Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides.
Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides.
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黑皮质素（神经免疫调节肽家族）的受体生物学。
DOI：
10.1159/000097281
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发表时间：
1996
影响因子：
2.4
通讯作者：
Tatro,JB
中科院分区：
文献类型：
--
作者：
Tatro,JB
黑素皮质激素、促黑素细胞激素（MSH）和促肾上腺皮质激素（ACTH）是由促肾上腺皮质激素（POMC）衍生的同源天然肽。黑素皮质素受体（MCR）生物学的最新突破与神经免疫调节有关，因为黑素皮质素已知通过作用于外周靶点和大脑内部来调节发烧、炎症和免疫。在发烧期间，内源性黑素皮质素通过作用于位于大脑内的MCR发挥解热作用，提示中枢黑素皮质素系统具有保护性的反调节作用。MCR也分别存在于α- msh和ACTH的经典靶点黑素细胞和肾上腺皮质细胞、髓系组织和淋巴组织、各种内分泌和外分泌腺、脂肪细胞和自主神经节中。在中枢神经系统中，MCR显著分布在黑素皮质能神经元的末端场附近，黑素皮质能神经元支配神经内分泌和自主运动核，以及其他在神经内分泌和自主调节、感觉加工和行为的各个方面重要的皮质下脑区域。此外，脑室周围器官中MCR的存在提供了系统性黑素皮质素激素直接进入中枢MCR的途径。总之，这些属性为大脑和外周之间双向mcr介导的通信提供了解剖学基础。一组五种g蛋白相关的MCR亚型，每一种都与腺苷酸环化酶正偶联，已被确定。其中，肾上腺ACTH受体（MC2-R）被ACTH选择性激活。相反，其他MCR亚型（MC1-R、MC3-R、MC4-R、MC5-R）识别一组共同的配体，包括各种形式的MSH和ACTH；然而，它们在配体选择性方面确实表现出重要的差异。MCR浓度和MCR mRNA水平受同源配体可用性、药物和病理刺激的影响。已经发现了两种内源性MCR拮抗剂蛋白：agouti蛋白和皮质抑制素。Agouti蛋白通过拮抗黑素细胞MC1-R显著改变哺乳动物的皮毛颜色。此外，在一些小鼠品系中，agoutigene的自发显性突变导致其普遍过度表达，不仅产生黄色毛色，还产生肥胖和胰岛素抵抗，这可能是其对其他MCR亚型的拮抗作用的结果。最近合成MCR拮抗剂的出现，以及靶向灭活单个MCR亚型的分子方法的可行性，应该有助于阐明内源性黑素皮质素在神经免疫调节中的作用和机制，并确定选择性药物靶向MCR是否最终具有治疗效用。版权所有©1996 S. Karger AG，巴塞尔
Melanocortins, melanocyte-stimulating hormones (MSH) and adrenocorticotropic hormone (ACTH) are homologous natural peptides derived from pro-opiomelanocortin (POMC). Recent breakthroughs in melanocortin receptor (MCR) biology are relevant to neuroimmunomodulation because melanocortins are known to modulate fever, inflammation and immunity, by acting both on peripheral targets and within the brain. During fever, endogenous melanocortins exert antipyretic effects by acting on MCR located within the brain, suggesting a protective counterregulatory role of the central melanocortin system. MCR are also found in melanocyte cells and adrenal cortical cells, the classical targets forα-MSH and ACTH, respectively, in myelogenous and lymphoid tissues, and in various endocrine and exocrine glands, adipocytes, and in autonomic ganglia. In the CNS, MCR are prominently distributed in close proximity to the terminal fields of melanocortinergic neurons that innervate neuroendocrine and autonomic motor nuclei as well as other subcortical brain regions important in neuroendocrine and autonomic regulation, sensory processing and various aspects of behavior. Furthermore, the presence of MCR in circumventricular organs of the brain provides direct access of systemic melanocortin hormones to central MCR. Together, these attributes provide an anatomical basis forbidirectionalMCR-mediated communication between brain and periphery. A group of five G-protein-associated MCR subtypes, each of which is positively coupled to adenylate cyclase, has been identified. Among these, the adrenal ACTH receptor (MC2-R) is selectively activated by ACTH. In contrast, the other MCR subtypes (MC1-R, MC3-R, MC4-R, MC5-R) recognize a common group of ligands that includes various forms of MSH as well as ACTH; nevertheles they do exhibit important differences in ligand selectivity. MCR concentrations and MCR mRNA levels are influenced by availability of cognate ligands, by drugs, and by pathological stimuli. Two types of endogenous MCR antagonist proteins have been discovered: agouti protein and the corticostatins. Agouti protein dramatically alters coat color in mammals by antagonizing melanocytic MC1-R. Moreover, spontaneous dominant mutations of theagoutigene in several strains of mice lead to its ubiquitous overexpression and produces not only yellow coat color, but also obesity and insulin resistance, perhaps as a result of its antagonism of other MCR subtypes. The recent emergence of synthetic MCR antagonists, and the feasibility of molecular approaches for targeted inactivation of individual MCR subtypes, should facilitate elucidation of the roles and mechanisms of neuroimmunomodulation by endogenous melanocortins, and the determination of whether selective pharmacological targeting of MCR may ultimately have therapeutic utility. Copyright© 1996 S. Karger AG, Basel