Disease relevance of MC2R

• Identification of adrenocorticotropin receptor messenger ribonucleic acid in the human pituitary and its loss of expression in pituitary adenomas [1].
• These results provide further evidence compatible with an ACTH feedback loop in the pituitary and suggest that loss of expression of the ACTH-R in corticotroph adenomas of patients with Cushing's disease may play a role in the resistance to feedback of the pituitary-adrenal axis seen in these patients [1].
• However, the ACTH receptor may act as a differentiation factor as suggested by LOH in adrenal carcinomas with an undifferentiated tumor type.In benign adrenal tumors, a strong correlation between ACTH-receptor expression and expression of P450 steroidogenic enzymes is evident [2].
• The MC-2 receptor is expressed in brain tissue but not in the melanoma cells [3].
• Objective Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R) [4].

High impact information on MC2R

• An ACTH receptor on human mononuclear leukocytes. Relation to adrenal ACTH-receptor activity [5].
• The regulation of ACTH receptor binding sites and mRNA by ACTH and angiotensin II (A-II) was studied using cultured human adrenal fasciculata reticularis cells (HAC) [6].
• Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor [7].
• We investigated the DNA base sequence in a family with this condition by polymerase chain reaction amplification of DNA with pairs of primers that span the ACTH-receptor domain [7].
• Persistent expression in the adenoma of ACTH-R alone, even in the absence of ACTH, might result in increased basal adenyl cyclase activity, as observed in the case of thyroid-stimulating hormone receptor, and thereby might play a role in the autonomous production of cortisol [8].

Chemical compound and disease context of MC2R

• Expression of adrenocorticotropin receptor gene in adrenocortical adenomas from patients with Cushing syndrome: possible contribution for the autonomous production of cortisol [8].
• To investigate whether ACTH-R down-regulation will also be induced in tumor cells, we studied the effect of AG on ACTH-R expression in the human NCI-h295 adrenocortical carcinoma cell line, which expresses functional ACTH receptors and produces steroids of the glucocorticoid, mineralocorticoid and androgen pathway [9].

Biological context of MC2R

• Using three markers flanking MC2R gene on chromosome 18, we were able to exclude linkage in a region of 12 centimorgans around the gene [10].
• OS-3 cells transfected with a cAMP-responsive luciferase reporter plasmid (pCREluc) were unresponsive to ACTH, but cotransfection with a vector expressing human MC2R increased luciferase activity more than 40-fold [11].
• Conclusions MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis [4].
• This assay provides excellent sensitivity in an easily assayed transient transfection system, providing a more rapid and efficient measurement of ACTH receptor activity [11].
• This study demonstrated for the first time that an E-box (located at -1020 bp) is involved in the repression of hMC2R gene expression in granulosa cells through interactions with several factors, such as activator protein 4, as suggested by electrophoretic mobility shift assay analyses [12].

Anatomical context of MC2R

• We report here the identification of ACTH-R mRNA in the human pituitary gland, which was confirmed by direct sequencing [1].
• In vivo, activation of the ACTH receptor (ACTHR) has a trophic effect on the adrenal cortex, while the effects on proliferation are still under discussion, especially since other POMC derived peptides have been characterized [13].
• Adrenocorticotropic hormone receptor (ACTHR) is expressed predominantly in the adrenal glands, and its expression is upregulated by its own ligand, ACTH, via a cAMP-dependent pathway [14].
• DISCUSSION: The expression of MC1-R and the lack of MC2-R in human adipose tissues indicate that the melanocortins may regulate cell proliferation and/or inflammatory signals rather than lipolysis [15].
• We conclude that AG induces profound ACTH-R down-regulation in the NCI-h295 cell line either by affecting the gene expression or by decreasing transcript accumulation via an effect on RNA stability [9].

Associations of MC2R with chemical compounds

• As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency [4].
• Sucrose pretreatment blocked receptor desensitization, indicating that hMC2R desensitization and internalization are interrelated [16].
• Down-regulation of ACTH-receptor expression in normal and neoplastic tissue can be achieved by adrenostatic compounds such as aminoglutethimide and metyrapone [2].
• Expression of the adrenocorticotropin receptor (MC2-R) is restricted to adrenocortical cells and is up-regulated by both adrenocorticotropin and angiotensin II through the activation of protein kinase A and protein kinase C pathways, respectively [17].
• After cloning of the promoter region of the human MC2-R gene (hMC2-R), we have shown that cyclic AMP-induced regulation of transcriptional activity of the gene is achieved through two SF1 binding elements located in the proximal promoter [17].
• ACTH only bound Myc-MC2R in the presence of MRAP [18].
• We propose a molecular explanation for the reduced activity exhibited by the MC2R alanine 126 by serine mutant [19].

Physical interactions of MC2R

• Three steroidogenic factor-1 binding elements are required for constitutive and cAMP-regulated expression of the human adrenocorticotropin receptor gene [20].
• In the present study, we have characterized two activator protein-1 (AP-1)-binding sites involved in the A-II stimulation of hMC2R gene transcription [21].

Regulatory relationships of MC2R

• Addition of ACTH to cells cotransfected with the pCREluc reporter and wild-type MC2R activated luciferase expression with a 50% effective concentration of 5.5 x 10(-9) M ACTH, which is similar to previously reported values [11].

Other interactions of MC2R

• Inactivating mutations of MC2R lead to hereditary unresponsiveness to ACTH, also known as familial glucocorticoid deficiency (FGD) [11].
• The novel MC-2 receptor and the MC-1 receptor, described earlier by us (8) showed identical order of affinity for the melanocortin peptides, but the affinities and the fold differences in the affinities to the melanocortin peptides were different when compared to the earlier described MC-1 receptor [3].
• However, ASIP-[90-132 (L89Y)] was found to be less potent than full-length recombinant ASIP and, surprisingly, only exhibited weak inhibitory activity at the hMC2R [22].
• By means of RT-PCR, the mRNA of the MC2R, MC3R, and MC4R receptors is undetectable [23].
• This is the first demonstration that both AP-1 and SF-1 are required for the cAMP-dependent induction of human ACTHR gene [14].

Analytical, diagnostic and therapeutic context of MC2R

• ACTH-R mRNA was detected in all normal pituitary specimens, and in situ hybridization colocalized expression to ACTH staining cells only [1].
• We studied the expression of the ACTH-R in 23 normal pituitary specimens and 53 pituitary adenomas (22 ACTH-secreting, nine GH-secreting, eight prolactin-secreting, one TSH-secreting, one FSH-secreting, 10 nonfunctioning, and two silent corticotroph adenomas), using the sensitive technique of real-time quantitative PCR [1].
• The levels of ACTH-R and cytochrome P450 side chain cleavage enzyme (P450scc) mRNAs were determined by Northern blot analysis [8].
• Immunohistochemistry showed positive staining against chromogranin A in a histological specimen obtained from the right-hand adrenal gland, while the left was negative; the left-hand adrenal gland stained positive against the ACTH receptor (MC2R) while the right was negative [24].
• Direct and allele-specific sequence analyses of the melanocortin 2 receptor gene (MC2R) revealed compound heterozygous mutations (C21Y and R146H) in the MC2R gene [25].

References