MSH RECEPTOR--STRUCTURE AND FUNCTION IN PIGMENTATION

阿黑皮素原肽α-MSH调节黑色素的产生 和黑素细胞的生长。 最近，我们报道了编码人类和 鼠MSH受体。 另外三种相关的受体， 和两种独特的神经黑皮质素受体（MC 30 R和MC 4-R） 也克隆了识别多种ACTH和MSH肽分子， 表征了 随后发现鼠MSH受体（MSH-R）定位于 小鼠8号染色体的远端部分，靠近一个基因位点， 色素沉着，称为延伸。 变异的延伸基因座等位基因 发现小鼠是由改变MSH受体的点突变引起的 功能 在小鼠中，隐性黄色延伸等位基因（e）导致 从一个框架转换产生一个提前终止的无功能 受体的 暗（Eso & Eso-31）和烟草变暗（Eob）等位基因， 这两种基因都有显著的黑化作用， 产生过度活跃的MSH受体。 Eso-eJ受体是 组成性激活，而Eob受体仍然是激素 反应，并产生更大的激活其效应，腺苷酸 环化酶，比野生型等位基因。 延伸基因座是同源基因座，其变体等位基因 在许多哺乳动物中都有描述。 我们建议 在人类和其他哺乳动物中表征变异的MSH-R/延伸等位基因， 确定这些等位基因在人类中的一般作用， 确定与皮肤、头发和眼睛颜色、黑色素瘤 易感性和其他色素沉着疾病。 MSH研究 受体不仅将进一步我们对色素沉着的理解;这 受体可能是研究G蛋白的最佳模型之一 偶联肽受体结构和活化。 MSH受体是 唯一已知的G蛋白与天然存在的功能性 变体。 四种黑皮质素受体基因的克隆 配体特异性（MSH-R，ACH-R，MC 3-R，MC$-R）和天然 具有可变活性的MSH受体的出现也提供了独特的 研究G蛋白偶联受体的资源。 获得的数据 从MSH-R等位基因的克隆和表征，从 MSH受体的生物化学和体外诱变研究，以及 从其他POMC受体的表征也将用于 开发一个详细的模型的结构和激活， 受体的

The proopiomelanocortin peptide alpha-MSH regulates melanin production and growth of melanocytes by binding to and activating the MSH receptor. Recently we reported the cloning of the genes encoding the human and murine MSH receptors. Three additional related receptors, the receptor for ACTH, and two unique neural melanocortin receptors (MC30R & MC4-R) that recognize a variety of ACTH and MSH peptides were also clone and characterized. The murine MSH receptor (MSH-R) was subsequently found to map to the distal portion of chromosome 8 in the mouse near a gene locus affecting pigmentation, called extension. Variant extension locus alleles in the mouse were found to result from point mutation s which alter MSH recaptor function. In mice, the recessive yellow extension allele (e) results from a frameshift producing a prematurely terminated non-functioning receptor. The sombre (Eso & Eso-31) and tobacco darkening (Eob) alleles, which both have dominant melanizing effects, result from point mutations which produce hyperactive MSH receptors. The Eso-eJ receptor is constitutively activated, while the Eob receptor remains hormone responsive, and produces a greater activation of its effector, adenylyl cyclase, than does the wild type allele. The extension locus is an homologous gene locus for which variant alleles have been described in many mammalian species. We propose to characterize variant MSH-R/extension alleles in man and other mammals to determine the general role of these alleles in man will be designed to identify correlations with skin, hair, and eye color, melanoma susceptibility, and other pigmentation disorders. Study of the MSH receptor will not only further our understanding of pigmentation; this receptor is perhaps one of the best models for the study of G protein coupled peptide receptor structure and activation. The MSH receptor is the only known G protein coupled with naturally occurring functional variants. The cloning of four melanocortin receptor with differing ligand specificities (MSH-R, ACH-R, MC3-R,MC$-R) and the natural occurrence of MSH receptors with variable activity also provide a unique resource for the study of G protein coupled receptors. Data obtained from cloning nd characterization of variant MSH-R alleles, from biochemical and in vitro mutagenesis studies of the MSH receptor, and from characterization of other POMC receptors will also be used to develop a detailed model of the structure and activation of this receptor.