Melanocortin Receptors The melanocortin system consists of five GPCRs that all stimulate the adenylyl cyclase signal transduction pathway. The endogenous agonists are derived by posttranslational processing of the proopiomela-nocortin gene transcript by the prohormone convertases PC1 and PC2 to generate adrenocorticotropin (ACTH) and the a-, P-, and y-melanocyte-stimulating hormones (MSH). The melanocortin system also has the only two known endogenous GPCR antagonists, termed agouti and agouti-related protein (AgRP) (for review, see Reference 168). Inactivating mutations in the genes of four of these receptors have now been linked to human diseases.
Pharmacological studies in rodents demonstrated a pivotal role of central melanocortin 4 receptors (MC4R) in the regulation of energy homeostasis (for review, see References 169, 170). Further evidence came from the observation that in MC4R null mice, obesity results from the combined effects of increased food intake (hyperphagia) and decreased energy expenditure [171-174]. Subsequently, genetic studies in severely obese patients confirmed that the MC4R is also critical for maintaining energy homeostasis in humans [175-178] - The prevalence of MC4R mutations in the human population now makes this the most common monogenic cause of early-onset morbid obesity . To date, 29 trafficking-defective mutant forms of MC4R have been reported among the 80 mutations described in the human population, suggesting that pharmacological chaperones could be utilized for some forms of this disease .
Strong evidence for a causative role of melanocortin 3 receptor (MC3R) mutations in obesity has also recently emerged. In MC3R knockout mice, high feed efficiency (i.e., mice gain more fat per calorie of food consumed compared to wild-type littermates), rather than hyperphagia, seems to contribute to increased fat mass. The first potential human obesity-linked mutation in MC3R from two related obese patients in Singapore was reported in 2002 . This mutation, I183N, changes a highly conserved Ile at the junction between TM domain III and intracellular loop II, residing within the highly conserved DRYxxI/V motif. Two groups have independently reported the functional properties of I183N MC3R [182, 183]. Both studies showed that this mutation indeed results in a complete loss of function, but there was a discrepancy regarding its cell surface expression. This discrepancy could be due to the use a green fluorescent protein (GFP)--agged MC3R - 182] - which might affect intracellular trafficking of the receptor. Recently, three additional mutations have been identified in obese patients from Italy, including A293T in TM domain VI, I335S in TM domain VII, and X361S (which changes the stop codon to Ser, resulting in the addition of seven amino acids before a downstream stop codon) . In vitro expression demonstrated a loss of function of I335S MC3R caused by intracellular retention. This Ile is part of the conserved N/DPxxY motif (DPLIY) in TM domain VII and is fully conserved in all five melanocortin receptors. The amino acid Ile335 in MC3R corresponds to Ile301 in MC4R. The I301T mutation in MC4R has been described as a loss-of-function mutation, suggesting a critical role of this amino acid position for full biological function of both MC3R and MC4R . The in vitro analysis of the A293T and X361S mutant receptors showed normal cell surface expression and signaling capacity in the presence of the superagonist NDP-MSH and the endogenous agonist a-MSH [184, 185]. However, a more complete signaling study with y-MSH and AgRP would be required in order to draw any conclusion regarding the role of these mutations in the development of obesity.
Mutations in the melanocortin 2 receptor (MC2R), or ACTH receptor, are responsible for familial glucocorticoid deficiency (FGD) syndrome and account for approximately 25% of FGD cases. Thirty distinct mutations associated with FGD have been reported, including 27 missense mutations (for review, see Reference 180). Functional studies of the MC2R mutants have been hindered by the fact that MC2R cell surface expression depends on expression of a melanocortin receptor accessory protein, which is only expressed in cells derived from the adrenal gland [186, 187] - In most studies, ligand binding and localization experiments were not done, preventing conclusions from being drawn on whether the mutant MC2Rs are defective in cell surface expression, ligand binding, and/or signaling.
Lastly, mutations in the melanocortin 1 receptor (MC1R) are responsible for pigmentation defects in humans. The MC1R is a major factor in controlling skin and hair pigmentation, with activation increasing intracellular cAMP levels and producing eumelanin that leads to a darkening of skin and hair - 188] - Mutant forms of MC1R that are responsible for the red hair color (RHC) phenotype in humans (red hair, fair skin, and poor ability to tan) have been reported . To date, more than 60 mutant forms have been identified in MC1R with various skin and hair abnormalities, including RHC and an increased susceptibility to melanoma and other skin cancers. Recently, four of these MC1R mutants were shown to have greatly decreased cell surface expression (D84E in TM domain II, R151C, I155T, and R160W in intracellular loop II), with two others showing a smaller decrease in cell surface expression (V60L in TM domain I and R163Q in TM domain IV) . A good correlation was seen between those alleles strongly associated with the RHC pheno-type and significantly decreased cell surface expression of the MC1R.
Glycoprotein Hormone Receptors Loss-of-function mutations have also been described for a number of glycoprotein hormone receptors. This receptor family is unique among the GPCRs, because in contrast to other receptors, this contains a large amino-terminal, extracellular (ecto-) domain (ECD) containing leucine-rich repeats that are important for recognition and binding of its glycoprotein ligands (for review, see Reference 191). A priori, this specific feature could present a challenge for the design of pharmacological chaper-ones. However, it has been demonstrated that highly conserved residues in the TM domains of these receptors can modulate constitutive activity of the receptor, thereby also regulating the efficiency of hormone recognition by the ECD. This observation potentially opens up the possibility of using allosteric compounds that bind in the TM domains as pharmacological chaperones for gly-coprotein hormone receptors with mutations in the ECD. Allosteric modulators have been reported for one member of this receptor subfamily, the FSH receptor , and have proven their utility as pharmacological chaperones for the related Family C CaR  (see below).
Thyroid- stimulating hormone (TSH) binds and activates the cell surface TSH receptor (TSHR), resulting in thyroid hormone synthesis and secretion as well as cell proliferation and differentiation within the thyroid gland. Inactivating mutations in the TSHR cause congenital hypothyroidism, which has an autosomal recessive mode of inheritance, with patients either homozygous or compound heterozygous for TSHR mutations. The first inactivating mutations in TSHR causing TSH resistance were reported in 1995 -194] - To date, 32 distinct mutations have been reported in this gene, and among them, six result in intracellular retention of the receptor. Specifically, four missense mutations, I167N and L252P in the ECD, T447I in extracellular loop I, and A553T in TM domain IV [195-198], as well as two frameshift mutations , have been characterized as intracellularly retained or partially expressed at the cell surface.
Loss-of-function mutations in the LH receptor (LHR) lead to Leydig cell hypoplasia, a rare form of male pseudohermaphroditism. In females, LHR inactivation results in hypergonatropic hypogonadism and primary amenor-rhea. Like congenital hypothyroidism, the pattern of inheritance is autosomal recessive, with homozygous or compound heterozygous patients. To date, 22 distinct mutations have been described in this receptor (for review, see Reference 180. . The mutant forms V144F, F194V, and C343S in the ECD, C543R in TM domain V, A593P in TM domain VI, S616Y and I625K in TM domain VII, and two frameshift mutations, 33 base pairs in exon 1 and a microdeletion in TM domain VII (AL608/V609), impair trafficking and cell surface expression [200-206].
Lastly, inactivating mutations in the FSH receptor (FSHR) have been reported. FSH is important for spermatogenesis in males and is absolutely required for follicle growth in females. Mutations in the FSHR result in ovarian dysgenesis, with amenorrhea and infertility in women. Since the first missense mutation, A189T, in the ECD of the receptor was reported in 1995 , eight additional loss-of-function missense mutations have been described. Four of those nine mutants have been characterized as trafficking defective: A189T, I160T, and D224V in the ECD and P519T of extracellular loop II [208-211].
Endothelin b Receptor The endothelin b receptor (ETbR) is derived from one of the primary gene targets (ETRB) involved in Hirschprung disease. Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of ganglion cells in the nerve plexuses of the lower digestive tract. Although mutations in eight different genes (ETRB, EDN3, ECE1, SOX10, RET, GDNF, NTN, and SIP1) have been identified in affected individuals, it is now clear that RET and ETRB are the primary genes implicated in the etiology of HSCR (for review, see Reference 212). All eight genes are involved in the early development of the enteric nervous system, and most act through two distinct biochemical pathways mediated by the products of RET and ETRB. Mutations in ETRB account for 5-10% of the HSCR cases in the general population. To date, only two of the 22 mutations thus far reported, C109R in TM domain I and P383L in TM domain VII of the N/DPxxY conserved motif, have been described as trafficking-defective mutants of ETbR [213, 214].
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Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.