Affinage

MC2R

Adrenocorticotropic hormone receptor · UniProt Q01718

Length
297 aa
Mass
33.9 kDa
Annotated
2026-06-10
69 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MC2R (the ACTH receptor) is a G protein-coupled receptor that drives adrenocortical steroidogenesis and restrains pigment cell development, as established by mc2r knockout in zebrafish, which impairs interrenal steroidogenesis and produces skin hyperpigmentation with expanded melanophore and xanthophore populations (PMID:41639367). Productive ACTH binding and cAMP signaling require the accessory protein MRAP, without which ACTH does not bind MC2R, even though MRAP is dispensable for plasma membrane localization per se; MRAPβ confers higher cell-surface receptor density and maximal cAMP output than MRAPα, and the MRAP isoforms' C-termini dictate their topology and subcellular localization to tune receptor targeting and signaling (PMID:17456795, PMID:22366472). This MRAP1 dependence together with ACTH selectivity over α-MSH is an ancestral feature conserved across bony fish (PMID:35973587). ACTH binding specificity and activation are governed by the fourth and fifth transmembrane domains and by an aromatic-residue-rich segment of the second extracellular loop, while intracellular retention signals reside in TM3/TM4 and the N-terminus modulates trafficking efficiency (PMID:20206229, PMID:25074265, PMID:28495271). Downstream, ACTH/MC2R signals through cAMP/PKA to activate p44/p42 and p38 MAPK (PMID:21195128), drives PKA-dependent desensitization and GRK-dependent, arrestin/clathrin/dynamin-mediated internalization, followed by Rab4/5/11-dependent recycling that itself contributes to total cAMP accumulation (PMID:21920850, PMID:12851305). Transcription of MC2R is controlled in a tissue-specific manner: SF-1 (NR5A1) cooperating with an AP-1 element drives adrenal-specific and cAMP-inducible expression (PMID:10811295), FOXL2 synergizes with NR5A1 (PMID:20650879), JDP2 acts as a cAMP-response-element-binding activator (PMID:28146118), and a PPARγ/RXRα-bound PPRE mediates SF-1-independent expression in adipocytes (PMID:15028712). Loss-of-function MC2R mutations cause familial/isolated glucocorticoid deficiency, with separate variants disrupting ligand binding, cell-surface trafficking, or protein expression (PMID:20962024, PMID:7608277, PMID:35506146).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1995 Low

    Before any in vitro structure-function work, a patient mutation implicated specific receptor regions in ACTH binding and linked MC2R loss to disease.

    Evidence Direct sequencing of the intronless MC2R gene identifying a homozygous Y254C in the third extracellular loop in isolated glucocorticoid deficiency

    PMID:7608277

    Open questions at the time
    • No direct in vitro binding assay performed
    • Functional consequence inferred from topology, not measured
  2. 2000 Medium

    Established how MC2R achieves adrenal-specific and cAMP-inducible expression, defining the core transcriptional logic of the receptor.

    Evidence 5' deletion luciferase reporters, EMSA, and SF-1 overexpression/mutagenesis in Y1, JEG3, and Cos-1 cells

    PMID:10811295

    Open questions at the time
    • SF-1 alone insufficient in non-adrenal cells; additional co-factors needed
    • Promoter context studied in cell lines, not endogenous chromatin
  3. 2003 Medium

    Separated the kinases controlling MC2R desensitization versus internalization, distinguishing two regulatory arms of signaling termination.

    Evidence Y1/Y6 cell expression with kinase inhibitor studies and desensitization/internalization assays

    PMID:12851305

    Open questions at the time
    • Which specific GRK acts on MC2R not identified
    • Abstract-level mechanistic detail only
  4. 2004 Medium

    Identified a tissue-specific, SF-1-independent route to MC2R transcription, explaining adipocyte expression.

    Evidence 5' deletion reporters in differentiating 3T3-L1 cells, EMSA with adipocyte nuclear extracts, PPARγ2/RXRα co-transfection and PPRE mutagenesis

    PMID:15028712

    Open questions at the time
    • Studied in murine adipocyte model only
    • Physiological role of adipocyte MC2R not established
  5. 2004 Medium

    Showed that combinations of individually inactivating mutations can yield constitutive MC2R activity, revealing allele-level interaction effects.

    Evidence Stable expression of C21R/S247G single and double mutants in Y6 cells with cAMP accumulation and ligand binding assays

    PMID:15062562

    Open questions at the time
    • Structural basis of constitutive activation not resolved
    • Clinical correlate of compound allele not established
  6. 2004 Low

    Defined repressive cis-regulation that prevents MC2R expression where SF-1 is present but the receptor should be silent.

    Evidence Luciferase reporters and EMSA in bovine adrenocortical versus granulosa cells

    PMID:15171714

    Open questions at the time
    • Single method type with limited mechanistic depth
    • AP4 involvement not definitively established
  7. 2007 High

    Resolved the long-standing problem of MC2R functional reconstitution by showing MRAP is required for ACTH binding and signaling but not surface localization.

    Evidence Stable MC2R + MRAPα/β expression in isogenic HEK293/FRT cells lacking endogenous MCRs, with binding, cAMP, surface density, and localization readouts

    PMID:17456795

    Open questions at the time
    • Molecular mechanism by which MRAP enables binding not resolved
    • Stoichiometry of MC2R/MRAP complex not defined here
  8. 2010 High

    Mapped the MC2R domains responsible for intracellular retention versus ACTH-binding selectivity, separating trafficking from ligand recognition.

    Evidence Systematic MC2R/MC4R chimeric constructs with confocal localization, ACTH(1-24) binding, and cAMP assays

    PMID:20206229

    Open questions at the time
    • Residue-level binding contacts not defined
    • No structural model of the binding pocket
  9. 2010 Medium

    Defined the downstream effector cascade, showing MC2R activates MAPK strictly through cAMP/PKA and not via Epac or arrestin.

    Evidence HEK293/FRT cells expressing MC2R + MRAPβ with pharmacological inhibitors, dominant-negative arrestin, and phospho-MAPK immunoblot

    PMID:21195128

    Open questions at the time
    • Downstream physiological output of MAPK activation not addressed
    • Single cell system
  10. 2010 Medium

    Showed that MRAP binding is insufficient for MC2R trafficking, identifying the C-terminus as an independent trafficking determinant in disease.

    Evidence OS3/cell surface expression assays, confocal localization, and co-IP of C-terminal mutants (K289fs, M290X) with MRAP

    PMID:20962024

    Open questions at the time
    • C-terminal trafficking motif not precisely defined
    • Single lab
  11. 2010 Low

    Added FOXL2 to the transcriptional network controlling MC2R, demonstrating synergy with NR5A1.

    Evidence Mc2r promoter mapping and luciferase co-transfection with FOXL2 and NR5A1 in Y1 cells

    PMID:20650879

    Open questions at the time
    • Single assay type (reporter/co-transfection)
    • Endogenous FOXL2 occupancy not shown
  12. 2011 High

    Characterized the full internalization/recycling itinerary of activated MC2R and showed recycling sustains cAMP output.

    Evidence HEK293/FRT cells with monensin/brefeldin A inhibitors, S/T residue mutagenesis, Rab GTPase colocalization, and cAMP assays

    PMID:21920850

    Open questions at the time
    • Adaptor proteins linking MC2R to clathrin not identified
    • Studied in heterologous cells, not adrenal cells
  13. 2012 Medium

    Defined how MRAP1 isoform C-termini and membrane topology differentially tune MC2R localization and cAMP output.

    Evidence Stable expression in HEK293/FRT and B16-G4F cells with confocal imaging, topology assays, and cAMP accumulation

    PMID:22366472

    Open questions at the time
    • Functional significance of dual topology in vivo unclear
    • MRAP2 role only partially addressed
  14. 2012 Low

    Used a natural human double-mutant to prove that ACTH-driven MC1R activation, not MC2R itself, causes the skin hyperpigmentation seen in glucocorticoid deficiency.

    Evidence Whole-gene sequencing plus in vitro characterization of MC2R T152K as trafficking-defective with clinical phenotype correlation

    PMID:22337906

    Open questions at the time
    • Limited in vitro functional detail for MC2R variant
    • Single family
  15. 2014 Medium

    Refined the structural basis of ACTH recognition, implicating the EC2 aromatic segment in engaging the second ACTH pharmacophore.

    Evidence Twenty segment-replacement (MC2R/MC4R) constructs with EGFP localization and cAMP assays

    PMID:25074265

    Open questions at the time
    • No direct binding measurements, only functional readout
    • Single lab
  16. 2017 Medium

    Pinpointed individual TM4/TM5 residues required for ACTH activation while leaving trafficking intact, separating activation from surface delivery.

    Evidence Single and triple alanine mutagenesis of rainbow trout MC2R with cAMP assay and cell surface ELISA

    PMID:28495271

    Open questions at the time
    • Demonstrated in fish ortholog; human residue conservation not directly tested
    • No structural confirmation of contacts
  17. 2017 Medium

    Added JDP2 as a CRE-binding transcriptional activator of Mc2r and showed its activity depends on phosphorylation and SUMOylation.

    Evidence Luciferase reporters, real-time ChIP, promoter deletion mapping, and phospho-/SUMO-deficient JDP2 mutants in Y1 cells

    PMID:28146118

    Open questions at the time
    • Upstream signals controlling JDP2 modification in adrenal cells unclear
    • Mouse promoter context
  18. 2022 Medium

    Established the evolutionary depth of MC2R's MRAP1 dependence and ACTH selectivity in a basal bony fish.

    Evidence Heterologous co-expression of Polypterus MC2R with multiple Mrap1 orthologs in CHO cells and luciferase cAMP reporter with ACTH and α-MSH

    PMID:35973587

    Open questions at the time
    • Does not address human-specific regulation
    • Single lab
  19. 2022 Low

    Functionally confirmed pathogenicity of a novel disease missense variant through expression and signaling defects.

    Evidence HEK293 transfection of wild-type and p.Leu109Gln MC2R with cAMP assay and Western blot

    PMID:35506146

    Open questions at the time
    • Single in vitro assay in heterologous system
    • Mechanism of defect (folding vs trafficking) not dissected
  20. 2024 Medium

    Validated MC2R as a druggable target by demonstrating an orally active selective antagonist suppresses ACTH-driven steroid output in vivo.

    Evidence SAR medicinal chemistry yielding CRN04894 with in vivo rat ACTH-stimulated corticosterone assay after oral dosing

    PMID:38628803

    Open questions at the time
    • Binding mode on MC2R not structurally defined
    • Efficacy in disease models not shown
  21. 2026 Medium

    Provided in vivo genetic proof that MC2R is required for steroidogenesis and restrains pigment cell development.

    Evidence CRISPR/Cas9 mc2r knockout zebrafish with histological pigment cell quantification and transcriptomic analysis

    PMID:41639367

    Open questions at the time
    • Pigment phenotype mechanism (cell-autonomous vs systemic ACTH/MC1R) not dissected in this system
    • Mammalian relevance of pigment role not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the MC2R/MRAP/ACTH complex defining how MRAP enables ligand binding and how TM4/TM5 and EC2 contact ACTH remains unresolved.
  • No experimental structure of the activated complex
  • Molecular mechanism of MRAP-dependent binding not defined
  • Stoichiometry of MC2R:MRAP not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1430728 Metabolism 1
Partners
FOXL2JDP2MRAPMRAP2PPARGRXRASF-1/NR5A1
Complex memberships
MC2R/MRAP1 receptor complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Human MRAP isoforms (MRAPα and MRAPβ) are essential for ACTH binding to MC2R and for ACTH-induced cAMP production, but are not required for MC2R localization at the plasma membrane. MRAPβ confers higher cell-surface MC2R density and higher maximal cAMP responses compared to MRAPα. ACTH bound MC2R only in the presence of MRAP, demonstrated in isogenic HEK293 cells devoid of endogenous MCRs. Stable expression in HEK293/Flp-recombinase target site cells; cAMP assay; ACTH binding assay; immunofluorescence; epitope-tagged constructs (c-Myc, Flag, 6xHis) Molecular endocrinology High 17456795
2011 ACTH induces concentration-dependent, arrestin-, clathrin-, and dynamin-dependent internalization of the MC2R/MRAP1 complex, followed by colocalization with Rab4-, Rab5-, and Rab11-positive recycling endosomes; ~28% of internalized receptors recycle back to the plasma membrane and contribute to total cAMP accumulation. Specific intracellular Ser/Thr residues (T131, S140, T143, T147, T204, S208, S280) regulate plasma membrane targeting, function, and internalization of MC2R. HEK293/Flp-recombinase target site cells; pharmacological inhibitors (monensin, brefeldin A); site-directed mutagenesis of S/T residues; colocalization with Rab GTPase markers; cAMP assay Molecular endocrinology High 21920850
2010 The third and fourth transmembrane domains of MC2R are the main determinants of its intracellular retention in non-adrenal cells, while the N-terminal segment influences membrane transport efficiency. The fourth and fifth transmembrane domains are involved in ACTH-binding selectivity. These were identified using systematic chimeric MC2R/MC4R receptors. Chimeric receptor mutagenesis (15 constructs); confocal fluorescence microscopy with EGFP fusion; ACTH(1-24) binding assay; cAMP assay; quantitative cell-membrane localization analysis Molecular and cellular endocrinology High 20206229
2014 Both the ligand-recognition specificity determinant and the intracellular retention signal of MC2R are formed by a specific extracellular structure supported by correct transmembrane domain alignment. The aromatic-residue-rich segment of the second extracellular loop (EC2) is involved in effects mediated by the second ACTH pharmacophore (-K-K-R-R-). Replacement of 2–5 amino acid segments within TM domains with MC4R counterparts disrupted membrane trafficking or cAMP signaling. Directed mutagenesis (20 segment-replacement constructs); EGFP fusion; cAMP assay; membrane trafficking quantification Journal of molecular endocrinology Medium 25074265
2004 Two MC2R mutations (C21R and S247G) individually produce an inactive receptor lacking ligand binding and ACTH responsiveness, but their co-occurrence on the same allele leads to constitutively elevated basal cAMP accumulation (constitutive activation). Co-expression of the normal MC2R allele restores a normal ACTH dose-response despite the constitutive activity. Stable expression in Y6 cells; cAMP accumulation assay; ligand binding assay Molecular and cellular endocrinology Medium 15062562
2010 ACTH binding to MC2R activates p44/p42 MAPK and p38 MAPK phosphorylation via a cAMP/PKA-dependent pathway (blocked by H89, KI(6-22), Rp-cAMPS), but not via cAMP/Epac1/2 or arrestin-coupled internalization. Receptor recycling (sensitive to brefeldin A and monensin) also contributes to cAMP accumulation and MAPK phosphorylation. HEK293/Flp cells stably expressing MC2R + MRAPβ; pharmacological inhibitors; dominant-negative arrestin constructs; phospho-MAPK immunoblot; cAMP assay Molecular and cellular endocrinology Medium 21195128
2003 MC2R desensitization after agonist stimulation is protein kinase A (PKA)-dependent, whereas internalization is PKA-independent and requires a G protein-coupled receptor kinase (GRK). This was established using the Y1 and Y6 cell systems. Y1/Y6 cell expression system; kinase inhibitor studies; desensitization and internalization assays Annals of the New York Academy of Sciences Medium 12851305
2010 Loss of the MC2R C-terminus (K289fs and M290X mutations) impairs cell surface expression by blocking transport from the endoplasmic reticulum to the plasma membrane, abolishing ACTH responsiveness. Importantly, co-immunoprecipitation showed that these C-terminal mutants retain normal interaction with MRAP, indicating MRAP binding alone is insufficient for proper MC2R trafficking. OS3 cell-based reporter assay; cell surface expression assay; confocal localization; co-immunoprecipitation of mutant MC2R with MRAP; alanine substitution constructs The Journal of clinical endocrinology and metabolism Medium 20962024
2012 The C-terminal domains of MRAP1 isoforms dictate their intracellular localization and differentially regulate ACTH-induced cAMP production: MRAPβ localizes predominantly at the plasma membrane and induces the highest cAMP accumulation, while MRAPα localizes near the nuclear envelope/intracellular endosomes and promotes MC2R targeting. MRAPβ and MRAPdCT exhibit dual membrane topology (N_cyto/C_exo and N_exo/C_cyto), while MRAPα adopts only N_cyto/C_exo topology at the plasma membrane. MRAP2 and MC2R mutually enhance MRAP1 isoform expression. Stable expression in HEK293/FRT and B16-G4F cells; confocal immunofluorescence; topology assays; cAMP accumulation assay General and comparative endocrinology Medium 22366472
2000 The human MC2R (ACTHR) promoter contains two SF-1 (steroidogenic factor 1) binding sites at -209 and -35 bp that are required for adrenal-specific basal expression; an AP-1 site at -764 to -503 is required for cAMP/forskolin-dependent transcriptional induction. Both AP-1 and SF-1 are required for the cAMP-dependent induction of MC2R. SF-1 is necessary but not sufficient alone to drive expression in non-adrenal cells. 5' deletion reporter (luciferase) constructs in Y1, JEG3, and Cos-1 cells; EMSA; SF-1 overexpression; site-directed mutagenesis of binding elements Endocrine journal Medium 10811295
2004 A peroxisome proliferator-response element (PPRE)-like sequence in the murine mc2-r promoter binds PPARγ and RXRα (confirmed in adipocyte nuclear extracts) and is required for adipocyte-specific transcriptional activation of mc2-r during 3T3-L1 differentiation. Mutation of the PPRE completely abrogated promoter activity in differentiated adipocytes. This reveals a novel, SF-1-independent mechanism for mc2-r transcription in adipocytes. 5' deletion reporter analysis in undifferentiated and differentiated 3T3-L1 cells; EMSA with adipocyte nuclear extracts; PPARγ2/RXRα co-transfection; PPRE mutagenesis The Journal of biological chemistry Medium 15028712
2004 An E-box element at -1020 bp in the human MC2R promoter mediates repression of MC2R expression in granulosa cells, involving interactions with factors including activator protein 4 (AP4). SF-1 is necessary but not sufficient for adrenal-specific MC2R expression, as it is expressed in granulosa cells but cannot drive MC2R expression there without the E-box-mediated repression being relieved. Luciferase reporter transfection in bovine adrenocortical and bovine granulosa cells; EMSA Journal of molecular endocrinology Low 15171714
2010 FOXL2 and NR5A1 (SF-1) synergistically activate Mc2r promoter transcription in mammalian adrenal systems. FOXL2 alone activates Mc2r promoter activity in a dose-dependent manner, and two distal NR5A1 response elements at -1410 and -975 bp are required for the synergistic effect. Mc2r promoter mapping; luciferase reporter co-transfection with FOXL2 and NR5A1 expression constructs in Y1 cells; deletion constructs Biology of reproduction Low 20650879
2017 JDP2 (Jun dimerization protein 2) acts as a transcriptional activator of the mouse Mc2r gene by binding cAMP response elements between -1320 and -720 bp (major binding site at -830 bp confirmed by ChIP). Phosphorylation of JDP2 is required for its Mc2r transcriptional activation, and SUMOylation of JDP2 modulates this activity. Luciferase reporter assay in Y1 cells; real-time ChIP; Mc2r promoter deletion mapping; phosphorylation-deficient and SUMO-deficient JDP2 mutants; Western blot International journal of molecular sciences Medium 28146118
1995 A homozygous Y254C mutation in the third extracellular loop of the ACTH receptor (MC2R) causes isolated glucocorticoid deficiency, likely by interfering with ligand binding. This establishes the third extracellular loop as important for ACTH binding. Direct sequencing of the intronless MC2R gene; mutation not found in 100 normal alleles; structural inference from receptor topology The Journal of clinical endocrinology and metabolism Low 7608277
2017 Alanine substitution studies on rainbow trout MC2R identified V159 in TM4, F171 in TM5, and F175 in TM5 as critical residues for receptor activation by ACTH. A triple alanine mutant (V159A/F171A/F175A) could not be activated by ACTH at concentrations up to 10⁻⁶ M, while cell surface trafficking was unimpaired, pointing to a specific role for TM4 and TM5 in ACTH binding/activation rather than trafficking. Single and triple alanine mutagenesis of rtMC2R; cAMP assay; Cell Surface ELISA for trafficking General and comparative endocrinology Medium 28495271
2013 In rat bone marrow stromal cells, ACTH promotes chondrogenic nodule formation and induces transient elevations in intracellular calcium via MC2R signaling. Neither α-MSH (MC5R agonist) nor γ2-MSH (MC3R agonist) replicated these effects, and the cells express MC2R and MRAP by immunoblot, implicating MC2R specifically. Dexamethasone upregulates MC2R and MRAP expression, amplifying ACTH responses. Bone marrow stromal cell culture; MC-R-specific peptide agonists; immunoblot of membrane fractions; calcium flux assay; chondrogenic nodule quantification Cell and tissue research Low 23358747
2022 MC2R from the Senegal bichir (Polypterus senegalus, a basal bony fish) requires Mrap1 (but not Mrap2) for membrane trafficking and ACTH-stimulated activation, and is selective for ACTH over α-MSH, demonstrating that Mrap1 dependence and ACTH selectivity are ancestral features of all bony fish Mc2rs. Heterologous co-expression in CHO cells; luciferase cAMP reporter assay; stimulation with ACTH and α-MSH; multiple vertebrate Mrap1 constructs tested General and comparative endocrinology Medium 35973587
2012 In a patient with familial glucocorticoid deficiency lacking skin hyperpigmentation, co-existing homozygous MC2R T152K (trafficking-defective) and MC1R R160W mutations were identified. This experimentally demonstrates that ACTH-driven MC1R activation is the cause of skin hyperpigmentation in FGD, as loss of MC1R function abolishes hyperpigmentation even in the context of severely elevated ACTH. Whole-gene sequencing; in vitro characterization of MC2R T152K as trafficking defective; clinical phenotype correlation The Journal of clinical endocrinology and metabolism Low 22337906
2024 CRN04894 (17h), a nonpeptide MC2R antagonist derived from MC4R ligand modification, potently and selectively blocks MC2R and suppresses ACTH-stimulated corticosterone secretion in a dose-dependent manner in rats following oral administration, confirming the pharmacological tractability of MC2R as a drug target. Structure-activity relationship medicinal chemistry; in vivo rat ACTH-stimulated corticosterone assay; oral dosing at ≥3 mg/kg ACS medicinal chemistry letters Medium 38628803
2026 CRISPR/Cas9-generated mc2r knockout zebrafish show impaired interrenal steroidogenesis and pronounced skin hyperpigmentation with increased numbers of melanophores and xanthophores (while preserving normal patterning), with transcriptomic upregulation of genes involved in melanosome formation, melanin synthesis, lipid metabolism, and carotenoid accumulation. This establishes a direct role for MC2R in steroidogenesis and in restraining pigment cell development. CRISPR/Cas9 mc2r knockout in zebrafish; histological quantification of pigment cells; transcriptomic analysis Scientific reports Medium 41639367
2022 In vitro study in HEK293 cells transfected with wild-type and MC2R mutant (p.Leu109Gln) plasmids showed defects in MC2R protein expression and cAMP generation upon ACTH stimulation, functionally confirming pathogenicity of this novel missense mutation. HEK293 cell transfection; cAMP assay; Western blot protein expression Journal of the Endocrine Society Low 35506146

Source papers

Stage 0 corpus · 69 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Differential regulation of the human adrenocorticotropin receptor [melanocortin-2 receptor (MC2R)] by human MC2R accessory protein isoforms alpha and beta in isogenic human embryonic kidney 293 cells. Molecular endocrinology (Baltimore, Md.) 85 17456795
2017 ACTH Receptor (MC2R) Specificity: What Do We Know About Underlying Molecular Mechanisms? Frontiers in endocrinology 61 28220105
2007 Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia. Clinical endocrinology 61 17223989
1995 A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome. The Journal of clinical endocrinology and metabolism 60 7608277
2004 Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene. Molecular and cellular endocrinology 43 15062562
2013 Molecular characterization and functional regulation of melanocortin 2 receptor (MC2R) in the sea bass. A putative role in the adaptation to stress. PloS one 35 23724142
2008 Association of polymorphisms in the melanocortin receptor type 2 (MC2R, ACTH receptor) gene with heroin addiction. Neuroscience letters 29 18359160
2008 Modeling the evolution of the MC2R and MC5R genes: studies on the cartilaginous fish, Heterondotus francisci. General and comparative endocrinology 29 19100739
2000 Involvement of AP-1 and steroidogenic factor (SF)-1 in the cAMP-dependent induction of human adrenocorticotropic hormone receptor (ACTHR) promoter. Endocrine journal 29 10811295
2015 Abundance of DLK1, differential expression of CYP11B1, CYP21A2 and MC2R, and lack of INSL3 distinguish testicular adrenal rest tumours from Leydig cell tumours. European journal of endocrinology 28 25609776
2013 Evolution of the melanocortin-2 receptor in tetrapods: studies on Xenopus tropicalis MC2R and Anolis carolinensis MC2R. General and comparative endocrinology 26 23639234
2010 Identification of domains responsible for specific membrane transport and ligand specificity of the ACTH receptor (MC2R). Molecular and cellular endocrinology 26 20206229
2014 Increased expression of ACTH (MC2R) and androgen (AR) receptors in giant bilateral myelolipomas from patients with congenital adrenal hyperplasia. BMC endocrine disorders 25 24884994
2011 Mechanisms of melanocortin-2 receptor (MC2R) internalization and recycling in human embryonic kidney (hek) cells: identification of Key Ser/Thr (S/T) amino acids. Molecular endocrinology (Baltimore, Md.) 24 21920850
2012 An atypical case of familial glucocorticoid deficiency without pigmentation caused by coexistent homozygous mutations in MC2R (T152K) and MC1R (R160W). The Journal of clinical endocrinology and metabolism 20 22337906
2008 Genetic polymorphisms of MC2R gene associated with responsiveness to adrenocorticotropic hormone therapy in infantile spasms. Chinese medical journal 19 19024088
2004 A peroxisome proliferator-response element in the murine mc2-r promoter regulates its transcriptional activation during differentiation of 3T3-L1 adipocytes. The Journal of biological chemistry 19 15028712
1998 Exclusion of the adrenocorticotropin (ACTH) receptor (MC2R) locus in some families with ACTH resistance but no mutations of the MC2R coding sequence (familial glucocorticoid deficiency type 2). The Journal of clinical endocrinology and metabolism 19 9768670
2014 Acupuncture Relieves the Excessive Excitation of Hypothalamic-Pituitary-Adrenal Cortex Axis Function and Correlates with the Regulatory Mechanism of GR, CRH, and ACTHR. Evidence-based complementary and alternative medicine : eCAM 16 24761151
2012 The C-terminal domains of melanocortin-2 receptor (MC2R) accessory proteins (MRAP1) influence their localization and ACTH-induced cAMP production. General and comparative endocrinology 16 22366472
2010 Melanocortin receptor type 2 (MC2R, ACTH receptor) expression in patients with alopecia areata. Experimental dermatology 16 20590821
1998 Expression of ACTH receptors (MC2-R and MC5-R) in the glomerulosa and the fasciculata-reticularis zones of bovine adrenal cortex. Endocrine research 16 9888520
2020 Ginsenoside Rd attenuates ACTH-induced corticosterone secretion by blocking the MC2R-cAMP/PKA/CREB pathway in Y1 mouse adrenocortical cells. Life sciences 15 31972205
2010 Synergistic activation of the Mc2r promoter by FOXL2 and NR5A1 in mice. Biology of reproduction 15 20650879
2012 Expression of melanocortin receptors in human prostate cancer cell lines: MC2R activation by ACTH increases prostate cancer cell proliferation. International journal of oncology 14 22842514
2010 ACTH receptor (MC2R) promoter variants associated with infantile spasms modulate MC2R expression and responsiveness to ACTH. Pharmacogenetics and genomics 14 20042918
2010 Adrenocorticotropin hormone (ACTH) effects on MAPK phosphorylation in human fasciculata cells and in embryonic kidney 293 cells expressing human melanocortin 2 receptor (MC2R) and MC2R accessory protein (MRAP)β. Molecular and cellular endocrinology 13 21195128
2012 Leptin alters adrenal responsiveness by decreasing expression of ACTH-R, StAR, and P450c21 in hypoxemic fetal sheep. Reproductive sciences (Thousand Oaks, Calif.) 12 22534336
2003 Expression, desensitization, and internalization of the ACTH receptor (MC2R). Annals of the New York Academy of Sciences 12 12851305
2021 A variant in the 3'-untranslated region of the MC2R gene decreases the risk of schizophrenia in a female Han Chinese population. The Journal of international medical research 10 34266338
2014 Replacement of short segments within transmembrane domains of MC2R disrupts retention signal. Journal of molecular endocrinology 10 25074265
2008 Familial glucocorticoid deficiency type 1 due to a novel compound heterozygous MC2R mutation. Hormone research 10 18504396
2002 Adrenocorticotrophic hormone (ACTH) stimulation of sheep fetal adrenal cortex can occur without increased expression of ACTH receptor (ACTH-R) mRNA. Reproduction, fertility, and development 10 12051514
2021 MC2R/MRAP2 activation could affect bovine ovarian steroidogenesis potential after ACTH treatment. Theriogenology 9 34425302
2018 Effect of a melanocortin type 2 receptor (MC2R) antagonist on the corticosterone response to hypoxia and ACTH stimulation in the neonatal rat. American journal of physiology. Regulatory, integrative and comparative physiology 9 29718699
2013 ACTH promotes chondrogenic nodule formation and induces transient elevations in intracellular calcium in rat bone marrow cell cultures via MC2-R signaling. Cell and tissue research 9 23358747
2006 Novel compound heterozygous mutation of the MC2R gene in a patient with familial glucocorticoid deficiency. Journal of pediatric endocrinology & metabolism : JPEM 9 17128565
2024 Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist. ACS medicinal chemistry letters 8 38628803
2022 A basal actinopterygian melanocortin receptor: Molecular and functional characterization of an Mc2r ortholog from the Senegal bichir (Polypterus senegalus). General and comparative endocrinology 8 35973587
2017 Jun Dimerization Protein 2 Activates Mc2r Transcriptional Activity: Role of Phosphorylation and SUMOylation. International journal of molecular sciences 8 28146118
2011 A novel mutation in the MC2R gene causing familial glucocorticoid deficiency type 1. Neonatology 8 21701219
2011 Familial glucocorticoid deficiency in five Arab kindreds with homozygous point mutations of the ACTH receptor (MC2R): genotype and phenotype correlations. Hormone research in paediatrics 8 21778684
2010 Loss of the C terminus of melanocortin receptor 2 (MC2R) results in impaired cell surface expression and ACTH insensitivity. The Journal of clinical endocrinology and metabolism 8 20962024
2020 Activation of PPARγ reduces N-acetyl-cysteine -induced hypercorticoidism by down-regulating MC2R expression into adrenal glands. Free radical biology & medicine 7 32574682
2022 A Novel Homozygous MC2R Variant Leading to Type-1 Familial Glucocorticoid Deficiency. Journal of the Endocrine Society 6 35506146
2004 An E-box-containing region is involved in the tissue-specific expression of the human MC2R gene. Journal of molecular endocrinology 6 15171714
2002 Characterization of the porcine melanocortin 2 receptor gene (MC2R ). Animal genetics 6 12464015
2023 A rare homozygous variant of MC2R gene identified in a Chinese family with familial glucocorticoid deficiency type 1: A case report. Frontiers in endocrinology 5 36909322
2022 Analyzing the Hypothalamus/Pituitary/Interrenal axis of the neopterygian fish, Lepisosteus oculatus: Co-localization of MC2R, MC5R, MRAP1, and MRAP2 in interrenal cells. General and comparative endocrinology 5 35447133
2011 Familial glucocorticoid deficiency due to compound heterozygosity of two novel MC2R mutations. Journal of pediatric endocrinology & metabolism : JPEM 4 21823545
2002 Expression of the melanocortin receptors MC2-R (ACTH-receptor) and MC5-R during embryonic development of ovine adrenals. Endocrine research 4 12530674
2023 Trends in the evolution of the elasmobranch melanocortin-2 receptor: Insights from structure/function studies on the activation of whale shark Mc2r. General and comparative endocrinology 3 36996927
2017 The melanocortin-2 receptor of the rainbow trout: Identifying a role for critical positions in transmembrane domain 4, extracellular loop 2, and transmembrane domain 5 in the activation of rainbow trout MC2R. General and comparative endocrinology 3 28495271
2009 Isolated Addison's disease is unlikely to be caused by mutations in MC2R, MRAP or STAR, three genes responsible for familial glucocorticoid deficiency. European journal of endocrinology 3 19903795
2004 Ontogeny of StAR and ACTH-R genes in ovine placenta. Placenta 3 15193873
2024 NGT: Generative AI with Synthesizability Guarantees Discovers MC2R Inhibitors from a Tera-Scale Virtual Screen. Journal of medicinal chemistry 2 39471377
2023 Functional characterization of melanocortin 2 receptor (Mc2r) from a lobe-finned fish (Protopterus annectens) and insights into the molecular evolution of melanocortin receptors. General and comparative endocrinology 2 37562700
2015 Association between two promoter polymorphisms (rs1893219 and rs1893220) of MC2R gene and intracerebral hemorrhage in Korean population. Neuroscience letters 2 26115626
2023 A Rare Presentation of Homozygous Pathogenic Variant in MC2R Gene with Salt-Wasting Crisis in a Neonate. Molecular syndromology 1 38357256
2014 Modeling the interactions between MC2R and ACTH models from human. Journal of biomolecular structure & dynamics 1 24708442
2012 [Association between plasma lipid, glucose, cortisol and adrenocorticotropic hormone levels and GR and ACTHR gene polymorphisms]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 22487832
2011 [Associations of GR and ACTHR gene polymorphisms with quantitative trait of strain]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 1 22357529
2026 Loss-of-function mutations in the melanocortin-2-receptor (mc2r) lead to skin hyperpigmentation in teleost fish. Scientific reports 0 41639367
2025 Uniparental disomy leads to a novel cause of MC2R-related familial glucocorticoid deficiency type 1. European journal of endocrinology 0 40729435
2024 Interaction between birth characteristics and CRHR1, MC2R, NR3C1, GLCCI1 variants in the childhood lymphoblastic leukemia risk. Frontiers in oncology 0 38348123
2024 Establishment of human induced pluripotent stem cell line SDQLCHi029-A from one Type 1 familial glucocorticoid deficiency patient carrying compound heterozygote mutations in MC2R gene. Stem cell research 0 38430736
2024 Expanding the Phenotype of Congenital Glucocorticoid Deficiency: An Iranian Patient with Cholestasis due to Pathogenic Variants in the MC2R Gene. International journal of endocrinology 0 39135905
2024 Clinical and Genetic Mechanisms in Patients with <italic>MC2R</italic> Deficiency Presenting with Early Puberty. Hormone research in paediatrics 0 39496238
2023 [Clinical characteristics and genetic analysis of two children with Familial glucocorticoid deficiency type 1 due to variants of MC2R gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 37994136

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