Affinage

MC2R

Adrenocorticotropic hormone receptor · UniProt Q01718

Length
297 aa
Mass
33.9 kDa
Annotated
2026-04-28
69 papers in source corpus 21 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MC2R is a Gs-coupled receptor uniquely selective for ACTH that drives cAMP/PKA-dependent steroidogenesis and MAPK signaling in adrenocortical cells. Functional cell-surface expression of MC2R requires the accessory protein MRAP1, which overcomes intrinsic ER-retention signals encoded in TM3/TM4 and the N-terminus; MRAP1 isoforms differentially regulate receptor density and maximal signaling capacity (PMID:17456795, PMID:20206229). ACTH engages MC2R through dual pharmacophore contacts — the HFRW motif interacting with TM2/TM3/TM6 and the KKRRP motif contacting the second extracellular loop and TM4/TM5 — and stimulation triggers PKA-dependent desensitization, GRK/clathrin/dynamin-dependent internalization, and Rab4/5/11-mediated recycling (PMID:21920850, PMID:28495271, PMID:23639234). Adrenal-specific MC2R transcription is governed by SF-1 and AP-1 elements required for basal and cAMP-induced expression, with additional regulation by FOXL2, PPARγ/RXRα in adipocytes, and JDP2 via CRE sites (PMID:10811295, PMID:15028712, PMID:20650879, PMID:28146118).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1995 Low

    Establishing that MC2R mutations are causal in familial glucocorticoid deficiency linked the receptor directly to adrenal ACTH responsiveness in humans, though without functional proof of the mutation's biochemical effect.

    Evidence Homozygous Y254C mutation identified by direct sequencing in a family with isolated glucocorticoid deficiency

    PMID:7608277

    Open questions at the time
    • No functional assay performed for Y254C; causality inferred from segregation and structural position only
    • No binding or signaling data for this mutation
  2. 2000 High

    Defining the transcriptional architecture of the MC2R promoter resolved how adrenal-specific and cAMP-inducible expression are achieved, identifying SF-1 and AP-1 as essential elements.

    Evidence Promoter deletion, EMSA, site-directed mutagenesis, and luciferase reporter assays in Y1, JEG3, and Cos-1 cells

    PMID:10811295

    Open questions at the time
    • Chromatin-level regulation and histone marks at the MC2R locus not addressed
    • In vivo validation of promoter element requirements not performed
  3. 2003 Medium

    Dissecting desensitization and internalization pathways revealed that MC2R desensitization is PKA-dependent whereas internalization is GRK-dependent, and established that a then-unknown cofactor was needed for heterologous surface expression.

    Evidence PKA inhibitor studies and GRK-dependent internalization assays in Y1 and Y6 adrenocortical cells

    PMID:12851305

    Open questions at the time
    • Identity of the cofactor (later MRAP) was unknown at this stage
    • GRK isoform specificity not determined
  4. 2004 Medium

    Parallel studies expanded understanding of MC2R regulation: (1) intramolecular epistasis between two loss-of-function mutations producing constitutive activity revealed conformational constraints on receptor activation; (2) PPARγ/RXRα-dependent transcription defined an SF-1-independent adipocyte-specific mechanism; (3) an E-box repressor element further explained tissue-restricted expression.

    Evidence Constitutive activity measured by cAMP accumulation with double-mutant receptor in Y6 cells; PPRE mutagenesis and PPARγ2/RXRα cotransfection in 3T3-L1 adipocytes; E-box/AP-4 identified by EMSA and promoter reporter in granulosa vs adrenocortical cells

    PMID:15028712 PMID:15062562 PMID:15171714

    Open questions at the time
    • Structural basis for C21R/S247G intramolecular synergy unknown
    • In vivo relevance of PPARγ-driven MC2R in adipose tissue not tested
    • AP-4 binding to E-box not confirmed by ChIP
  5. 2007 High

    Identification of MRAP as the essential cofactor for ACTH binding resolved the long-standing puzzle of why MC2R was non-functional in non-adrenal cells, and showed that MRAP isoforms differentially tune receptor surface density and signaling capacity.

    Evidence ACTH binding assays, cAMP production, and immunofluorescence in isogenic HEK293/Flp cells stably expressing MC2R with MRAPα or MRAPβ

    PMID:17456795

    Open questions at the time
    • Structural basis of MRAP–MC2R interaction not resolved
    • Whether MRAP isoform ratio varies across adrenal zones not determined
  6. 2010 High

    Systematic chimeric receptor analysis mapped intracellular retention signals to TM3/TM4 and the N-terminus, and ACTH selectivity determinants to TM4/TM5 and EC2, defining how MC2R structure encodes both trafficking restriction and ligand discrimination.

    Evidence 15 MC2R/MC4R chimeras assessed by confocal microscopy, ACTH binding, and cAMP response ± MRAP coexpression

    PMID:20206229

    Open questions at the time
    • Atomic-level contacts between MRAP and the retention signal not resolved
    • Contribution of individual residues within TM3/TM4 to retention not mapped
  7. 2010 High

    Downstream of cAMP, MC2R was shown to activate p44/42 and p38 MAPK via a cAMP/PKA-dependent rather than Epac- or arrestin-dependent route, establishing the signaling logic downstream of the receptor.

    Evidence PKA inhibitors, selective Epac activator, dominant-negative arrestin, recycling inhibitors, and phospho-MAPK immunoblots in HEK293 and primary human fasciculata cells

    PMID:21195128

    Open questions at the time
    • Direct PKA substrates linking to MAPK cascade not identified
    • Whether MAPK activation drives specific steroidogenic gene programs through MC2R remains unclear
  8. 2010 Medium

    Loss-of-function C-terminal truncation mutations (K289fs, M290X) showed that the MC2R C-terminus is required for ER-to-plasma membrane transport but not for MRAP binding, separating trafficking from accessory protein interaction.

    Evidence Co-immunoprecipitation, cell-surface ELISA, confocal microscopy, and cAMP reporter in OS3 cells

    PMID:20962024

    Open questions at the time
    • Specific trafficking machinery interacting with MC2R C-terminus not identified
    • Only two mutations tested; generalizability of C-terminal role uncertain
  9. 2011 High

    Mapping intracellular Ser/Thr residues governing internalization and recycling defined the receptor's post-activation trafficking itinerary through Rab4/5/11-positive compartments, revealing how MC2R/MRAP complexes are dynamically regulated.

    Evidence Site-directed mutagenesis of seven Ser/Thr residues combined with Rab GTPase colocalization and cAMP assays in HEK293/FRT cells

    PMID:21920850

    Open questions at the time
    • Kinase(s) phosphorylating specific Ser/Thr residues not identified beyond GRK
    • Fate of MRAP during recycling not tracked
  10. 2012 Medium

    MRAP isoform-specific localization was resolved: MRAPα concentrates at endosomes and the nuclear envelope while MRAPβ strongly localizes to the plasma membrane, explaining their differential effects on MC2R signaling output.

    Evidence Confocal localization, topology assays, and cAMP accumulation in HEK293/FRT and B16-G4F cells

    PMID:22366472

    Open questions at the time
    • Determinants of differential MRAP isoform sorting not identified
    • Dual topology of MRAPβ not mechanistically explained
  11. 2017 Medium

    Alanine scanning of ACTH and mutagenesis of MC2R orthologs defined dual pharmacophore contacts: HFRW engages one receptor region while KKRRP contacts EC2/TM4/TM5 residues (V159, F171, F175), with triple alanine substitution abolishing activation without affecting trafficking.

    Evidence Systematic alanine substitution of ACTH(1-24) tested on human, reptile, and amphibian MC2Rs; single and triple alanine mutagenesis of rainbow trout MC2R with cAMP reporter and cell-surface ELISA

    PMID:23639234 PMID:28495271

    Open questions at the time
    • No co-crystal or cryo-EM structure of MC2R–ACTH–MRAP complex available
    • Precise contacts of the HFRW motif on the receptor not mapped at residue resolution for mammalian MC2R
  12. 2017 Medium

    JDP2 was identified as a transcriptional activator of MC2R through CRE elements, with its activity regulated by phosphorylation and SUMOylation, adding a stress-responsive transcriptional layer to MC2R regulation.

    Evidence ChIP, luciferase reporter, CRE mutagenesis, and phosphorylation/SUMOylation mutants of JDP2 in Y1 cells

    PMID:28146118

    Open questions at the time
    • In vivo relevance of JDP2 to MC2R expression in adrenal not demonstrated
    • Whether JDP2 cooperates with SF-1/AP-1 at the endogenous promoter not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the MC2R–MRAP–ACTH signaling complex is lacking, and the precise mechanism by which MRAP overcomes ER retention signals, the in vivo roles of MC2R in extra-adrenal tissues (adipose, bone, prostate), and the kinase specificity for trafficking-regulatory phosphosites remain undefined.
  • No cryo-EM or crystal structure of MC2R–MRAP complex
  • In vivo validation of extra-adrenal MC2R functions (thermogenesis, chondrogenesis, prostate proliferation) lacking
  • Complete phosphosite-to-kinase mapping for internalization/recycling residues not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 2
Partners
FOXL2JDP2MRAPNR5A1PPARGRXRA
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 MRAP isoforms alpha and beta are essential for ACTH binding to MC2R and ACTH-induced cAMP production, but are not required for MC2R localization at the plasma membrane. MRAPα and MRAPβ differentially regulate cell membrane density and functional properties of MC2R, with MRAPβ-expressing cells showing higher cell surface MC2R density and higher maximal cAMP responses. Stable expression of Myc-MC2R with MRAP isoforms in isogenic HEK293/Flp cells; ACTH binding assays; cAMP production assays; immunofluorescence Molecular endocrinology High 17456795
2010 The N-terminal segment and the third and fourth transmembrane regions of MC2R contain signals responsible for its intracellular retention in non-adrenal cells; the fourth and fifth transmembrane domains are involved in ACTH binding selectivity. MRAP interaction bypasses these retention signals. Systematic chimeric MC2R/MC4R receptor mutagenesis; confocal fluorescence microscopy quantification of cell-membrane localization; ACTH binding assays; cAMP response assays Molecular and cellular endocrinology High 20206229
2011 ACTH induces concentration-dependent, arrestin-, clathrin-, and dynamin-dependent MC2R/MRAP1 internalization, followed by recycling via Rab4-, Rab5-, and Rab11-positive endosomes. Specific intracellular Ser/Thr residues (T131, S140, T143, T147, T204, S208, S280) regulate plasma membrane targeting, internalization, and cAMP signaling; the second intracellular loop is critical for MC2R expression and functional regulation. Mutagenesis of Ser/Thr residues; internalization assays with monensin/brefeldin A; colocalization with Rab GTPases; cAMP accumulation assays in HEK293/FRT cells Molecular endocrinology High 21920850
2010 ACTH binding to MC2R activates p44/p42 MAPK and p38 MAPK phosphorylation through a cAMP/PKA-dependent pathway, but not via cAMP/Epac1/2 or arrestin-coupled internalization. Recycling inhibitors brefeldin A and monensin attenuated both cAMP accumulation and MAPK phosphorylation proportionally. PKA inhibitors (H89, KI-6-22, Rp-cAMPS); selective Epac1/2 activator; dominant-negative arrestin constructs; recycling inhibitors; phospho-MAPK immunoblot in HEK293 cells and primary human fasciculata cells Molecular and cellular endocrinology High 21195128
2003 MC2R desensitization is protein kinase A-dependent, whereas internalization is PKA-independent and dependent on a G protein receptor kinase (GRK). MC2R requires a cofactor (later identified as MRAP) for cell surface expression in heterologous cells. Y1 and Y6 cell expression systems; PKA inhibitor studies; GRK-dependent internalization assays Annals of the New York Academy of Sciences Medium 12851305
2004 Two naturally occurring MC2R missense mutations (C21R and S247G), each individually causing loss of ligand binding and signaling, together produce constitutive cAMP accumulation when present in the same receptor molecule, demonstrating a synergistic interaction leading to constitutive activation. Stable expression in Y6 cells; basal cAMP accumulation measurement; ACTH dose-response assays Molecular and cellular endocrinology Medium 15062562
2010 Loss of the MC2R C-terminus (K289fs and M290X mutations) impairs cell surface expression by disrupting transport from the ER to the cell membrane, without altering interaction of MC2R with MRAP as shown by co-immunoprecipitation. Cell surface assays; confocal localization studies; co-immunoprecipitation; OS3 cell-based reporter assay for cAMP The Journal of clinical endocrinology and metabolism Medium 20962024
2012 The C-terminal domains of MRAP1 isoforms dictate their intracellular localization: MRAPα localizes near the nuclear envelope and intracellular endosomes while MRAPβ localizes strongly at the plasma membrane. MRAPβ induces the highest ACTH-stimulated cAMP accumulation. MRAP1 is required for ACTH to activate MC2R; its presence enhances MC2R cell-surface expression. MRAPβ exhibits dual topology (N-cyto/C-exo and N-exo/C-cyto) at the plasma membrane. Stable expression in HEK293/FRT and B16-G4F cells; confocal localization; cAMP accumulation assays; topology assays General and comparative endocrinology Medium 22366472
2014 Both the ligand-recognition specificity determinant and the intracellular retention signal of MC2R are formed by a specific extracellular structure supported by correct alignment of transmembrane domains. The aromatic-residue-rich segment of the second extracellular loop is involved in effects mediated by the second ACTH pharmacophore (-K-K-R-R-). Directed mutagenesis replacing 2-5 amino acid segments of MC2R with MC4R equivalents; 20 recombinant EGFP-fusion receptors; membrane trafficking efficiency assays; cAMP response to α-MSH and ACTH(1-24) with/without MRAP coexpression Journal of molecular endocrinology Medium 25074265
2000 Two SF-1 binding sites at -209 and -35 in the human ACTHR/MC2R promoter are required for adrenal-specific expression; AP-1 binding at -764 to -503 is required for cAMP/forskolin-dependent induction of MC2R transcription. Both AP-1 and SF-1 are necessary for full cAMP-dependent MC2R gene expression. Promoter deletion analysis; luciferase reporter assays in Y1, JEG3, and Cos-1 cells; electrophoretic mobility shift assay (EMSA); site-directed mutagenesis of AP-1 and SF-1 sites; SF-1 cotransfection Endocrine journal High 10811295
2004 In murine adipocytes, a PPRE-like sequence in the MC2R promoter binds PPARγ and RXRα; PPARγ2/RXRα cotransfection activates MC2R transcription in preadipocytes, and mutation of the PPRE abolishes MC2R promoter activity in differentiated 3T3-L1 adipocytes. This defines a novel adipocyte-specific SF-1-independent mechanism of MC2R transcription. 5' deletion analysis of mc2-r promoter; luciferase reporter in undifferentiated and differentiated 3T3-L1 cells; EMSA with adipocyte nuclear extracts; PPARγ2/RXRα cotransfection; PPRE mutagenesis The Journal of biological chemistry High 15028712
2010 FOXL2 and NR5A1 (SF-1) synergistically activate the Mc2r promoter. FOXL2 alone activates Mc2r promoter activity dose-dependently, and the synergistic effect with NR5A1 requires distal NR5A1 response elements at -1410 and -975 bp. Promoter mapping; luciferase reporter assays in Y1 adrenocortical cells; cotransfection of FOXL2 and NR5A1 expression plasmids; deletion constructs of Mc2r promoter Biology of reproduction Medium 20650879
2004 An E-box element at -1020 bp of the human MC2R promoter represses MC2R transcription in granulosa cells through interactions with transcription factors including AP-4; this contributes to adrenal-specific expression independently of SF-1. Promoter luciferase reporter assays in bovine adrenocortical and granulosa cells; EMSA; serial promoter deletions Journal of molecular endocrinology Medium 15171714
2017 JDP2 activates Mc2r promoter transcription dose-dependently via cAMP response elements (particularly at -830 bp), as demonstrated by ChIP. Phosphorylation of JDP2 is required for its transcriptional activation of Mc2r, and SUMOylation of JDP2 modulates this activity. Luciferase reporter assays; real-time ChIP; promoter mapping; mutations of CRE sites; phosphorylation-deficient and SUMOylation mutants of JDP2 in Y1 adrenocortical cells International journal of molecular sciences Medium 28146118
2010 MC2R promoter haplotype TCCT confers ~4-fold higher basal transcriptional activity and ~5-fold greater ACTH-induced MC2R expression compared to TCCC haplotype, as shown by luciferase reporter and RT-PCR assays, providing a molecular basis for variable ACTH responsiveness. Luciferase reporter assay; real-time quantitative RT-PCR of MC2R cDNA expression driven by TCCT vs TCCC promoters in presence and absence of ACTH Pharmacogenetics and genomics Medium 20042918
1995 A homozygous Y254C mutation in the third extracellular loop of MC2R causes isolated glucocorticoid deficiency, consistent with disruption of ligand binding at this position. Direct sequencing of MC2R gene; family analysis confirming autosomal recessive inheritance; functional inference from receptor structure The Journal of clinical endocrinology and metabolism Low 7608277
2020 Ginsenoside Rd inhibits ACTH-induced corticosterone biosynthesis by blocking the MC2R-cAMP/PKA/CREB signaling pathway and downregulating MC2R and MRAP expression in adrenocortical Y1 cells. cAMP content measurement; PKA activity assay; Western blot and qPCR for MC2R and MRAP in Y1 cells treated with ACTH ± ginsenoside Rd Life sciences Medium 31972205
2013 In rat bone marrow stromal cells expressing MC2R and MRAP, ACTH via MC2-R signaling promotes chondrogenic nodule formation and induces transient elevations in intracellular calcium; neither α-MSH (MC5-R agonist) nor γ2-MSH (MC3-R agonist) replicate these effects, defining MC2-R as the specific mediator. MC-R-specific peptide agonists; calcium flux assays; immunoblot of membrane fractions; chondrogenic nodule formation assay; dexamethasone modulation of MC2-R and MRAP expression Cell and tissue research Medium 23358747
2012 In human prostate cancer cell lines, ACTH acting via MC2R induces cAMP production, increases androgen receptor nuclear localization, and promotes concentration-dependent cell proliferation, with the effect partially blocked by a non-selective MCR antagonist (SHU9119). MTT cell proliferation assay; cAMP production assay; immunocytochemistry for AR nuclear localization; MCR antagonist (SHU9119) inhibition International journal of oncology Medium 22842514
2017 Activation of tetrapod MC2R orthologs (human, Anolis carolinensis, Xenopus tropicalis) requires both the H6F7R8W9 (HFRW) pharmacophore and the K15K16R17R18P19 motifs of ACTH(1-24); alanine substitution at these positions has more severe effects on non-mammalian MC2Rs than on human MC2R, pointing to conserved but differentially tuned dual binding sites on the receptor. Alanine-substituted ACTH(1-24) analog stimulation; cAMP assays in cells coexpressing tetrapod MC2R orthologs with MRAP1 General and comparative endocrinology Medium 23639234
2017 The second extracellular loop (EC2)/TM5 region of MC2R is a contact site for the K/KKRRP motif of ACTH; specifically V159 in TM4, F171 in TM5, and F175 in TM5 are critical for receptor activation—triple alanine substitution at these positions completely abolishes ACTH-stimulated activation without impairing receptor trafficking to the plasma membrane. Single and triple alanine mutagenesis of rainbow trout MC2R; cAMP luciferase reporter assay; cell surface ELISA for trafficking General and comparative endocrinology Medium 28495271
2025 ACTH directly stimulates MC2R in brown adipocytes to promote thermogenesis; glucocorticoids act permissively to enhance ACTH-mediated energy expenditure via MC2R, while also separately driving cold-induced hyperphagia. In vitro brown adipocyte assays; in vivo cold exposure model; MC2R-specific signaling readouts bioRxivpreprint Low

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
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
2017 ACTH Receptor (MC2R) Specificity: What Do We Know About Underlying Molecular Mechanisms? Frontiers in endocrinology 58 28220105
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
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
2008 Modeling the evolution of the MC2R and MC5R genes: studies on the cartilaginous fish, Heterondotus francisci. General and comparative endocrinology 28 19100739
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 24 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
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
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 15 24761151
2010 Synergistic activation of the Mc2r promoter by FOXL2 and NR5A1 in mice. Biology of reproduction 15 20650879
2020 Ginsenoside Rd attenuates ACTH-induced corticosterone secretion by blocking the MC2R-cAMP/PKA/CREB pathway in Y1 mouse adrenocortical cells. Life sciences 14 31972205
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
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
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 8 34266338
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
2022 A basal actinopterygian melanocortin receptor: Molecular and functional characterization of an Mc2r ortholog from the Senegal bichir (Polypterus senegalus). General and comparative endocrinology 7 35973587
2020 Activation of PPARγ reduces N-acetyl-cysteine -induced hypercorticoidism by down-regulating MC2R expression into adrenal glands. Free radical biology & medicine 7 32574682
2024 Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist. ACS medicinal chemistry letters 6 38628803
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 4 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
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 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 2 36996927
2015 Association between two promoter polymorphisms (rs1893219 and rs1893220) of MC2R gene and intracerebral hemorrhage in Korean population. Neuroscience letters 2 26115626
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 1 37562700
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