MELANOCORTIN SYSTEM PATHWAY (PW:0000365) Description
The melanocortin peptides - a collective term for the alpha-, beta- and gamma-melanocyte-stimulating hormones and the adenocorticotropin hormone (ACTH) - are derived from the sequential processing of the pro-opiomelanocortin (POMC) gene product. They bind to specific G-protein coupled melanocortin receptors (Mcr) to elicit a range of responses that include anti-inflammatory and immunomodulatory effects, regulation of energy homeostasis and feeding behavior and induction of melanogenesis. The five Mc receptors have rather distinct expression patterns. MC1R (human gene shown) is expressed in skin and also immune cells; in addition to its role in melanogenesis studies have shown that it may also function in inflammation and immunoregulation. Mc3r and 4, expressed in the central nervous system (CNS) and the brain are known regulators of energy homeostasis. Mc3r, also expressed in other tissues and Mc5r in peripheral, play a role in inflammation and immunity. Mc2r is the only receptor that exclusively binds the ACTH peptide; the others appear to bind all POMC derived peptides but with distinct affinities. A distinguishing feature of the system is the presence of natural antagonists. Asip acts as an antagonist of MC1R while Agrp is an antagonist of Mc3r and Mc4r. As the exclusive ACTH binder, Mc2r is an important effector of the hypothalamus-pituitary-adenal (HPA) axis which responds to various stresses and whose end effect is the stimulation of glucocorticoid synthesis. Activation of HPA axis leads to release of corticotropin-releasing hormone (CRH) from the hypothalamus. CRH signaling activates protein kinase A (PKA) pathway leading to expression of POMC gene and the release of ACTH. Melanocortin receptors couple to G alphas family of heterotrimeric G proteins that stimulates adenylyl cyclases; cAMP production activates PKA pathway. Mc2r requires an additional factor - Mrap, which assists in the trafficking of the receptor to the cell surface. Mrap binding the other receptors appears to have an inhibitory effect (not shown). A second Mrap-related human protein - MRAP2, appears to promote similar inhibitory effects on the receptors, except for Mc2r; its exact role in the function of Mc2r remains to be established. Other accessory proteins include Atrn and the Atrn-related, Atrnl. Atrn may act as a co-receptor for Asip while Atrnl is a binding partner for Mc4r. An intracellular protein that may also be involved in the inhibition of MC1R signaling (and possibly Mc4r) is Mgrn1. Some syndecans may act as co-receptors for Agrp (not shown). ACTH-mediated pathway is subject to inhibition by the negative feedback loop provided by the cortisol signaling pathway. The nuclear glucocorticoid receptor forms a complex with a mediator of POMC expression, the orphan nuclear receptor Nr4a1. The complex is stabilized by Smarca4 and recruits Hdac2 to silence gene expression.
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Pathway Diagram:
GO TO:
Genes in Pathway:
Symbol Object Name
Evidence Notes Source PubMed Reference(s) RGD Reference(s) Position
G
Adcy2
adenylate cyclase 2
ISO
SMPDB SMP:00310
NCBI chr 1:36,204,054...36,650,645
G
Agrp
agouti related neuropeptide
TAS ISO
RGD
PMID:10875247 PMID:15189116 RGD:632165 , RGD:1357925
NCBI chr19:50,357,899...50,396,758
G
Asip
agouti signaling protein
ISO
RGD
PMID:15189116 RGD:1357925
NCBI chr 3:163,933,768...164,021,377
G
Atrn
attractin
ISO
RGD
PMID:20654690 RGD:5144214
NCBI chr 3:138,563,271...138,697,360
G
Atrnl1
attractin like 1
ISO
RGD
PMID:20654690 RGD:5144214
NCBI chr 1:256,670,976...257,219,291
G
Cpe
carboxypeptidase E
ISS
RGD
PMID:11874690 RGD:1357926
NCBI chr16:29,796,707...29,908,647
G
Gnas
GNAS complex locus
ISO
SMPDB PMID:20852827 SMP:00310, RGD:5144213
NCBI chr 3:183,489,648...183,554,570
G
Gnb1
G protein subunit beta 1
ISO
SMPDB SMP:00310
NCBI chr 5:171,357,778...171,424,489
G
Gng12
G protein subunit gamma 12
ISO
SMPDB SMP:00310
NCBI chr 4:97,340,830...97,464,422
G
Mc1r
melanocortin 1 receptor
ISO
RGD
PMID:20852827 RGD:5144213
NCBI chr19:68,360,950...68,363,877
G
Mc2r
melanocortin 2 receptor
ISO
SMPDB PMID:20852827 SMP:00310, RGD:5144213
NCBI chr18:64,279,878...64,291,775
G
Mc3r
melanocortin 3 receptor
ISO IDA
RGD
PMID:20852827 PMID:8415620 RGD:5144213 , RGD:69884
NCBI chr 3:181,434,776...181,435,873
G
Mc4r
melanocortin 4 receptor
TAS ISO
RGD
PMID:11963824 PMID:20852827 RGD:729360 , RGD:5144213
NCBI chr18:62,689,798...62,691,685
G
Mc5r
melanocortin 5 receptor
ISO
RGD
PMID:9512481 PMID:20852827 RGD:1626223 , RGD:5144213
NCBI chr18:61,915,188...61,920,229
G
Mgrn1
mahogunin ring finger 1
ISO
RGD
PMID:20654690 RGD:5144214
NCBI chr10:11,142,626...11,194,773
G
Mrap
melanocortin 2 receptor accessory protein
ISO
RGD
PMID:20654690 RGD:5144214
NCBI chr11:29,991,974...30,003,024
G
Mrap2
melanocortin 2 receptor accessory protein 2
ISO
RGD PMID:20654690 RGD:5144214
NCBI chr 8:96,968,239...97,024,581
G
Pam
peptidylglycine alpha-amidating monooxygenase
ISO
RGD
PMID:11874690 RGD:1357926
NCBI chr 9:105,445,812...105,719,287
G
Pcsk1
proprotein convertase subtilisin/kexin type 1
ISS ISO
RGD
PMID:11874690 PMID:15189116 RGD:1357926 , RGD:1357925
NCBI chr 2:6,130,045...6,176,974
G
Pcsk2
proprotein convertase subtilisin/kexin type 2
ISO
RGD
PMID:11874690 RGD:1357926
NCBI chr 3:151,333,938...151,636,628
G
Pomc
proopiomelanocortin
ISS ISO
SMPDB PMID:11874690 PMID:15189116 SMP:00310, RGD:1357926 , RGD:1357925
NCBI chr 6:32,659,137...32,665,175
G
Prkacb
protein kinase cAMP-activated catalytic subunit beta
ISO
SMPDB SMP:00310
NCBI chr 2:238,297,140...238,389,317
G
Sdc1
syndecan 1
ISO
RGD
PMID:15189116 RGD:1357925
NCBI chr 6:37,282,041...37,304,503
G
Sdc3
syndecan 3
ISO
RGD
PMID:15189116 RGD:1357925
NCBI chr 5:148,249,792...148,282,524
Symbol Object Name
Evidence Notes Source PubMed Reference(s) RGD Reference(s) Position
G
Agrp
agouti related neuropeptide
ISO
RGD
PMID:15189116 RGD:1357925
NCBI chr19:50,357,899...50,396,758
G
Mc4r
melanocortin 4 receptor
ISS
RGD
PMID:15189116 RGD:1357925
NCBI chr18:62,689,798...62,691,685
G
Pcsk1
proprotein convertase subtilisin/kexin type 1
ISS ISO
RGD
PMID:11874690 PMID:15189116 RGD:1357926 , RGD:1357925
NCBI chr 2:6,130,045...6,176,974
G
Pomc
proopiomelanocortin
ISS ISO
RGD
PMID:15189116 PMID:11874690 RGD:1357925 , RGD:1357926
NCBI chr 6:32,659,137...32,665,175
G
Sdc1
syndecan 1
ISO
RGD
PMID:15189116 RGD:1357925
NCBI chr 6:37,282,041...37,304,503
Altered Pathway:
Additional Elements in Pathway: (includes Gene Groups, Small Molecules, Other Pathways..etc.) Pathway corticotropin-releasing hormone signaling pathway Activation of HPA axis by various stresses leads to release of corticotropin-releasing hormone from the hypothalamus and initiation of its signaling pathway which leads to activation of POMC gene expression Pathway G protein mediated signaling via Gaphas family Based on sequence similarity, the Galpha genes have been grouped into four classes. Effectors of activated Galphas are adenylyl cyclases that catalyze the formation of cAMP Small Molecule cAMP cAMP binding to the PKA complex leads to dissociation of the catalytic subunits Pathway cortisol biosynthetic pathway Cortisol, the main C21 glucocorticoid, is primarily synthesized in the cortex of the adrenal gland. Like all steroid hormones, glucocorticoids are derived from cholesterol; their biosynthesis is tightly regulated by the hypothalamus-pituitary-gonadal axis. The chronic steroidogenic response involves the change in the expression of steroidogenic genes while the acute response involves the quick delivery of cholesterol to the site of the first enzymatic reaction Pathway protein kinase A (PKA) signaling pathway Protein kinase A (PKA) signaling is a widely used intracellular pathway and the major route for channeling the second messenger cAMP signal
Pathway Gene Annotations
Disease Annotations Associated with Genes in the melanocortin system pathway
Adcy2 asthma , bipolar disorder Agrp autosomal dominant dyskeratosis congenita 6 , Chromosome 16q12 Duplication Syndrome , Hyperphagia , obesity , Thinness , type 2 diabetes mellitus Asip basal cell carcinoma , dermatitis , diabetes mellitus , Diabetic Nephropathies , disease of cellular proliferation , Edema , Failure to Thrive , Fibrosis , Furunculosis , glutathione synthetase deficiency , glutatione synthetase deficiency with 5-oxoprolinuria , hepatic veno-occlusive disease , hyperglycemia , hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase , Hyperplasia , keratosis , Liver Neoplasms , long QT syndrome , melanoma , obesity , Obesity and Hypopigmentation , pigmentation disease , Prenatal Exposure Delayed Effects , Skin Neoplasms , Sunburn , type 2 diabetes mellitus , Weight Gain Atrn autistic disorder , Experimental Liver Cirrhosis , Huntington's disease-like 1 , Inosine Triphosphatase Deficiency , Nerve Degeneration , obesity , pantothenate kinase-associated neurodegeneration , Tremor Cpe alcohol dependence , atherosclerosis , BDV Syndrome , coronary artery disease , endocrine system disease , genetic disease , glioblastoma , Insulin Resistance , Lung Neoplasms , Memory Disorders , morbid obesity , obesity , steatotic liver disease , type 2 diabetes mellitus , Weight Gain Gnas acromegaly , ACTH-independent macronodular adrenal hyperplasia , ACTH-independent macronodular adrenal hyperplasia 1 , Adrenal Gland Neoplasms , Alzheimer's disease , amyotrophic lateral sclerosis type 8 , B-Cell Chronic Lymphocytic Leukemia , brachydactyly , Cafe-au-Lait Spots , cholangiocarcinoma , Cushing Syndrome , Duane retraction syndrome , endocrine system disease , Gallstones , genetic disease , growth hormone secreting pituitary adenoma , hemorrhagic disease , hepatocellular carcinoma , hereditary spastic paraplegia 4 , Heterotopic Ossification , hypertension , Hypoxia , Insulin Resistance , intellectual disability , McCune Albright syndrome , Metabolic Bone Diseases , neuroblastoma , obesity , Orthostatic Hypotension , pancreatic cancer , Parasitic Liver Diseases , pituitary adenoma 3 , Pituitary Neoplasms , polycystic kidney disease , polycystic ovary syndrome , Precocious Puberty , primary hyperaldosteronism , progressive osseous heteroplasia , pseudohypoaldosteronism , pseudohypoparathyroidism , pseudohypoparathyroidism type 1A , pseudohypoparathyroidism type 1B , pseudohypoparathyroidism type 1C , pseudopseudohypoparathyroidism , Respiration Disorders , schizophrenia , sex cord-gonadal stromal tumor , Tachycardia , withdrawal disorder Gnb1 acute lymphoblastic leukemia , anxiety disorder , autism spectrum disorder , autosomal dominant intellectual developmental disorder , autosomal dominant intellectual developmental disorder 42 , cerebral palsy , chromosome 1p36 deletion syndrome , cleft palate , congenital myasthenic syndrome 8 , congestive heart failure , depressive disorder , Developmental Disabilities , dilated cardiomyopathy 1LL , dystonia , Ehlers-Danlos syndrome spondylodysplastic type 2 , epilepsy , epilepsy with generalized tonic-clonic seizures , Failure to Thrive , focal epilepsy , genetic disease , Goldberg-Shprintzen syndrome , Growth Disorders , hypothyroidism , Idiopathic Generalized Epilepsy , immunodeficiency 16 , immunodeficiency 38 , intellectual disability , Joubert syndrome 25 , Language Development Disorders , microcephaly , Muscle Hypotonia , myelodysplastic syndrome , Neurodevelopmental Disorders , pathologic nystagmus , Peroxisome Biogenesis Disorder, Complementation Group 7 , Shprintzen-Goldberg Craniosynostosis , strabismus Gng12 intellectual disability Mc1r Acute-Phase Reaction , age related macular degeneration 7 , allergic contact dermatitis , atopic dermatitis , autosomal recessive chronic granulomatous disease 4 , bacterial pneumonia , basal cell carcinoma , bilateral breast cancer , breast cancer , colitis , Experimental Melanoma , familial melanoma , Fanconi anemia , Hyperalgesia , Hyperoxia , Hypopigmentation , KBG syndrome , Kidney Reperfusion Injury , major depressive disorder , melanoma , oculocutaneous albinism type II , primary ciliary dyskinesia 33 , Reperfusion Injury , Seasonal Allergic Rhinitis , skin melanoma , SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 2 , UV-Induced Skin Damage , vitiligo Mc2r Acute-Phase Reaction , chromosome 18p deletion syndrome , genetic disease , glucocorticoid deficiency 1 , Hyperoxia , hypertension , intellectual disability , Metabolic Brain Diseases, Inborn , Prostatic Neoplasms , toxic shock syndrome , West syndrome Mc3r Acute-Phase Reaction , obesity Mc4r Acute-Phase Reaction , alcohol dependence , anxiety disorder , Binge-Eating Disorder , Body Weight , Bradycardia , Cachexia , chromosome 18q deletion syndrome , cone-rod dystrophy , depressive disorder , diabetes mellitus , Endotoxemia , Hyperalgesia , hyperinsulinism , Hyperphagia , immunodeficiency 12 , Insulin Resistance , isolated microphthalmia 3 , metabolic dysfunction-associated steatohepatitis , morbid obesity , morphine dependence , obesity , schizophrenia , sciatic neuropathy , steatotic liver disease , Tachycardia Mc5r Acute-Phase Reaction , chromosome 18p deletion syndrome , intellectual disability Mgrn1 epilepsy , hyperglycemia , hyperinsulinism , Idiopathic Generalized Epilepsy , Kohlschutter-Tonz syndrome , obesity , Rubinstein-Taybi syndrome , short-rib thoracic dysplasia 9 with or without polydactyly Mrap adrenal gland disease , amyotrophic lateral sclerosis type 1 , autosomal dominant intellectual developmental disorder 7 , Familial Platelet Disorder with Associated Myeloid Malignancy , genetic disease , glucocorticoid deficiency 1 , Glucocorticoid Deficiency 2 , immunodeficiency 28 , Parkinson's disease 20 , ZTTK syndrome Mrap2 obesity Pam anxiety disorder , Brain Hypoxia , Experimental Arthritis , familial adenomatous polyposis 1 , Hereditary Neoplastic Syndromes , Hyperplasia , hypothyroidism , Neurodevelopmental Disorders , prostate adenocarcinoma , type 2 diabetes mellitus Pcsk1 Body Weight , Dehydration , Dwarfism , endocrine system disease , Endotoxemia , Experimental Diabetes Mellitus , Experimental Seizures , familial adenomatous polyposis 1 , genetic disease , glucose intolerance , Hereditary Neoplastic Syndromes , hyperglycemia , hyperthyroidism , hypogonadism , hypothyroidism , Inflammation , islet cell tumor , morbid obesity , Neurodevelopmental Disorders , obesity , proprotein convertase 1/3 deficiency , type 1 diabetes mellitus , type 2 diabetes mellitus Pcsk2 cataract 33 , chronic kidney disease , Endotoxemia , Experimental Diabetes Mellitus , familial hyperinsulinemic hypoglycemia 1 , Inflammation , myocardial infarction , Reperfusion Injury , type 2 diabetes mellitus Pomc ACTH Syndrome, Ectopic , acute kidney failure , acute kidney tubular necrosis , Acute Liver Failure , adrenal cortex disease , Adrenal Insufficiency , alcohol dependence , alcohol use disorder , alcohol withdrawal syndrome , Alcohol-Related Disorders , amnestic disorder , anxiety disorder , autistic disorder , Binge Drinking , bipolar disorder , Body Weight , Bradycardia , Burns , calcinosis , Cardiomegaly , cardiomyopathy , Catalepsy , Cerebral Hemorrhage , cerebral palsy , cholestasis , chondrocalcinosis , Cocaine-Related Disorders , congestive heart failure , Constipation , Cushing Syndrome , cystitis , depressive disorder , diabetes insipidus , diabetes mellitus , disease by infectious agent , disease of mental health , Edema , epilepsy , epilepsy with generalized tonic-clonic seizures , Experimental Arthritis , Experimental Liver Cirrhosis , eye disease , Eye Pain , facial paralysis , familial Mediterranean fever , Femur Head Necrosis , fetal alcohol spectrum disorder , Fetal Growth Retardation , Fever , gastrointestinal system disease , genetic disease , glomerulonephritis , Gouty Arthritis , Hematuria , Hemorrhage , heroin dependence , Hirsutism , human immunodeficiency virus infectious disease , Hyperalgesia , Hypercalciuria , Hypernatremia , Hyperphagia , hypertension , hypertrophic cardiomyopathy , Hypocalcemia , hypokalemia , Hypotension , hypothyroidism , Hypoxia , immune system disease , Inflammation , inflammatory bowel disease , Kidney Calculi , kidney disease , long QT syndrome , melanoma , morbid obesity , morphine dependence , morphine withdrawal syndrome , multiple sclerosis , myasthenia gravis , Myocardial Ischemia , Myoclonic Epilepsies , Nausea , Necrosis , nephrocalcinosis , Neuralgia , Neurogenic Inflammation , nicotine dependence , Nociceptive Pain , obesity , Oliguria , opiate dependence , opioid abuse , Opsoclonus-Myoclonus Syndrome , osteoarthritis , osteoporosis , Pain , pancreas disease , penile disease , pituitary-dependent Cushing's disease , pneumonia , Postoperative Complications , Prenatal Exposure Delayed Effects , Proopiomelanocortin Deficiency , proteinuria , Recurrence , renal cell carcinoma , restless legs syndrome , Rhabdomyoma , Sacroiliitis , severe acute respiratory syndrome , sick sinus syndrome , Sleep Deprivation , sleep disorder , steatotic liver disease , stress-related disorder , subvalvular aortic stenosis , synovitis , Tatton-Brown-Rahman syndrome , type 2 diabetes mellitus , urinary tract infection , Weight Gain , Weight Loss , Wernicke-Korsakoff syndrome , West syndrome , withdrawal disorder Prkacb adrenal cortical adenoma , biliary tract benign neoplasm , brain ischemia , Cardioacrofacial Dysplasia 2 , cholangiocarcinoma , Cushing Syndrome , genetic disease , Hypoglossal Nerve Injuries , Prostatic Neoplasms Sdc1 COVID-19 , familial hyperlipidemia , Hodgkin's lymphoma , hyperglycemia , Inflammation , long QT syndrome , lung adenocarcinoma , Lymphoma, AIDS-Related , malignant mesothelioma , myocardial infarction , obesity , proteinuria Sdc3 obesity
acromegaly Gnas ACTH Syndrome, Ectopic Pomc ACTH-independent macronodular adrenal hyperplasia Gnas ACTH-independent macronodular adrenal hyperplasia 1 Gnas acute kidney failure Pomc acute kidney tubular necrosis Pomc Acute Liver Failure Pomc acute lymphoblastic leukemia Gnb1 Acute-Phase Reaction Mc1r , Mc2r , Mc3r , Mc4r , Mc5r adrenal cortex disease Pomc adrenal cortical adenoma Prkacb adrenal gland disease Mrap Adrenal Gland Neoplasms Gnas Adrenal Insufficiency Pomc age related macular degeneration 7 Mc1r alcohol dependence Cpe , Mc4r , Pomc alcohol use disorder Pomc alcohol withdrawal syndrome Pomc Alcohol-Related Disorders Pomc allergic contact dermatitis Mc1r Alzheimer's disease Gnas amnestic disorder Pomc amyotrophic lateral sclerosis type 1 Mrap amyotrophic lateral sclerosis type 8 Gnas anxiety disorder Gnb1 , Mc4r , Pam , Pomc asthma Adcy2 atherosclerosis Cpe atopic dermatitis Mc1r autism spectrum disorder Gnb1 autistic disorder Atrn , Pomc autosomal dominant dyskeratosis congenita 6 Agrp autosomal dominant intellectual developmental disorder Gnb1 autosomal dominant intellectual developmental disorder 42 Gnb1 autosomal dominant intellectual developmental disorder 7 Mrap autosomal recessive chronic granulomatous disease 4 Mc1r B-Cell Chronic Lymphocytic Leukemia Gnas bacterial pneumonia Mc1r basal cell carcinoma Asip , Mc1r BDV Syndrome Cpe bilateral breast cancer Mc1r biliary tract benign neoplasm Prkacb Binge Drinking Pomc Binge-Eating Disorder Mc4r bipolar disorder Adcy2 , Pomc Body Weight Mc4r , Pcsk1 , Pomc brachydactyly Gnas Bradycardia Mc4r , Pomc Brain Hypoxia Pam brain ischemia Prkacb breast cancer Mc1r Burns Pomc Cachexia Mc4r Cafe-au-Lait Spots Gnas calcinosis Pomc Cardioacrofacial Dysplasia 2 Prkacb Cardiomegaly Pomc cardiomyopathy Pomc Catalepsy Pomc cataract 33 Pcsk2 Cerebral Hemorrhage Pomc cerebral palsy Gnb1 , Pomc cholangiocarcinoma Gnas , Prkacb cholestasis Pomc chondrocalcinosis Pomc Chromosome 16q12 Duplication Syndrome Agrp chromosome 18p deletion syndrome Mc2r , Mc5r chromosome 18q deletion syndrome Mc4r chromosome 1p36 deletion syndrome Gnb1 chronic kidney disease Pcsk2 cleft palate Gnb1 Cocaine-Related Disorders Pomc colitis Mc1r cone-rod dystrophy Mc4r congenital myasthenic syndrome 8 Gnb1 congestive heart failure Gnb1 , Pomc Constipation Pomc coronary artery disease Cpe COVID-19 Sdc1 Cushing Syndrome Gnas , Pomc , Prkacb cystitis Pomc Dehydration Pcsk1 depressive disorder Gnb1 , Mc4r , Pomc dermatitis Asip Developmental Disabilities Gnb1 diabetes insipidus Pomc diabetes mellitus Asip , Mc4r , Pomc Diabetic Nephropathies Asip dilated cardiomyopathy 1LL Gnb1 disease by infectious agent Pomc disease of cellular proliferation Asip disease of mental health Pomc Duane retraction syndrome Gnas Dwarfism Pcsk1 dystonia Gnb1 Edema Asip , Pomc Ehlers-Danlos syndrome spondylodysplastic type 2 Gnb1 endocrine system disease Cpe , Gnas , Pcsk1 Endotoxemia Mc4r , Pcsk1 , Pcsk2 epilepsy Gnb1 , Mgrn1 , Pomc epilepsy with generalized tonic-clonic seizures Gnb1 , Pomc Experimental Arthritis Pam , Pomc Experimental Diabetes Mellitus Pcsk1 , Pcsk2 Experimental Liver Cirrhosis Atrn , Pomc Experimental Melanoma Mc1r Experimental Seizures Pcsk1 eye disease Pomc Eye Pain Pomc facial paralysis Pomc Failure to Thrive Asip , Gnb1 familial adenomatous polyposis 1 Pam , Pcsk1 familial hyperinsulinemic hypoglycemia 1 Pcsk2 familial hyperlipidemia Sdc1 familial Mediterranean fever Pomc familial melanoma Mc1r Familial Platelet Disorder with Associated Myeloid Malignancy Mrap Fanconi anemia Mc1r Femur Head Necrosis Pomc fetal alcohol spectrum disorder Pomc Fetal Growth Retardation Pomc Fever Pomc Fibrosis Asip focal epilepsy Gnb1 Furunculosis Asip Gallstones Gnas gastrointestinal system disease Pomc genetic disease Cpe , Gnas , Gnb1 , Mc2r , Mrap , Pcsk1 , Pomc , Prkacb glioblastoma Cpe glomerulonephritis Pomc glucocorticoid deficiency 1 Mc2r , Mrap Glucocorticoid Deficiency 2 Mrap glucose intolerance Pcsk1 glutathione synthetase deficiency Asip glutatione synthetase deficiency with 5-oxoprolinuria Asip Goldberg-Shprintzen syndrome Gnb1 Gouty Arthritis Pomc Growth Disorders Gnb1 growth hormone secreting pituitary adenoma Gnas Hematuria Pomc Hemorrhage Pomc hemorrhagic disease Gnas hepatic veno-occlusive disease Asip hepatocellular carcinoma Gnas Hereditary Neoplastic Syndromes Pam , Pcsk1 hereditary spastic paraplegia 4 Gnas heroin dependence Pomc Heterotopic Ossification Gnas Hirsutism Pomc Hodgkin's lymphoma Sdc1 human immunodeficiency virus infectious disease Pomc Huntington's disease-like 1 Atrn Hyperalgesia Mc1r , Mc4r , Pomc Hypercalciuria Pomc hyperglycemia Asip , Mgrn1 , Pcsk1 , Sdc1 hyperinsulinism Mc4r , Mgrn1 hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase Asip Hypernatremia Pomc Hyperoxia Mc1r , Mc2r Hyperphagia Agrp , Mc4r , Pomc Hyperplasia Asip , Pam hypertension Gnas , Mc2r , Pomc hyperthyroidism Pcsk1 hypertrophic cardiomyopathy Pomc Hypocalcemia Pomc Hypoglossal Nerve Injuries Prkacb hypogonadism Pcsk1 hypokalemia Pomc Hypopigmentation Mc1r Hypotension Pomc hypothyroidism Gnb1 , Pam , Pcsk1 , Pomc Hypoxia Gnas , Pomc Idiopathic Generalized Epilepsy Gnb1 , Mgrn1 immune system disease Pomc immunodeficiency 12 Mc4r immunodeficiency 16 Gnb1 immunodeficiency 28 Mrap immunodeficiency 38 Gnb1 Inflammation Pcsk1 , Pcsk2 , Pomc , Sdc1 inflammatory bowel disease Pomc Inosine Triphosphatase Deficiency Atrn Insulin Resistance Cpe , Gnas , Mc4r intellectual disability Gnas , Gnb1 , Gng12 , Mc2r , Mc5r islet cell tumor Pcsk1 isolated microphthalmia 3 Mc4r Joubert syndrome 25 Gnb1 KBG syndrome Mc1r keratosis Asip Kidney Calculi Pomc kidney disease Pomc Kidney Reperfusion Injury Mc1r Kohlschutter-Tonz syndrome Mgrn1 Language Development Disorders Gnb1 Liver Neoplasms Asip long QT syndrome Asip , Pomc , Sdc1 lung adenocarcinoma Sdc1 Lung Neoplasms Cpe Lymphoma, AIDS-Related Sdc1 major depressive disorder Mc1r malignant mesothelioma Sdc1 McCune Albright syndrome Gnas melanoma Asip , Mc1r , Pomc Memory Disorders Cpe Metabolic Bone Diseases Gnas Metabolic Brain Diseases, Inborn Mc2r metabolic dysfunction-associated steatohepatitis Mc4r microcephaly Gnb1 morbid obesity Cpe , Mc4r , Pcsk1 , Pomc morphine dependence Mc4r , Pomc morphine withdrawal syndrome Pomc multiple sclerosis Pomc Muscle Hypotonia Gnb1 myasthenia gravis Pomc myelodysplastic syndrome Gnb1 myocardial infarction Pcsk2 , Sdc1 Myocardial Ischemia Pomc Myoclonic Epilepsies Pomc Nausea Pomc Necrosis Pomc nephrocalcinosis Pomc Nerve Degeneration Atrn Neuralgia Pomc neuroblastoma Gnas Neurodevelopmental Disorders Gnb1 , Pam , Pcsk1 Neurogenic Inflammation Pomc nicotine dependence Pomc Nociceptive Pain Pomc obesity Agrp , Asip , Atrn , Cpe , Gnas , Mc3r , Mc4r , Mgrn1 , Mrap2 , Pcsk1 , Pomc , Sdc1 , Sdc3 Obesity and Hypopigmentation Asip oculocutaneous albinism type II Mc1r Oliguria Pomc opiate dependence Pomc opioid abuse Pomc Opsoclonus-Myoclonus Syndrome Pomc Orthostatic Hypotension Gnas osteoarthritis Pomc osteoporosis Pomc Pain Pomc pancreas disease Pomc pancreatic cancer Gnas pantothenate kinase-associated neurodegeneration Atrn Parasitic Liver Diseases Gnas Parkinson's disease 20 Mrap pathologic nystagmus Gnb1 penile disease Pomc Peroxisome Biogenesis Disorder, Complementation Group 7 Gnb1 pigmentation disease Asip pituitary adenoma 3 Gnas Pituitary Neoplasms Gnas pituitary-dependent Cushing's disease Pomc pneumonia Pomc polycystic kidney disease Gnas polycystic ovary syndrome Gnas Postoperative Complications Pomc Precocious Puberty Gnas Prenatal Exposure Delayed Effects Asip , Pomc primary ciliary dyskinesia 33 Mc1r primary hyperaldosteronism Gnas progressive osseous heteroplasia Gnas Proopiomelanocortin Deficiency Pomc proprotein convertase 1/3 deficiency Pcsk1 prostate adenocarcinoma Pam Prostatic Neoplasms Mc2r , Prkacb proteinuria Pomc , Sdc1 pseudohypoaldosteronism Gnas pseudohypoparathyroidism Gnas pseudohypoparathyroidism type 1A Gnas pseudohypoparathyroidism type 1B Gnas pseudohypoparathyroidism type 1C Gnas pseudopseudohypoparathyroidism Gnas Recurrence Pomc renal cell carcinoma Pomc Reperfusion Injury Mc1r , Pcsk2 Respiration Disorders Gnas restless legs syndrome Pomc Rhabdomyoma Pomc Rubinstein-Taybi syndrome Mgrn1 Sacroiliitis Pomc schizophrenia Gnas , Mc4r sciatic neuropathy Mc4r Seasonal Allergic Rhinitis Mc1r severe acute respiratory syndrome Pomc sex cord-gonadal stromal tumor Gnas short-rib thoracic dysplasia 9 with or without polydactyly Mgrn1 Shprintzen-Goldberg Craniosynostosis Gnb1 sick sinus syndrome Pomc skin melanoma Mc1r Skin Neoplasms Asip SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 2 Mc1r Sleep Deprivation Pomc sleep disorder Pomc steatotic liver disease Cpe , Mc4r , Pomc strabismus Gnb1 stress-related disorder Pomc subvalvular aortic stenosis Pomc Sunburn Asip synovitis Pomc Tachycardia Gnas , Mc4r Tatton-Brown-Rahman syndrome Pomc Thinness Agrp toxic shock syndrome Mc2r Tremor Atrn type 1 diabetes mellitus Pcsk1 type 2 diabetes mellitus Agrp , Asip , Cpe , Pam , Pcsk1 , Pcsk2 , Pomc urinary tract infection Pomc UV-Induced Skin Damage Mc1r vitiligo Mc1r Weight Gain Asip , Cpe , Pomc Weight Loss Pomc Wernicke-Korsakoff syndrome Pomc West syndrome Mc2r , Pomc withdrawal disorder Gnas , Pomc ZTTK syndrome Mrap
Pathway Annotations Associated with Genes in the melanocortin system pathway
Adcy2 adenosine signaling pathway , bile acid transport pathway , calcium/calcium-mediated signaling pathway , chemokine mediated signaling pathway , dilated cardiomyopathy pathway , dopamine signaling pathway via D1 family of receptors , endothelin signaling pathway , follicle-stimulating hormone signaling pathway , G protein mediated signaling pathway via Galphas family , glutamate signaling pathway , gonadotropin-releasing hormone signaling pathway , histamine signaling pathway, immunological , luteinizing hormone signaling pathway , melanocortin system pathway , prostaglandin D2 signaling pathway , prostaglandin I2 signaling pathway , protein kinase A (PKA) signaling pathway , purine metabolic pathway , serotonin signaling pathway via receptors engaging G alphas protein family , vasopressin signaling pathway via receptor type 2 Agrp altered melanocortin system pathway , melanocortin system pathway , obesity pathway , syndecan signaling pathway Asip insulin responsive facilitative sugar transporter mediated glucose transport pathway , melanocortin system pathway Atrn melanocortin system pathway Atrnl1 melanocortin system pathway Cpe melanocortin system pathway , type 1 diabetes mellitus pathway Gnas adenosine signaling pathway , bile acid transport pathway , calcium/calcium-mediated signaling pathway , Chagas disease pathway , corticotropin-releasing hormone signaling pathway , dilated cardiomyopathy pathway , dopamine signaling pathway via D1 family of receptors , Entamoebiasis pathway , epinephrine signaling pathway via adrenergic receptor beta , follicle-stimulating hormone signaling pathway , G protein mediated signaling pathway via Galphas family , glucagon signaling pathway , glutamate signaling pathway , gonadotropin-releasing hormone signaling pathway , histamine signaling pathway, immunological , long term depression , luteinizing hormone signaling pathway , melanocortin system pathway , prostaglandin D2 signaling pathway , prostaglandin I2 signaling pathway , serotonin signaling pathway via receptors engaging G alphas protein family , vasopressin signaling pathway , vasopressin signaling pathway via receptor type 2 Gnb1 adenosine signaling pathway , chemokine mediated signaling pathway , dopamine signaling pathway via D1 family of receptors , eicosanoid signaling pathway , follicle-stimulating hormone signaling pathway , G protein mediated signaling pathway via Galpha12/Galpha13 family , glutamate signaling pathway , Hedgehog signaling pathway , histamine signaling pathway, immunological , luteinizing hormone signaling pathway , melanocortin system pathway , prostaglandin D2 signaling pathway , prostaglandin I2 signaling pathway , serotonin signaling pathway via receptors engaging G alphas protein family , vasopressin signaling pathway via receptor type 2 , visual phototransduction pathway Gng12 adenosine signaling pathway , chemokine mediated signaling pathway , dopamine signaling pathway via D1 family of receptors , follicle-stimulating hormone signaling pathway , glutamate signaling pathway , histamine signaling pathway, immunological , luteinizing hormone signaling pathway , melanocortin system pathway , mitogen activated protein kinase signaling pathway , prostaglandin D2 signaling pathway , prostaglandin I2 signaling pathway , serotonin signaling pathway via receptors engaging G alphas protein family , vasopressin signaling pathway via receptor type 2 Mc1r G protein mediated signaling pathway via Galphas family , melanocortin system pathway Mc2r G protein mediated signaling pathway via Galphas family , melanocortin system pathway Mc3r G protein mediated signaling pathway via Galphas family , melanocortin system pathway Mc4r altered energy homeostasis pathway , altered melanocortin system pathway , G protein mediated signaling pathway via Galphas family , melanocortin system pathway , obesity pathway , syndecan signaling pathway Mc5r G protein mediated signaling pathway via Galphas family , melanocortin system pathway Mgrn1 melanocortin system pathway , ubiquitin/proteasome degradation pathway Mrap melanocortin system pathway Mrap2 melanocortin system pathway Pam melanocortin system pathway Pcsk1 altered energy homeostasis pathway , altered melanocortin system pathway , melanocortin system pathway , obesity pathway , orexin/hypocretin signaling pathway Pcsk2 alfentanil pharmacodynamics pathway , bupivacaine pharmacodynamics pathway , buprenorphine pharmacodynamics pathway , chloroprocaine pharmacodynamics pathway , citalopram pharmacodynamics pathway , cocaine pharmacodynamics pathway , codeine and morphine pharmacodynamics pathway , desipramine pharmacodynamics pathway , diphenoxylate pharmacodynamics pathway , escitalopram pharmacodynamics pathway , ethylmorphine pharmacodynamics pathway , fentanyl pharmacodynamics pathway , fluoxetine pharmacodynamics pathway , heroin pharmacodynamics pathway , hydrocodone pharmacodynamics pathway , hydromorphone pharmacodynamics pathway , imipramine pharmacodynamics pathway , levacetylmethadol pharmacodynamics pathway , levobupivacaine phgarmacodynamics pathway , levorphanol pharmacodynamics pathway , lidocaine pharmacodynamics pathway , melanocortin system pathway , mepivacaine pharmacodynamics pathway , methadone pharmacodynamics pathway , nalbuphine pharmacodynamics pathway , naloxone pharmacodynamics pathway , naltrexone pharmacodynamics pathway , nicotine pharmacodynamics pathway , oxybuprocaine pharmacodynamics pathway , oxycodone pharmacodynamics pathway , oxymorphone pharmacodynamics pathway , pentazocine pharmacodynamics pathway , prilocaine pharmacodynamics pathway , procaine pharmacodynamics pathway , remifentanil pharmacodynamics pathway , ropivacaine pharmacodynamics pathway , tramadol pharmacodynamics pathway Pomc alfentanil pharmacodynamics pathway , altered energy homeostasis pathway , altered melanocortin system pathway , bupivacaine pharmacodynamics pathway , buprenorphine pharmacodynamics pathway , chloroprocaine pharmacodynamics pathway , citalopram pharmacodynamics pathway , cocaine pharmacodynamics pathway , codeine and morphine pharmacodynamics pathway , desipramine pharmacodynamics pathway , diphenoxylate pharmacodynamics pathway , escitalopram pharmacodynamics pathway , ethylmorphine pharmacodynamics pathway , fentanyl pharmacodynamics pathway , fluoxetine pharmacodynamics pathway , heroin pharmacodynamics pathway , hydrocodone pharmacodynamics pathway , hydromorphone pharmacodynamics pathway , imipramine pharmacodynamics pathway , levacetylmethadol pharmacodynamics pathway , levobupivacaine phgarmacodynamics pathway , levorphanol pharmacodynamics pathway , lidocaine pharmacodynamics pathway , melanocortin system pathway , mepivacaine pharmacodynamics pathway , methadone pharmacodynamics pathway , nalbuphine pharmacodynamics pathway , naloxone pharmacodynamics pathway , naltrexone pharmacodynamics pathway , nicotine pharmacodynamics pathway , obesity pathway , oxybuprocaine pharmacodynamics pathway , oxycodone pharmacodynamics pathway , oxymorphone pharmacodynamics pathway , pentazocine pharmacodynamics pathway , prilocaine pharmacodynamics pathway , procaine pharmacodynamics pathway , remifentanil pharmacodynamics pathway , ropivacaine pharmacodynamics pathway , syndecan signaling pathway , tramadol pharmacodynamics pathway Prkacb adenosine signaling pathway , apoptotic cell death pathway , bile acid transport pathway , calcium/calcium-mediated signaling pathway , chemokine mediated signaling pathway , dilated cardiomyopathy pathway , dopamine signaling pathway , dopamine signaling pathway via D1 family of receptors , Entamoebiasis pathway , follicle-stimulating hormone signaling pathway , glutamate signaling pathway , gonadotropin-releasing hormone signaling pathway , granulocyte-macrophage colony-stimulating factor signaling pathway , Hedgehog signaling pathway , histamine signaling pathway, immunological , insulin signaling pathway , interleukin-3 signaling pathway , long term potentiation , luteinizing hormone signaling pathway , melanocortin system pathway , mitogen activated protein kinase signaling pathway , prion disease pathway , prostaglandin D2 signaling pathway , prostaglandin I2 signaling pathway , protein kinase A (PKA) signaling pathway , serotonin signaling pathway via receptors engaging G alphas protein family , vasopressin signaling pathway via receptor type 2 , Wnt signaling pathway Sdc1 altered melanocortin system pathway , cell-extracellular matrix signaling pathway , malaria pathway , melanocortin system pathway , obesity pathway , syndecan signaling pathway Sdc3 cell-extracellular matrix signaling pathway , malaria pathway , melanocortin system pathway , syndecan signaling pathway
adenosine signaling pathway Adcy2 , Gnas , Gnb1 , Gng12 , Prkacb alfentanil pharmacodynamics pathway Pcsk2 , Pomc altered energy homeostasis pathway Mc4r , Pcsk1 , Pomc altered melanocortin system pathway Agrp , Mc4r , Pcsk1 , Pomc , Sdc1 apoptotic cell death pathway Prkacb bile acid transport pathway Adcy2 , Gnas , Prkacb bupivacaine pharmacodynamics pathway Pcsk2 , Pomc buprenorphine pharmacodynamics pathway Pcsk2 , Pomc calcium/calcium-mediated signaling pathway Adcy2 , Gnas , Prkacb cell-extracellular matrix signaling pathway Sdc1 , Sdc3 Chagas disease pathway Gnas chemokine mediated signaling pathway Adcy2 , Gnb1 , Gng12 , Prkacb chloroprocaine pharmacodynamics pathway Pcsk2 , Pomc citalopram pharmacodynamics pathway Pcsk2 , Pomc cocaine pharmacodynamics pathway Pcsk2 , Pomc codeine and morphine pharmacodynamics pathway Pcsk2 , Pomc corticotropin-releasing hormone signaling pathway Gnas desipramine pharmacodynamics pathway Pcsk2 , Pomc dilated cardiomyopathy pathway Adcy2 , Gnas , Prkacb diphenoxylate pharmacodynamics pathway Pcsk2 , Pomc dopamine signaling pathway Prkacb dopamine signaling pathway via D1 family of receptors Adcy2 , Gnas , Gnb1 , Gng12 , Prkacb eicosanoid signaling pathway Gnb1 endothelin signaling pathway Adcy2 Entamoebiasis pathway Gnas , Prkacb epinephrine signaling pathway via adrenergic receptor beta Gnas escitalopram pharmacodynamics pathway Pcsk2 , Pomc ethylmorphine pharmacodynamics pathway Pcsk2 , Pomc fentanyl pharmacodynamics pathway Pcsk2 , Pomc fluoxetine pharmacodynamics pathway Pcsk2 , Pomc follicle-stimulating hormone signaling pathway Adcy2 , Gnas , Gnb1 , Gng12 , Prkacb G protein mediated signaling pathway via Galpha12/Galpha13 family Gnb1 G protein mediated signaling pathway via Galphas family Adcy2 , Gnas , Mc1r , Mc2r , Mc3r , Mc4r , Mc5r glucagon signaling pathway Gnas glutamate signaling pathway Adcy2 , Gnas , Gnb1 , Gng12 , Prkacb gonadotropin-releasing hormone signaling pathway Adcy2 , Gnas , Prkacb granulocyte-macrophage colony-stimulating factor signaling pathway Prkacb Hedgehog signaling pathway Gnb1 , Prkacb heroin pharmacodynamics pathway Pcsk2 , Pomc histamine signaling pathway, immunological Adcy2 , Gnas , Gnb1 , Gng12 , Prkacb hydrocodone pharmacodynamics pathway Pcsk2 , Pomc hydromorphone pharmacodynamics pathway Pcsk2 , Pomc imipramine pharmacodynamics pathway Pcsk2 , Pomc insulin responsive facilitative sugar transporter mediated glucose transport pathway Asip insulin signaling pathway Prkacb interleukin-3 signaling pathway Prkacb levacetylmethadol pharmacodynamics pathway Pcsk2 , Pomc levobupivacaine phgarmacodynamics pathway Pcsk2 , Pomc levorphanol pharmacodynamics pathway Pcsk2 , Pomc lidocaine pharmacodynamics pathway Pcsk2 , Pomc long term depression Gnas long term potentiation Prkacb luteinizing hormone signaling pathway Adcy2 , Gnas , Gnb1 , Gng12 , Prkacb malaria pathway Sdc1 , Sdc3 melanocortin system pathway Adcy2 , Agrp , Asip , Atrn , Atrnl1 , Cpe , Gnas , Gnb1 , Gng12 , Mc1r , Mc2r , Mc3r , Mc4r , Mc5r , Mgrn1 , Mrap , Mrap2 , Pam , Pcsk1 , Pcsk2 , Pomc , Prkacb , Sdc1 , Sdc3 mepivacaine pharmacodynamics pathway Pcsk2 , Pomc methadone pharmacodynamics pathway Pcsk2 , Pomc mitogen activated protein kinase signaling pathway Gng12 , Prkacb nalbuphine pharmacodynamics pathway Pcsk2 , Pomc naloxone pharmacodynamics pathway Pcsk2 , Pomc naltrexone pharmacodynamics pathway Pcsk2 , Pomc nicotine pharmacodynamics pathway Pcsk2 , Pomc obesity pathway Agrp , Mc4r , Pcsk1 , Pomc , Sdc1 orexin/hypocretin signaling pathway Pcsk1 oxybuprocaine pharmacodynamics pathway Pcsk2 , Pomc oxycodone pharmacodynamics pathway Pcsk2 , Pomc oxymorphone pharmacodynamics pathway Pcsk2 , Pomc pentazocine pharmacodynamics pathway Pcsk2 , Pomc prilocaine pharmacodynamics pathway Pcsk2 , Pomc prion disease pathway Prkacb procaine pharmacodynamics pathway Pcsk2 , Pomc prostaglandin D2 signaling pathway Adcy2 , Gnas , Gnb1 , Gng12 , Prkacb prostaglandin I2 signaling pathway Adcy2 , Gnas , Gnb1 , Gng12 , Prkacb protein kinase A (PKA) signaling pathway Adcy2 , Prkacb purine metabolic pathway Adcy2 remifentanil pharmacodynamics pathway Pcsk2 , Pomc ropivacaine pharmacodynamics pathway Pcsk2 , Pomc serotonin signaling pathway via receptors engaging G alphas protein family Adcy2 , Gnas , Gnb1 , Gng12 , Prkacb syndecan signaling pathway Agrp , Mc4r , Pomc , Sdc1 , Sdc3 tramadol pharmacodynamics pathway Pcsk2 , Pomc type 1 diabetes mellitus pathway Cpe ubiquitin/proteasome degradation pathway Mgrn1 vasopressin signaling pathway Gnas vasopressin signaling pathway via receptor type 2 Adcy2 , Gnas , Gnb1 , Gng12 , Prkacb visual phototransduction pathway Gnb1 Wnt signaling pathway Prkacb
Phenotype Annotations Associated with Genes in the melanocortin system pathway
Atrn brain vacuoles , darkened coat color , tremors Mc4r abnormal food preference , decreased heart rate , decreased locomotor activity , decreased mean systemic arterial blood pressure , decreased vasoconstriction , increased body length , increased body weight , increased circulating cholesterol level , increased circulating free fatty acids level , increased circulating insulin level , increased circulating leptin level , increased circulating triglyceride level , increased defecation amount , increased fat cell size , increased fluid intake , increased glycosylated hemoglobin level , increased heart weight , increased kidney weight , increased subcutaneous adipose tissue amount , increased systemic vascular resistance , increased vasoconstriction , increased white adipose tissue amount , obese , polyphagia , polyuria
References Associated with the melanocortin system pathway:
Seeley RJ, etal., Annu Rev Nutr 2004;24:133-49.
Pritchard LE, etal., J Endocrinol 2002 Mar;172(3):411-21.
Catania A, etal., ScientificWorldJournal. 2010 Sep 14;10:1840-53.
Cooray SN and Clark AJ, Mol Cell Endocrinol. 2011 Jan 15;331(2):215-21. Epub 2010 Jul 21.
Aguilera G Exp Gerontol. 2011 Feb-Mar;46(2-3):90-5. Epub 2010 Sep 9.
Stevens A and White A, Results Probl Cell Differ. 2010;50:63-84.
Hinkle PM and Sebag JA, Mol Cell Endocrinol. 2009 Mar 5;300(1-2):25-31. Epub 2008 Nov 6.
Drouin J, etal., Clin Genet. 2007 Sep;72(3):175-82.
Xing Y, etal., J Mol Endocrinol. 2010 Jul;45(1):59-68. Epub 2010 May 11.
Ontology Path Diagram:
Import into Pathway Studio:
