Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system.

Abstract

Corticotropin (ACTH) and melanotropin (MSH) peptides (melanocortins) are produced not only in the pituitary but also in the brain, with highest concentrations in the arcuate nudeus of the hypothalamus and the commisural nucleus of the solitary tract. We have identified a receptor for MSH and ACTH peptides that is specdflcally expressed in regions of the hypothalamus and limbic system. This melanocortin receptor (MC3-R) is found in neurons of the arcuate nucleus known to express proopiomelanocortin (POMC) and in a subset of the nuclei to which these neurons send projections.The MC3-R is 43% identical to the MSH receptor present in melanocytes and is strongly coupled to adenylyl cyclase. Unlike the MSH or ACTH receptors, MC3-R is potendy activated by 'yMSH peptides, POMC products that were named for their amino acid homology with a-and f-MSH, but lack melanotropic activity. The primary biological role of the yMSH peptides is not yet understood. The location and properties of this receptor provide a pharmacological basis for the action of POMC peptides produced in the brain and possibly a specific physiological role for -MSH.The large proopiomelanocortin (POMC) protein is processed into three main families ofpeptides with adrenocorticotropic, melanotropic, or opiate activities. The melanocortins, which include all POMC peptides except (3-endorphin, are primarily known for their role in the regulation of adrenal steroid production [corticotropin (ACTH)] and pigmentation [a melanotropin (a-MSH)]. In addition to these well-known effects, administration of melanocortin peptides has been reported to increase retention of learned behaviors (1, 2), induce grooming behavior (3), decrease fever (4, 5), stimulate nerve regeneration (6, 7), and increase heart rate, blood pressure, and natriuresis (8, 9). Many ofthese biological activities have been demonstrated to result from direct action of the melanocortin peptides in the brain.Recently, the cloning of the MSH (10, 11) and ACTH receptors (10) (MSH-R and ACTH-R) has provided probes for the examination of MSH-R and ACTH-R mRNA expression. Thus far, MSH-R and ACTH-R mRNA expression has only been detected in melanocytes and in the adrenal cortex, respectively. Although specific high-affinity MSH and ACTH binding has been reported in brain, with highest levels in the hypothalamus (12, 13), no MSH-R or ACTH-R mRNA was detected in the brain by either Northern hybridization or in situ hybridization (14,15). Additionally, melanocortin binding and biological action in the brain display pharmacological profiles that do not match those of either the adrenal The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.ACTH-R or the melanocyte MSH-R. These data suggested the existence of unique melanocortin receptor(s) expressed specifically in the brain.We report here the cloning and characterization of a neural-specific melanocorti...

Structure–activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position

“…There are five known melanocortin receptor (MCR) subtypes, all of which belong to the family of seven transmembrane G-protein coupled receptors (GPCRs), and whose activation is linked to the generation of intracellular cAMP [3,7,8,12,[14][15][16]22,31,34,38]. Importantly, the interaction of the melanocortin peptides with their receptors can be modified by two endogenous protein antagonists, agouti, and agouti-related protein, which are the products of two distinct genes [33,35].…”

Body weight is regulated by the brain: a link between feeding and emotion

“…32 However, the anatomic substrate underlying coordinated food intake control still remained obscure, as scientists in the field lacked key tools to unravel this complex hypothalamic puzzle. Nevertheless, several molecular discoveries in 1990s, especially identification of leptin 5 and melanocortin receptors [33][34][35] implicated other hypothalamic and extra-hypothalamic sites in regulating energy homeostasis.…”

“…33,34,143 Notably, another POMC-derived peptide g-MSH binds to MC3-Rs with a high affinity, and AgRP antagonizes g-MSH action on MC3-Rs. 33,143 The brain distribution of MC3-Rs also significantly differs from that of MC4-Rs. The rat PVH, for example, expresses MC4-R mRNA but apparently not MC3-R mRNA.…”

“…33,79 Conversely, the ventromedial nucleus of the hypothalamus (VMH) is one of the sites that express high levels of MC3-R mRNA, whereas MC4-Rpositive VMH cells are relatively few. 33,79 Another noticeable difference is that POMC and AgRP neurons in the Arc express MC3-Rs but not MC4-Rs, suggesting a potential role of MC3-Rs in regulating the melanocortinergic local circuits within the Arc. 107 Although MC3-R-deficient mice are not hyperphagic, they do display an increased fat mass.…”

“…171 Here, it is interesting to note that high levels of MC3-R mRNA are expressed in the VTA, where g-MSH-positive axon terminals are distributed. 33,107 As opioid receptor antagonists block the feeding-stimulatory effect of AgRP, the melanocortin system may regulate appetite. 172 Thus, whether dopaminergic VTA neurons projecting to the Acb coexpress MC3-Rs is worth exploring.…”