Cone R D, Lu D, Koppula S, Vage D I, Klungland H, Boston B, Chen W, Orth D N, Pouton C, Kesterson R A
Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland 97201, USA.
Recent Prog Horm Res. 1996;51:287-317; discussion 318.
Molecular cloning experiments have led to the identification and characterization of a family of five receptors for the melanocortin (melanotropic and adrenocorticotropic) peptides. The first two members of the family cloned were the well-characterized melanocyte-stimulating hormone receptor (MSH-R) and adrenocorticotropin receptor (ACTH-R). The three new melanocortin receptors have been termed the MC3-R, MC4-R, and MC5-R, according to the order of their discovery, and little is known at this point concerning their function. Agouti and extension are two genetic loci known to control the amounts of eumelanin (brown-black) and phaeomelanin (yellow-red) pigments. Chromosomal mapping demonstrated that the MSH-R, now termed MCI-R, mapped to extension. Extension was shown to encode the MCI-R, and mutations in the MCI-R are responsible for the different pigmentation phenotypes caused by this locus. Functional variants of the MCI-R, originally characterized in the mouse, have now also been identified in the guinea pig and cow. Dominant constitutive mutants of the MCI-R are responsible for causing dark black coat colors while recessive alleles result in yellow or red coat colors. Agouti, a secreted 108 amino acid peptide produced within the hair follicle, acts on follicular melanocytes to inhibit alpha-MSH-induced eumelanin production. Experiments demonstrate that agouti is a high-affinity antagonist, acting at the MCI-R to block alpha-MSH stimulation of adenylyl cyclase, the effector through which alpha-MSH induces eumelanin synthesis. The MCI-R is thus a unique bifunctionally controlled receptor, activated by alpha-MSH and antagonized by agouti, both contributing to the variability seen in mammalian coat colors. The variable tan and black coat color patterns seen in the German Shepherd, for example, can now be understood on the molecular level as the interaction of a number of extension and agouti alleles encoding variably functioning receptors and a differentially expressed antagonist of the receptor, respectively.
分子克隆实验已鉴定并表征了一个由五个黑素皮质素（促黑素和促肾上腺皮质激素）肽受体组成的家族。该家族克隆出的前两个成员是已被充分表征的促黑素细胞激素受体（MSH-R）和促肾上腺皮质激素受体（ACTH-R）。根据发现顺序，这三个新的黑素皮质素受体被命名为MC3-R、MC4-R和MC5-R，目前对它们的功能知之甚少。刺鼠色（Agouti）和扩展（extension）是两个已知控制真黑素（棕黑色）和褐黑素（黄红色）色素含量的基因座。染色体定位表明，MSH-R（现称为MCI-R）定位于扩展基因座。扩展基因座被证明编码MCI-R，MCI-R中的突变是该基因座导致不同色素沉着表型的原因。MCI-R的功能变体最初在小鼠中得到表征，现在在豚鼠和牛中也已被鉴定出来。MCI-R的显性组成型突变体导致深黑色被毛颜色，而隐性等位基因则导致黄色或红色被毛颜色。刺鼠色蛋白是一种在毛囊内产生的由108个氨基酸组成的分泌肽，作用于毛囊黑素细胞以抑制α-MSH诱导的真黑素生成。实验表明，刺鼠色蛋白是一种高亲和力拮抗剂，作用于MCI-R以阻断α-MSH对腺苷酸环化酶的刺激，α-MSH通过该效应器诱导真黑素合成。因此，MCI-R是一种独特的双功能控制受体，由α-MSH激活并被刺鼠色蛋白拮抗，两者都导致了哺乳动物被毛颜色的多样性。例如，德国牧羊犬中可见的可变棕褐色和黑色被毛颜色模式，现在可以在分子水平上理解为分别编码功能可变受体的多个扩展基因座和刺鼠色基因座等位基因以及该受体差异表达拮抗剂之间的相互作用。
