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

alpha-Melanophore-stimulating hormone (alpha-MSH) antagonizes interleukin-1beta-induced hyperalgesia and Fos expression in the paraventricular and arcuate nucleus of the rat

Item does not contain fulltextIt is known that intracerebroventricular (ICV) administration of a low dose of interleukin-1beta (IL-1beta) induces hyperalgesia and that this effect can be inhibited by alpha-melanophore-stimulating hormone (alpha-MSH). To identify the part of the brain that is affected by hyperalgesia-induced IL-1beta and the possible site of alpha-MSH inhibition, we have examined Fos expression in the rat brain in response to ICV microinjection of alpha-MSH and/or IL-1beta. Following injection of 10 pg IL-1beta, hyperalgesia was induced and Fos became expressed in the paraventricular nucleus (PVN) of the hypothalamus and in the arcuate nucleus (ARC), which contains alpha-MSH-producing neurons. IL-1beta injection did not induce Fos expression in the pars intermedia of the pituitary gland, which contains endocrine melanotrope cells that release alpha-MSH into the systemic circulation. ICV co-injection of IL-1beta with 30 ng alpha-MSH fully inhibited both hyperalgesia and Fos expression in the PVN and the ARC. We conclude that PVN neurons are activated by hyperalgesic IL-1beta and propose that this effect is abolished by alpha-MSH possibly released from the ARC but not from the pituitary gland

The role of melanocortin 3 receptor gene in childhood obesity

10.2337/db07-0225Diabetes56102622-263