MC4R signaling controls energy balance.
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            Targeting melanocortin receptors as a novel strategy to control inflammation.

            Adrenocorticotropic hormone and alpha-, beta-, and gamma-melanocyte-stimulating hormones, collectively called melanocortin peptides, exert multiple effects upon the host. These effects range from modulation of fever and inflammation to control of food intake, autonomic functions, and exocrine secretions. Recognition and cloning of five melanocortin receptors (MCRs) has greatly improved understanding of peptide-target cell interactions. Preclinical investigations indicate that activation of certain MCR subtypes, primarily MC1R and MC3R, could be a novel strategy to control inflammatory disorders. As a consequence of reduced translocation of the nuclear factor kappaB to the nucleus, MCR activation causes a collective reduction of the major molecules involved in the inflammatory process. Therefore, anti-inflammatory influences are broad and are not restricted to a specific mediator. Short half-life and lack of selectivity could be an obstacle to the use of the natural melanocortins. However, design and synthesis of new MCR ligands with selective chemical properties are already in progress. This review examines how marshaling MCR could control inflammation.
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              The melanocortin pathway and control of appetite-progress and therapeutic implications

              The initial discovery that ob/ob mice become obese because of a recessive mutation of the leptin gene has been crucial to discover the melanocortin pathway to control appetite. In the melanocortin pathway, the fed state is signaled by abundance of circulating hormones such as leptin and insulin, which bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH). The α-MSH released by POMC neurons then signals to decrease energy intake by binding to melanocortin-4 receptor (MC4R) expressed by MC4R neurons to the paraventricular nucleus (PVN). Conversely, in the ‘starved state’ activity of agouti-related neuropeptide (AgRP) and of neuropeptide Y (NPY)-expressing neurons is increased by decreased levels of circulating leptin and insulin and by the orexigenic hormone ghrelin to promote food intake. This initial understanding of the melanocortin pathway has recently been implemented by the description of the complex neuronal circuit that controls the activity of POMC, AgRP/NPY and MC4R neurons and downstream signaling by these neurons. This review summarizes the progress done on the melanocortin pathway and describes how obesity alters this pathway to disrupt energy homeostasis. We also describe progress on how leptin and insulin receptors signal in POMC neurons, how MC4R signals and how altered expression and traffic of MC4R change the acute signaling and desensitization properties of the receptor. We also describe how the discovery of the melanocortin pathway has led to the use of melanocortin agonists to treat obesity derived from genetic disorders.
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                Author and article information

                Journal
                Neuroreport
                Neuroreport
                NR
                Neuroreport
                Lippincott Williams & Wilkins
                0959-4965
                1473-558X
                17 August 2020
                7 October 2020
                : 31
                : 14
                : 1007-1014
                Affiliations
                [1]Department of Anesthesiology and Pain Management, Sir Run-Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
                Author notes
                Correspondence to Yue Wu, Department of Anesthesiology & Pain Management, Sir Run-Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China, Tel: +86 571 87887667; e-mail: 3416236@ 123456zju.edu.cn
                Article
                00002
                10.1097/WNR.0000000000001508
                7467152
                32815825
                e0b68cf8-1476-42a3-9071-ab8062a1715e
                Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CC-BY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                : 01 May 2020
                : 10 June 2020
                Categories
                Cellular, Molecular and Developmental Neuroscience
                Custom metadata
                TRUE

                brain-derived neurotrophic factor,camp-response element binding protein,epigenetic modification,melanocortin,melanocortin 4 receptor,mitogen- and stress-activated protein kinase-1

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