Disease relevance of MC4R

• Mutations in MC4R are the most common genetic cause of obesity [1].
• These findings form a basis to further investigate the relevance of constitutive activity of the MC4R and of inverse agonism of AgRP for the regulation of body weight [2].
• In particular, we found no evidence for an increased rate of binge-eating behavior in obese carriers of MC4R variants [3].
• We initially performed a mutation screen of the coding region of the MC4R in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls allowing for a case-control study [4].
• In addition, complete MC4R deficiency is not a cause of relative hyperinsulinemia as recently observed in children with heterozygous MC4R mutations [5].

Psychiatry related information on MC4R

• The synthetic melanocortin analog SHU9119 has been widely used to characterize the physiological role of MC4R in feeding behavior and energy homeostasis [6].
• Melanocortin-4 receptor gene and physical activity in the Québec Family Study [7].
• Notably mutations in the melanocortin MC4 receptor are found in up to 4% of the morbidly obese, and in a proportion of patients with anorexia nervosa mutations have been identified in the agouti-related peptide gene (AgRP), which codes for an endogenous antagonist of this receptor [8].

High impact information on MC4R

• A frameshift mutation in MC4R associated with dominantly inherited human obesity [9].
• Our results also suggest that the tonic satiety signal provided by the constitutive activity of MC4R may be required for maintaining long-term energy homeostasis in humans [1].
• Haploinsufficiency of the melanocortin-4 receptor: part of a thrifty genotype [10]?
• Genomic sequencing of the MC4R gene revealed three polymorphisms in the noncoding region that displayed strong linkage disequilibrium with V103I [11].
• Using this method we analyzed the cell surface expression of all the 14 described childhood obesity-associated MC4R missense mutations [12].

Chemical compound and disease context of MC4R

• Likewise, its homologous MC4R in human obesity, MC3R gene is also a good candidate for genetic susceptibility to glucose intolerance and T2DM [13].
• To determine whether MC4R has a role in causing severe obesity in Pima Indians, we sequenced the coding region of this gene in 426 full-heritage, non-first-degree related, adult Pima Indians (300 severely obese and 126 nondiabetic nonobese control subjects) [14].
• In our study, we addressed the hypothesis that a G-->A substitution at codon 103 (Val-103Ile) of the MC4R gene influences abdominal obesity, insulin, glucose, and lipid metabolism as well as circulating hormones, including salivary cortisol [15].
• Ten structurally similar melanocortin subtype-4 receptor (MC4R) ligands from an aryl piperazine chemical platform were evaluated in female Fischer 344 rats to assess the toxicity of this class of compounds [16].
• This regulation apparently requires genomic regulatory sequences because Dex did not increase MC4 receptor expression or signaling in CHO cells expressing the MC4 receptor under the control of a cytomegalovirus promoter [17].

Biological context of MC4R

• Since activation of this receptor leads to a decrease in food intake, MC4R is also a major therapeutic target for the treatment of obesity [1].
• This new regulatory mechanism was likewise detectable in a cell line derived from murine hypothalamic neurons endogenously expressing MC4R, pointing to the physiological relevance of Agrp-promoted receptor endocytosis [18].
• Up to a remarkable 6% of morbidly obese adults and children studied possess single nucleotide polymorphisms (SNPs) of the MC4R [19].
• Upon stimulation by agonist, the MC4R signals through the intracellular adenylate cyclase signal transduction pathway [19].
• MC4R mRNA was detected in astrocytes, however radioligand binding experiments failed to detect measurable MC4R in astrocyte membranes, in contrast to membranes from HEK-rMC4R cells that display a binding site density of 18.1+/-1.5fmol/mg [20].

Anatomical context of MC4R

• Melancortin agonists stimulate cAMP in a concentration-dependent manner in both astrocytes and human embryonic kidney cells recombinantly expressing rat MC4R (HEK-rMC4R), however, the relative potency and intrinsic activity of both small molecule and peptide agonists are reduced in the native system [20].
• Considering the tissue distribution of the MCRs, there are two distinctions between mammals and fish: where in mammals the MC4R is exclusively expressed in the central nervous system, in the fish species examined so far it is also peripherally expressed [21].
• All the subtypes except MC4R could be detected in testis [22].
• Immunofluorescence studies showed that the mutant proteins were expressed and localized in the intracellular compartment but absent from the plasma membrane, suggesting that these mutations disrupted the proper cellular transport of MC4R [23].
• We then addressed the possible mechanisms underlying the desensitization using HEK293 and COS-1 cells transfected with hemagglutinin-tagged human MC4R [24].

Associations of MC4R with chemical compounds

• Substitutions of the extracytoplasmic NH2 terminus and the first extracytoplasmic loop (exoloop) of the MC4R with homologous domains of the MC1R had no effect on AGRP (87-132) binding affinity or inhibitory activity (the ability to inhibit melanocortin-stimulated cAMP generation) [25].
• STUDY DESIGN: Direct sequencing of the MC4R encoding sequence and single-strand polymorphism conformation analysis of AGRP and alpha MSH genes were performed in 63 severely obese children [26].
• Mutation of Ile125 (TM3) of the MC4R to the equivalent residue of the MC3R (phenylalanine) selectively decreased affinity and potency of MC4R-selective ligands [27].
• For these peptides, the affinity and activity at all three human receptors (MC3R, MC4R and MC5R) decreased significantly, demonstrating that the His-Phe-Arg-Trp sequence in gamma-MSH is important for activity at these three melanocortin receptors [28].
• Compared to wild-type beta-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R [29].
• The novel variant Cys84Arg showed a significant reduction in cAMP signal properties of the MC4R [30].

Physical interactions of MC4R

• Molecular determinants of melanocortin 4 receptor ligand binding and MC4/MC3 receptor selectivity [27].
• The G-protein coupled melanocortin 4 receptor (MC4r) plays an important role in the energy metabolism [31].

Regulatory relationships of MC4R

• These mutations suggest the critical role of central signaling systems composed of leptin/leptin receptor and alpha-melanocyte stimulating hormone/MC4-R in human energy homeostasis [32].
• NDP-alpha MSH induced a time-dependent internalization of MC4-R that was partially prevented by AgRP [33].

Other interactions of MC4R

• Sustained exposure of human embryonic kidney 293 cells to Agrp induced endocytosis of the MC3R or the MC4R [18].
• This report provides the details of the molecular recognition of SHU9119 antagonism at hMC4R and shows that amino acid Leu(133) of hMC4R plays a key role in melanocortin receptor subtype specificity [6].
• The anatomical characterization shows that the MC2R is expressed in the brain in addition to the head-kidney, whereas the MC4R and MC5R are found in both brain regions and peripheral tissues [34].
• Furthermore, we have found that AGRP(83-132) has no effect on the dissociation kinetics of radiolabelled Nle4,D-Phe7 MSH from the MC4-R, indicating an absence of allosteric effects [35].
• By means of RT-PCR, the mRNA of the MC2R, MC3R, and MC4R receptors is undetectable [36].

Analytical, diagnostic and therapeutic context of MC4R

• Using dual-label in situ hybridization we found that MC4-R mRNA is coexpressed in PVH cells expressing pro-TRH mRNA [37].
• The missense mutation C142T, resulting in the substitution of proline with serine at codon 48, within the first MC4R transmembrane domain, was detected at the heterozygous state in a 15-y-old obese girl (body mass index (BMI)=35 kg/m(2)) who has been obese since she was 8 y old [38].
• MC4R coding region was screened using both single-strand conformation polymorphism (SSCP) analysis and denaturing high-performance liquid chromatography (DHPLC) [38].
• Assignment of the melanocortin 4 receptor (MC4R) gene to human chromosome band 18q22 by in situ hybridisation and radiation hybrid mapping [39].
• We constructed several mutant human MC4R cDNAs by site directed mutagenesis and expressed these receptors in COS-1 cells [40].

References