Melanocortin 4 receptor is a class A seven-transmembrane G protein-coupled receptor expressed mainly in the brain, notably in neurons of the hypothalamic paraventricular nucleus, where it localises to the plasma membrane and the primary cilium. It is activated by the POMC-derived melanocortins alpha- and beta-MSH (and by ACTH in vitro) and antagonised by agouti-related protein (AgRP), which also acts as an inverse agonist. Agonist-bound MC4R couples to Gs to stimulate adenylate cyclase (ADCY3 at the cilium) and cAMP signalling, and can also close the KCNJ13/Kir7.1 channel independently of Gs. MC4R is the central effector node of the leptin-melanocortin pathway: its activation suppresses appetite and promotes energy expenditure. Accessory proteins such as MRAP2 and MGRN1 modulate its trafficking and signalling. Heterozygous and homozygous loss-of-function MC4R variants are the commonest monogenic cause of severe early-onset obesity, with hyperphagia, increased linear growth and hyperinsulinaemia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: G protein-coupled receptor activity (InterPro2GO). Reason: Correct but generic; MC4R is a melanocortin receptor activated principally by alpha- and beta-MSH, and the specific term is experimentally supported. Proposed replacements: melanocyte-stimulating hormone receptor activity Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating PMID:14764818 signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma(1)-MSH were impaired |
| GO:0004977 melanocortin receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Melanocortin receptor activity (IEA). Reason: MC4R is one of the five melanocortin receptors and signals in response to POMC-derived melanocortins (alpha-MSH, ACTH, gamma-MSH). Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating PMID:8392067 leads to increases in intracellular cyclic 3',5'-adenosine monophosphate |
| GO:0004977 melanocortin receptor activity | TAS PMID:8794897 Morphine down-regulates melanocortin-4 receptor expression i... | ACCEPT | Summary: Melanocortin receptor activity (TAS). Reason: MC4R is one of the five melanocortin receptors and signals in response to POMC-derived melanocortins (alpha-MSH, ACTH, gamma-MSH). Supporting Evidence: PMID:8794897 the potency of melanocortin peptides to stimulate cAMP production is similar in these two species homologs PMID:8392067 leads to increases in intracellular cyclic 3',5'-adenosine monophosphate |
| GO:0004978 corticotropin receptor activity | IDA PMID:33858992 Structure reveals the activation mechanism of the MC4 recept... | KEEP AS NON CORE | Summary: Corticotropin receptor activity (IDA). Reason: MC4R is activated by ACTH with potency comparable to alpha-MSH in vitro, but the physiological brain ligands are alpha- and beta-MSH; ACTH signalling is the core role of MC2R. Supporting Evidence: PMID:8794897 the potency of melanocortin peptides to stimulate cAMP production is similar in these two species homologs Reactome:R-HSA-388596 The majority of melanocortin receptors (MC1R, MC3R, MC4R and MC5R) are semi-selective in their ability to bind multiple melanocortins (MSH and ACTH). |
| GO:0004980 melanocyte-stimulating hormone receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Melanocyte-stimulating hormone receptor activity (IBA). Reason: The defining activity of MC4R: binding alpha-/beta-MSH and activating Gs-cAMP signalling; loss of this activity causes the commonest monogenic obesity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002733667 SUPPORTS TRANSFER MC4R orthology node; MSH receptor activity is experimentally established for human MC4R, which appears among the sources. Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating PMID:12588803 four were completely unable to generate cAMP in response to ligand and five were partially impaired |
| GO:0004980 melanocyte-stimulating hormone receptor activity | IDA PMID:14764818 Identification and characterization of melanocortin-4 recept... | ACCEPT | Summary: Melanocyte-stimulating hormone receptor activity (IDA). Reason: The defining activity of MC4R: binding alpha-/beta-MSH and activating Gs-cAMP signalling; loss of this activity causes the commonest monogenic obesity. Supporting Evidence: PMID:14764818 signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma(1)-MSH were impaired PMID:12588803 four were completely unable to generate cAMP in response to ligand and five were partially impaired |
| GO:0004980 melanocyte-stimulating hormone receptor activity | IDA PMID:33858992 Structure reveals the activation mechanism of the MC4 recept... | ACCEPT | Summary: Melanocyte-stimulating hormone receptor activity (IDA). Reason: The defining activity of MC4R: binding alpha-/beta-MSH and activating Gs-cAMP signalling; loss of this activity causes the commonest monogenic obesity. Supporting Evidence: PMID:33858992 we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide PMID:12588803 four were completely unable to generate cAMP in response to ligand and five were partially impaired |
| GO:0004980 melanocyte-stimulating hormone receptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Melanocyte-stimulating hormone receptor activity (IEA). Reason: The defining activity of MC4R: binding alpha-/beta-MSH and activating Gs-cAMP signalling; loss of this activity causes the commonest monogenic obesity. Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt G protein-coupled receptor that binds melanocyte-stimulating PMID:12588803 four were completely unable to generate cAMP in response to ligand and five were partially impaired |
| GO:0004980 melanocyte-stimulating hormone receptor activity | IPI PMID:19743876 Novel binding motif of ACTH analogues at the melanocortin re... | ACCEPT | Summary: Melanocyte-stimulating hormone receptor activity (IPI). Reason: The defining activity of MC4R: binding alpha-/beta-MSH and activating Gs-cAMP signalling; loss of this activity causes the commonest monogenic obesity. Supporting Evidence: PMID:19743876 Substitutions of these amino acid residues reduced or abolished agonist activity at hMC3R and hMC4R. PMID:12588803 four were completely unable to generate cAMP in response to ligand and five were partially impaired |
| GO:0005515 protein binding | IPI PMID:19329486 MRAP and MRAP2 are bidirectional regulators of the melanocor... | REMOVE | Summary: Protein binding with MRAP (IPI). Reason: The interaction with MRAP is real and MRAP-family accessory proteins modulate melanocortin receptor trafficking and responsiveness, but 'protein binding' conveys no function of MC4R and no more informative MC4R molecular function term describes this accessory-protein association. Removal does not mean the interaction is false. Supporting Evidence: PMID:19329486 We report that MRAP and MRAP2 can interact with all 5 MCRs. PMID:19329486 MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness |
| GO:0005515 protein binding | IPI PMID:19329486 MRAP and MRAP2 are bidirectional regulators of the melanocor... | REMOVE | Summary: Protein binding with MRAP2 (IPI). Reason: The interaction with MRAP2 is real and MRAP-family accessory proteins modulate melanocortin receptor trafficking and responsiveness, but 'protein binding' conveys no function of MC4R and no more informative MC4R molecular function term describes this accessory-protein association. Removal does not mean the interaction is false. Supporting Evidence: PMID:19329486 We report that MRAP and MRAP2 can interact with all 5 MCRs. PMID:19329486 MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness |
| GO:0005515 protein binding | IPI PMID:19743876 Novel binding motif of ACTH analogues at the melanocortin re... | MODIFY | Summary: Protein binding with POMC (ACTH analogues; IPI). Reason: The binding is that of a melanocortin peptide ligand to its receptor; melanocortin receptor activity captures the function. Proposed replacements: melanocortin receptor activity Supporting Evidence: PMID:19743876 Substitutions of these amino acid residues reduced or abolished agonist activity at hMC3R and hMC4R. Reactome:R-HSA-388596 The majority of melanocortin receptors (MC1R, MC3R, MC4R and MC5R) are semi-selective in their ability to bind multiple melanocortins (MSH and ACTH). |
| GO:0005515 protein binding | IPI PMID:21719532 The cytosolic chaperone Hsc70 promotes traffic to the cell s... | REMOVE | Summary: Protein binding with DNAJB2 isoform (IPI). Reason: Chaperone association studied in the context of misfolded, ER-retained MC4R mutants; 'protein binding' does not describe a function of MC4R. Removal does not mean the interaction is false. Supporting Evidence: PMID:21719532 Clinically occurring MC4R mutants S58C, P78L, and D90N were demonstrated to have reduced trafficking to the plasma membrane |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Cytoplasm (IBA). Reason: MC4R is an integral plasma membrane and ciliary membrane GPCR; intracellular pools exist during biosynthesis and for misfolded mutants, but cytoplasm is not its functional location. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN002733616 SUPPORTS SOURCE BUT NOT TARGET Melanocortin receptor family node; members are plasma-membrane GPCRs, so a cytoplasm assertion reflects intracellular trafficking pools rather than the functional compartment. Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane PMID:29311635 We demonstrate that MC4R colocalizes with ADCY3 at the primary cilia of a subset of hypothalamic neurons |
| GO:0005886 plasma membrane | EXP PMID:25163632 Functional characterization of a new human melanocortin-4 re... | ACCEPT | Summary: Plasma membrane (EXP). Reason: MC4R is a seven-transmembrane receptor at the cell surface (including the primary cilium membrane); trafficking-defective mutants that fail to reach the plasma membrane lose function. Supporting Evidence: PMID:25163632 Cells expressing N-terminal HA and C-terminal GFP-tagged MC4R were assessed by immunofluorescence confocal microscopy and flow cytometry for correct cell-surface localization. file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane (IBA). Reason: MC4R is a seven-transmembrane receptor at the cell surface (including the primary cilium membrane); trafficking-defective mutants that fail to reach the plasma membrane lose function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002733616 SUPPORTS TRANSFER GPCR family node; plasma-membrane localisation is conserved and shown for human MC4R. Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | IDA PMID:39951488 Hypothalamic opsin 3 suppresses MC4R signaling and potentiat... | ACCEPT | Summary: Plasma membrane (IDA). Reason: MC4R is a seven-transmembrane receptor at the cell surface (including the primary cilium membrane); trafficking-defective mutants that fail to reach the plasma membrane lose function. Supporting Evidence: PMID:39951488 negatively regulates MC4R-mediated cAMP signaling in a specific and GΞ±i/o-dependent manner file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane (IEA). Reason: MC4R is a seven-transmembrane receptor at the cell surface (including the primary cilium membrane); trafficking-defective mutants that fail to reach the plasma membrane lose function. Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | TAS PMID:10585465 Functional characterization of mutations in melanocortin-4 r... | ACCEPT | Summary: Plasma membrane (TAS). Reason: MC4R is a seven-transmembrane receptor at the cell surface (including the primary cilium membrane); trafficking-defective mutants that fail to reach the plasma membrane lose function. Supporting Evidence: PMID:10585465 the mutant proteins were expressed and localized in the intracellular compartment but absent from the plasma membrane file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-379044 | ACCEPT | Summary: Plasma membrane (TAS). Reason: MC4R is a seven-transmembrane receptor at the cell surface (including the primary cilium membrane); trafficking-defective mutants that fail to reach the plasma membrane lose function. Supporting Evidence: Reactome:R-HSA-379044 The liganded receptor undergoes a conformational change file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-388596 | ACCEPT | Summary: Plasma membrane (TAS). Reason: MC4R is a seven-transmembrane receptor at the cell surface (including the primary cilium membrane); trafficking-defective mutants that fail to reach the plasma membrane lose function. Supporting Evidence: Reactome:R-HSA-388596 The majority of melanocortin receptors (MC1R, MC3R, MC4R and MC5R) are semi-selective in their ability to bind multiple melanocortins (MSH and ACTH). file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-744886 | ACCEPT | Summary: Plasma membrane (TAS). Reason: MC4R is a seven-transmembrane receptor at the cell surface (including the primary cilium membrane); trafficking-defective mutants that fail to reach the plasma membrane lose function. Supporting Evidence: Reactome:R-HSA-744886 Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-744887 | ACCEPT | Summary: Plasma membrane (TAS). Reason: MC4R is a seven-transmembrane receptor at the cell surface (including the primary cilium membrane); trafficking-defective mutants that fail to reach the plasma membrane lose function. Supporting Evidence: Reactome:R-HSA-744887 The role of the guanine nucleotide-binding protein G alpha-s subunit (G alpha-s) file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: G protein-coupled receptor signaling pathway (InterPro2GO). Reason: Correct but generic; MC4R couples to Gs and activates adenylate cyclase. Proposed replacements: adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt couples to G(s) protein, stimulating adenylate cyclase and the cAMP PMID:33858992 we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide |
| GO:0007188 adenylate cyclase-modulating G protein-coupled receptor signaling pathway | TAS PMID:8794897 Morphine down-regulates melanocortin-4 receptor expression i... | MODIFY | Summary: Adenylate cyclase-modulating GPCR signaling pathway (TAS). Reason: MC4R signalling increases cAMP, so the more precise child term adenylate cyclase-activating GPCR signaling pathway applies. Proposed replacements: adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: PMID:8794897 the potency of melanocortin peptides to stimulate cAMP production is similar in these two species homologs PMID:8392067 leads to increases in intracellular cyclic 3',5'-adenosine monophosphate |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Adenylate cyclase-activating GPCR signaling pathway (IBA). Reason: Agonist-bound MC4R couples to Gs and stimulates cAMP production; this is the principal signalling output of the receptor. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002733616 SUPPORTS TRANSFER Melanocortin receptor family node; Gs-cAMP coupling is conserved across MC1R-MC5R and experimentally shown for human MC4R. Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt couples to G(s) protein, stimulating adenylate cyclase and the cAMP PMID:8392067 leads to increases in intracellular cyclic 3',5'-adenosine monophosphate |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:19329486 MRAP and MRAP2 are bidirectional regulators of the melanocor... | ACCEPT | Summary: Adenylate cyclase-activating GPCR signaling pathway (IDA). Reason: Agonist-bound MC4R couples to Gs and stimulates cAMP production; this is the principal signalling output of the receptor. Supporting Evidence: PMID:19329486 MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness PMID:8392067 leads to increases in intracellular cyclic 3',5'-adenosine monophosphate |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:19743876 Novel binding motif of ACTH analogues at the melanocortin re... | ACCEPT | Summary: Adenylate cyclase-activating GPCR signaling pathway (IDA). Reason: Agonist-bound MC4R couples to Gs and stimulates cAMP production; this is the principal signalling output of the receptor. Supporting Evidence: PMID:19743876 Substitutions of these amino acid residues reduced or abolished agonist activity at hMC3R and hMC4R. PMID:8392067 leads to increases in intracellular cyclic 3',5'-adenosine monophosphate |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:29311635 Subcellular localization of MC4R with ADCY3 at neuronal prim... | ACCEPT | Summary: Adenylate cyclase-activating GPCR signaling pathway (IDA). Reason: Agonist-bound MC4R couples to Gs and stimulates cAMP production; this is the principal signalling output of the receptor. Supporting Evidence: PMID:29311635 inhibition of adenylyl cyclase signaling at the primary cilia of these neurons increases body weight PMID:8392067 leads to increases in intracellular cyclic 3',5'-adenosine monophosphate |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:33858992 Structure reveals the activation mechanism of the MC4 recept... | ACCEPT | Summary: Adenylate cyclase-activating GPCR signaling pathway (IDA). Reason: Agonist-bound MC4R couples to Gs and stimulates cAMP production; this is the principal signalling output of the receptor. Supporting Evidence: PMID:33858992 we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide PMID:8392067 leads to increases in intracellular cyclic 3',5'-adenosine monophosphate |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: Adenylate cyclase-activating GPCR signaling pathway (IEA). Reason: Agonist-bound MC4R couples to Gs and stimulates cAMP production; this is the principal signalling output of the receptor. Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt couples to G(s) protein, stimulating adenylate cyclase and the cAMP PMID:8392067 leads to increases in intracellular cyclic 3',5'-adenosine monophosphate |
| GO:0007218 neuropeptide signaling pathway | IEA GO_REF:0000108 | ACCEPT | Summary: Neuropeptide signaling pathway (IEA, inferred from receptor activity). Reason: MC4R is the brain receptor for the neuropeptides alpha-MSH and AgRP, so participation in neuropeptide signaling is correct. Supporting Evidence: PMID:15927146 AgRP is a neuropeptide that stimulates food intake through inhibition of central melanocortin receptors (MCRs). PMID:8392067 this receptor is expressed primarily in the brain |
| GO:0007631 feeding behavior | TAS PMID:9771698 A frameshift mutation in MC4R associated with dominantly inh... | MODIFY | Summary: Feeding behavior (TAS). Reason: MC4R loss causes hyperphagic obesity; its role is to restrain food intake, better captured by negative regulation of appetite. Proposed replacements: negative regulation of appetite Supporting Evidence: PMID:9771698 A frameshift mutation in MC4R associated with dominantly inherited human obesity. PMID:12646665 The correlation between the signaling properties of these mutant receptors and energy intake emphasizes the key role of this receptor in the control of eating behavior in humans. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Membrane. Reason: Correct but uninformative; MC4R is a plasma membrane (and ciliary membrane) receptor. Proposed replacements: plasma membrane Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0016020 membrane | TAS PMID:8392067 Molecular cloning, expression, and gene localization of a fo... | MODIFY | Summary: Membrane. Reason: Correct but uninformative; MC4R is a plasma membrane (and ciliary membrane) receptor. Proposed replacements: plasma membrane Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt SUBCELLULAR LOCATION: Cell membrane PMID:8392067 leads to increases in intracellular cyclic 3',5'-adenosine monophosphate |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:19737927 Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase inhibits... | KEEP AS NON CORE | Summary: Ubiquitin protein ligase binding (MGRN1; IPI). Reason: MGRN1 binds MC4R and inhibits its cAMP signalling by competing with Gs; a regulatory interaction, not the core activity. Supporting Evidence: PMID:19737927 MGRN1 isoforms decreased MC1R and MC4R signaling to cAMP, without effect on beta(2)-adrenergic receptor. |
| GO:0032099 negative regulation of appetite | IDA PMID:29311635 Subcellular localization of MC4R with ADCY3 at neuronal prim... | ACCEPT | Summary: Negative regulation of appetite (IDA). Reason: MC4R activation suppresses food intake; human loss-of-function variants and mouse knockout cause hyperphagia and obesity. Supporting Evidence: PMID:29311635 inhibition of adenylyl cyclase signaling at the primary cilia of these neurons increases body weight PMID:12646665 The correlation between the signaling properties of these mutant receptors and energy intake emphasizes the key role of this receptor in the control of eating behavior in humans. PMID:9019399 Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. |
| GO:0032099 negative regulation of appetite | IMP PMID:12588803 Mutations in the human melanocortin-4 receptor gene associat... | ACCEPT | Summary: Negative regulation of appetite (IMP). Reason: MC4R activation suppresses food intake; human loss-of-function variants and mouse knockout cause hyperphagia and obesity. Supporting Evidence: PMID:12588803 four were completely unable to generate cAMP in response to ligand and five were partially impaired PMID:12646665 The correlation between the signaling properties of these mutant receptors and energy intake emphasizes the key role of this receptor in the control of eating behavior in humans. PMID:9019399 Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. |
| GO:0042923 neuropeptide binding | IMP PMID:15927146 Functional analysis of the Ala67Thr polymorphism in agouti r... | ACCEPT | Summary: Neuropeptide binding (IMP, AgRP). Reason: MC4R binds the neuropeptide antagonist/inverse agonist AgRP as well as melanocortin agonists; AgRP binding is physiologically important for orexigenic control. Supporting Evidence: PMID:15927146 AgRP is a neuropeptide that stimulates food intake through inhibition of central melanocortin receptors (MCRs). file:human/MC4R/MC4R-uniprot.txt Regulates food intake: activation by agonists suppresses appetite, |
| GO:0045780 positive regulation of bone resorption | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of bone resorption (IEA). Reason: MC4R haploinsufficiency lowers bone resorption and raises bone mass via increased CART; an indirect, non-core consequence of hypothalamic melanocortin signalling. Supporting Evidence: PMID:16614075 humans or mice lacking only one allele of Mc4r display a decrease in bone resorption parameters, high bone mass |
| GO:0045780 positive regulation of bone resorption | IMP PMID:16614075 Cart overexpression is the only identifiable cause of high b... | KEEP AS NON CORE | Summary: Positive regulation of bone resorption (IMP). Reason: MC4R haploinsufficiency lowers bone resorption and raises bone mass via increased CART; an indirect, non-core consequence of hypothalamic melanocortin signalling. Supporting Evidence: PMID:16614075 humans or mice lacking only one allele of Mc4r display a decrease in bone resorption parameters, high bone mass |
| GO:0060170 ciliary membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Ciliary membrane (IEA, UniProt subcellular location). Reason: MC4R localises to the primary cilium membrane of hypothalamic neurons, where it signals with ADCY3. Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt Cell projection, cilium membrane PMID:29311635 We demonstrate that MC4R colocalizes with ADCY3 at the primary cilia of a subset of hypothalamic neurons |
| GO:0060259 regulation of feeding behavior | IBA GO_REF:0000033 | ACCEPT | Summary: Regulation of feeding behavior (IBA). Reason: Conserved role of MC4R in regulating food intake across vertebrates. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002733667 SUPPORTS TRANSFER MC4R orthology node; feeding regulation is supported by human, mouse and other vertebrate MC4R loss-of-function data. Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt Regulates food intake: activation by agonists suppresses appetite, PMID:9019399 Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. |
| GO:0098804 non-motile cilium membrane | IDA PMID:29311635 Subcellular localization of MC4R with ADCY3 at neuronal prim... | ACCEPT | Summary: Non-motile cilium membrane (IDA). Reason: MC4R colocalises with ADCY3 at neuronal primary cilia, and ciliary localisation is required for its anti-obesity signalling. Supporting Evidence: PMID:29311635 We demonstrate that MC4R colocalizes with ADCY3 at the primary cilia of a subset of hypothalamic neurons PMID:29311635 inhibition of adenylyl cyclase signaling at the primary cilia of these neurons increases body weight |
| GO:1903998 regulation of eating behavior | IEA GO_REF:0000107 | ACCEPT | Summary: Regulation of eating behavior (IEA). Reason: MC4R controls food intake in humans and mice. Supporting Evidence: PMID:12646665 The correlation between the signaling properties of these mutant receptors and energy intake emphasizes the key role of this receptor in the control of eating behavior in humans. PMID:9019399 Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. |
| GO:1903998 regulation of eating behavior | ISS GO_REF:0000024 | ACCEPT | Summary: Regulation of eating behavior (ISS). Reason: MC4R controls food intake in humans and mice. Supporting Evidence: PMID:12646665 The correlation between the signaling properties of these mutant receptors and energy intake emphasizes the key role of this receptor in the control of eating behavior in humans. PMID:9019399 Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. |
| GO:1990680 response to melanocyte-stimulating hormone | IEA GO_REF:0000107 | ACCEPT | Summary: Response to melanocyte-stimulating hormone (IEA). Reason: MC4R is the receptor that mediates cellular responses to alpha-/beta-MSH in the hypothalamus. Supporting Evidence: PMID:14764818 signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma(1)-MSH were impaired |
| GO:1990680 response to melanocyte-stimulating hormone | ISS GO_REF:0000024 | ACCEPT | Summary: Response to melanocyte-stimulating hormone (ISS). Reason: MC4R is the receptor that mediates cellular responses to alpha-/beta-MSH in the hypothalamus. Supporting Evidence: PMID:14764818 signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma(1)-MSH were impaired |
| GO:2000252 negative regulation of feeding behavior | IEA GO_REF:0000107 | ACCEPT | Summary: Negative regulation of feeding behavior (IEA). Reason: Agonist activation of MC4R suppresses feeding; its loss causes hyperphagia. Supporting Evidence: file:human/MC4R/MC4R-uniprot.txt Regulates food intake: activation by agonists suppresses appetite, PMID:12646665 Mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia |
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