Molecular Mechanism of the Constitutive Activation of the L250Q Human Melanocortin-4 Receptor Polymorphism †

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65471/1/j.1747-0285.2006.00362.x.pd

Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function.

Coat colors in the chestnut horse, the yellow Labrador retriever, the red fox, and one type of yellow mouse are due to recessive alleles at the extension locus. Similarly, dominant alleles at this locus are often responsible for dark coat colors in mammals, such as the melanic form of the leopard, Panthera pardus. We show here that the murine extension locus encodes the melanocyte-stimulating hormone (MSH) receptor. In mice, the recessive yellow allele (e) results from a frameshift that produces a prematurely terminated, nonfunctioning receptor. The sombre (Eso and Eso-3J) and tobacco darkening (Etob) alleles, which both have dominant melanizing effects, results from point mutations that produce hyperactive MSH receptors. The Eso-3J receptor is constitutively activated, while the Etob receptor remains hormone responsive and produces a greater activation of its effector, adenylyl cyclase, than does the wild-type allele

Sensory neuron-specific receptor activation elicits central and peripheral nociceptive effects in rats

The sensory neuron-specific G protein coupled receptors (SNSRs) have been described as a family of receptors whose expression in small diameter sensory neurons in the trigeminal and dorsal root ganglia suggests an implication in nociception. To date, the physiological function(s) of SNSRs remain unknown. Hence, the aim of the present study was to determine the effects of rat SNSR1 activation on nociception in rats. The pharmacological characterization of rat SNSR1 was initially performed in vitro to identify a specific ligand, which could be used subsequently in the rat for physiological testing. Among all ligands tested, γ2-MSH was the most potent at activating rat SNSR1. Structure–activity relationship studies revealed that the active moiety recognized by rat SNSR1 was the C-terminal part of γ2-MSH. The radiolabeled C-terminal part of γ2-MSH, γ2-MSH-6–12, bound with high affinity to membranes derived from rat skin and spinal cord, demonstrating the presence of receptor protein at both the proximal and distal terminals of dorsal root ganglia. To investigate the physiological role of SNSR, specific ligands to rat SNSR1 were tested in behavioral assays of pain sensitivity in rats. Selective rat SNSR1 agonists produced spontaneous pain behavior, enhanced heat and mechanical sensitivity when injected intradermally, and heat hypersensitivity when injected centrally, consistent with the localization of rat SNSR1 protein at central and peripheral sites. Together, these results clearly indicate that the SNSR1 plays a role in nociception and may provide novel therapeutic opportunities for analgesia

The role of melanocortin 3 receptor gene in childhood obesity

10.2337/db07-0225Diabetes56102622-263

Different cardiovascular profiles of three melanocortins in conscious rats; evidence for antagonism between γ(2)-MSH and ACTH-(1–24)

1. We investigated the effects of [Nle(4),D-Phe(7)]α-melanocyte-stimulating hormone (NDP-MSH), adrenocorticotropin-(124) (ACTH-(124)) and γ(2)-MSH, three melanocortins with different agonist selectivity for the five cloned melanocortin receptors, on blood pressure and heart rate in conscious, freely moving rats following intravenous administration. 2. As was previously found by other investigators as well as by us, γ(2)-MSH, a peptide suggested to be an agonist with selectivity for the melanocortin MC(3) receptor, caused a dose-dependent, short lasting pressor response in combination with a tachycardia. Despite the fact that NDP-MSH is a potent agonist of various melanocortin receptor subtypes, among which the melanocortin MC(3) receptor, it did not affect blood pressure or heart rate, when administered i.v. in doses of up to 1000 nmol kg(−1). 3. ACTH-(124) caused a dose-dependent decrease in blood pressure in combination with a dose-dependent increase in heart rate in a dose-range from 15 to 500 nmol kg(−1). The cardiovascular effects of ACTH-(124) were independent of the presence of the adrenals. 4. Pretreatment with ACTH-(124) caused a pronounced, dose-dependent parallel shift to the right of the dose-response curve for the pressor and tachycardiac effects of γ(2)-MSH. The antagonistic effect of ACTH-(124) was already apparent following a dose of this peptide as low as 10 nmol kg(−1), which when given alone had no intrinsic hypotensive activity. 5. These results form further support for the notion that it is not via activation of one of the as yet cloned melanocortin receptors that γ-MSH-like peptides increase blood pressure and heart rate. The cardiovascular effects of ACTH-(124) seem not to be mediated by the adrenal melanocortin MC(2) receptors, for which ACTH-(124) is a selective agonist, or by adrenal catecholamines. 6. There appears to be a functional antagonism between ACTH-(124) and γ(2)-MSH, two melanocortins derived from a common precursor, with respect to their effect on blood pressure and heart rate. Whether this antagonism plays a (patho)physiological role remains to be shown

The role of the melanocortin 3 receptor in mediating the effects of gamma-MSH peptides on the adrenal

The pro-opiomelanocortin (POMC)-derived peptides, pro-gamma-MSH (16K fragment), and Lys-gamma(3)-MSH, have been shown to potentiate the steroidogenic action of corticotrophin (ACTH) on the adrenal cortex. Using a continuously perfused adrenal cell column system, we have tested the hypothesis that gamma-MSH peptides exert their effect through the Melanocortin 3 Receptor (MC3-R), since this is the only known receptor to have high affinity for gamma-MSH peptides and has been suggested to be expressed in the rat adrenal. To investigate this hypothesis we tested whether the MC3-R agonist MTII and antagonist SHU9119 could mimic or block the actions of pro-gamma-MSH. We found that MTII could not mimic, and SHU9119 could not block pro-gamma-MSH mediated potentiation of ACTH-induced steroidogenesis. These results suggest that the MC3-R is not involved in mediating the potentiation effect, adding further evidence to the argument that another melanocortin receptor exists