CORTICOTROPIN-RELEASING HORMONE SIGNALING PATHWAY (PW:0000493)
Description
Corticotropin-releasing hormone (CRH) and CRH-relate urocortin (UCN) peptides exert a wide range of functions, from setting in motion the stress-responding hypothalamus-pituitary-adrenal (HPA) axis to various actions in central nervous system (CNS) and the periphery. The signaling initiated by these peptides engages two receptor types belonging to the secretin family of G-protein coupled receptors (GPCR). CRH is a main component of the HPA axis; released by the hypothalamus in response to stress, it leads to activation and release of adrenocorticotropin (ACTH) from the pituitary which in turn activates the synthesis and release of glucocorticoids from the adrenal cortex. Glucocorticoid (cortisol in humans) signaling activates the nuclear glucocorticoid receptor which translocates to the nucleus to initiate a gene expression regulatory programme with important anti-inflammatory and metabolic roles. In addition, due to its expression in many tissues, CRH also plays important roles in metabolism, immunity, reproduction and behavior. UCN peptides are expressed in CNS and the periphery with no overlap between them and CRH. Their roles are less well understood but evidence suggests important functions in cardiovascular system and appetite control. Of the two types of receptors, CRH receptor type 1 (CRHR1), is expressed in the brain, pituitary and many other tissues. CRHR2 is also expressed in the brain and periphery; the distribution pattern of the two receptors is distinct. CRH preferentially binds CRHR1, UCN1 can bind either receptor, UCN2 and 3 bind CRHR2. A circulating protein of 37kDa can bind CRH and UCN; while it can block CRH-activated secretion of ACTH from pituitary cultures, its exact role remains to be determined. Both receptors predominantly couple to the Galphas class of heterotrimeric G proteins. Activated Galphas promotes stimulation of adenylyl cyclases and subsequent cAMP production which activated protein kinase A (PKA) signaling. Other classes of G protein such as Galphaq or Galpahai may also be coupled but it is not clear whether genetic background and/or species preferences are involved (not shown). Activated PKA via direct post-translational modification of target proteins in the cytoplasm and also in the nucleus or at the level of regulation of gene transcription via cAMP response element-binding (CREB) protein, impacts on many important cellular pathways and physiological processes. CRH-induced activation of CREB leads to the expression of genes such as the orphan nuclear receptors which in turn, activate the transcription of pro-opiomelanocortin (POMC) gene. POMC is the precursor of ACTH and several other functional peptides. ACTH employs the same intracellular route of PKA activation to prompt the transcription of steroidogenic enzymes and proteins along the PHA axis. CRHR1 is target of G-protein coupled receptor kinases (GRK) 3 and 6; phosphorylation promotes the interaction with beta-arrestin leading to receptor desensitization and internalization.
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Pathway Diagram:
Genes in Pathway:
G
Arrb1 arrestin, beta 1
ISO RGD
PMID:16918397 RGD:5147673
NCBI chr 1:153,837,964...153,912,111
G
Arrb2 arrestin, beta 2
ISO RGD
PMID:16918397 RGD:5147673
NCBI chr10:55,146,887...55,154,854
G
Crh corticotropin releasing hormone
TAS ISO RGD
PMID:12942143 PMID:16484629 RGD:1358326 , RGD:5147387
NCBI chr 2:102,143,055...102,144,919
G
Crhbp corticotropin releasing hormone binding protein
ISO RGD
PMID:16484629 RGD:5147387
NCBI chr 2:26,692,403...26,704,710
G
Crhr1 corticotropin releasing hormone receptor 1
TAS ISO RGD
PMID:12942143 PMID:16484629 RGD:1358326 , RGD:5147387
NCBI chr10:89,040,186...89,083,481
G
Crhr2 corticotropin releasing hormone receptor 2
TAS ISO RGD
PMID:12942143 PMID:16484629 RGD:1358326 , RGD:5147387
NCBI chr 4:84,222,897...84,265,924
G
Gnas GNAS complex locus
ISO RGD
PMID:16484629 RGD:5147387
NCBI chr 3:163,071,003...163,136,350
G
Grk3 G protein-coupled receptor kinase 3
ISO RGD
PMID:16484629 RGD:5147387
NCBI chr12:43,624,778...43,735,375
G
Grk6 G protein-coupled receptor kinase 6
ISO RGD
PMID:16484629 RGD:5147387
NCBI chr17:9,177,018...9,192,813
G
Ucn urocortin
ISO RGD
PMID:16484629 RGD:5147387
NCBI chr 6:25,238,120...25,238,950
G
Ucn2 urocortin 2
ISO RGD
PMID:16484629 RGD:5147387
NCBI chr 8:109,637,624...109,639,173
G
Ucn3 urocortin 3
ISO RGD
PMID:16484629 RGD:5147387
NCBI chr17:66,309,748...66,315,996
Pathway Gene Annotations
Disease Annotations Associated with Genes in the corticotropin-releasing hormone signaling pathway
Arrb1 3-methylglutaconic aciduria type 7b , Arteriovenous Fistula , colitis , congestive heart failure , Experimental Arthritis , intellectual disability , liver cirrhosis , major depressive disorder , Transplant Rejection Arrb2 alcohol dependence , amphetamine abuse , Arteriovenous Fistula , brain infarction , drug psychosis , Experimental Arthritis , Experimental Liver Cirrhosis , Experimental Liver Neoplasms , glioblastoma , hepatocellular carcinoma , heroin dependence , hypertension , liver cirrhosis , metabolic dysfunction and alcohol associated liver disease , Myocardial Reperfusion Injury , nicotine dependence , opiate dependence , pain agnosia , portal hypertension , renal fibrosis , Transplant Rejection , type 2 diabetes mellitus Crh alcohol use disorder , Alcohol-Related Disorders , alopecia , Alzheimer's disease , Anorexia , anxiety disorder , autosomal dominant nocturnal frontal lobe epilepsy , benign familial infantile seizures 6 , Bradycardia , brain edema , brain ischemia , Chest Pain , Cocaine-Related Disorders , cognitive disorder , Cushing Syndrome , Delayed Puberty , depressive disorder , Dyspepsia , Experimental Diabetes Mellitus , extrahepatic cholestasis , Fetal Hypoxia , Fever , hypoglycemia , Hypotension , middle cerebral artery infarction , movement disease , obesity , Pain , panic disorder , Parkinson's disease , pituitary apoplexy , polymyalgia rheumatica , primary hyperaldosteronism , Psychomotor Disorders , retinal degeneration , RETINAL DYSTROPHY WITH INNER RETINAL DYSFUNCTION AND GANGLION CELL ABNORMALITIES , retinitis , sciatic neuropathy , Sepsis , Sleep Deprivation , Spinal Cord Injuries , status epilepticus , stereotypic movement disorder , temporal arteritis , temporal lobe epilepsy , Weight Loss , West syndrome , withdrawal disorder Crhbp Cocaine-Related Disorders , depressive disorder , hepatocellular carcinoma , Hermansky-Pudlak syndrome 2 , Neurodevelopmental Disorders , obesity , temporal lobe epilepsy Crhr1 alcohol use disorder , Anorexia , anxiety disorder , asthma , Binge Drinking , Breast Neoplasms , chronic obstructive pulmonary disease , Cocaine-Related Disorders , contact dermatitis , depressive disorder , Experimental Arthritis , fetal alcohol spectrum disorder , Fetal Hypoxia , frontotemporal dementia , functional colonic disease , hereditary breast ovarian cancer syndrome , Hyperalgesia , Hyperkinesis , hypertension , intellectual disability , irritable bowel syndrome , Koolen de Vries syndrome , major depressive disorder , obesity , Osteoarthritis, Hip , Pneumococcal Pneumonia , Postoperative Pain , Prenatal Exposure Delayed Effects , rhinitis , stress-related disorder , thromboangiitis obliterans , type 2 diabetes mellitus Crhr2 Anorexia , anxiety disorder , asthma , Charcot-Marie-Tooth disease type 2 , Cocaine-Related Disorders , colitis , depressive disorder , Ehlers-Danlos syndrome kyphoscoliotic type 2 , Fetal Hypoxia , functional colonic disease , hypertension , Hypotension , Inflammation , irritable bowel syndrome , ischemia , Left Ventricular Hypertrophy , lung disease , muscular atrophy , pleomorphic xanthoastrocytoma , Pneumococcal Pneumonia , pneumonia , rhinitis Gnas acromegaly , ACTH-independent macronodular adrenal hyperplasia , ACTH-independent macronodular adrenal hyperplasia 1 , Adrenal Gland Neoplasms , adrenocortical carcinoma , Albright's hereditary osteodystrophy , Alzheimer's disease , amyotrophic lateral sclerosis type 8 , B-Cell Chronic Lymphocytic Leukemia , brachydactyly , Breast Neoplasms , Cafe-au-Lait Spots , cholangiocarcinoma , Colorectal Neoplasms , Cushing Syndrome , disease of cellular proliferation , Duane retraction syndrome , endocrine system disease , Gallstones , gastric adenocarcinoma , genetic disease , growth hormone secreting pituitary adenoma , head and neck squamous cell carcinoma , hemorrhagic disease , hepatocellular carcinoma , hereditary spastic paraplegia 4 , Heterotopic Ossification , hypertension , Hypoxia , Insulin Resistance , intellectual disability , lung adenocarcinoma , McCune Albright syndrome , melanoma , Metabolic Bone Diseases , neuroblastoma , obesity , Orthostatic Hypotension , pancreatic adenocarcinoma , 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 IB , Pseudohypoparathyroidism Type IC , pseudopseudohypoparathyroidism , Respiration Disorders , schizophrenia , sex cord-gonadal stromal tumor , skin melanoma , Tachycardia , Uterine Cervical Neoplasms , withdrawal disorder Grk3 bipolar disorder , Cardiomegaly , Cocaine-Related Disorders , congestive heart failure , Diabetic Nephropathies , hypertension , hypothyroidism , Parkinson's disease Grk6 Diabetic Nephropathies , Drug-Induced Dyskinesia , Ehlers-Danlos syndrome dermatosparaxis type , Ehlers-Danlos syndrome spondylodysplastic type 2 , Marfanoid Mental Retardation Syndrome, Autosomal , opiate dependence , Parkinson's disease , rheumatoid arthritis , Sotos syndrome , Spinal Cord Injuries Ucn anxiety disorder , asthma , Burns , Charcot-Marie-Tooth disease type 2EE , colitis , congestive heart failure , dilated cardiomyopathy , hypertension , hypertrophic cardiomyopathy , Hypotension , Inflammation , Left Ventricular Hypertrophy , mitochondrial DNA depletion syndrome 6 , Myocardial Reperfusion Injury , obesity , Parkinsonism , Tatton-Brown-Rahman syndrome , thromboangiitis obliterans Ucn2 Aicardi-Goutieres Syndrome 1 , Anorexia , atherosclerosis , colitis , congestive heart failure , hypertension , Progressive Microcephaly with Seizures and Cerebral and Cerebellar Atrophy Ucn3 hypoparathyroidism-deafness-renal disease syndrome , Inflammation , lung disease , schizophrenia
3-methylglutaconic aciduria type 7b Arrb1 acromegaly Gnas ACTH-independent macronodular adrenal hyperplasia Gnas ACTH-independent macronodular adrenal hyperplasia 1 Gnas Adrenal Gland Neoplasms Gnas adrenocortical carcinoma Gnas Aicardi-Goutieres Syndrome 1 Ucn2 Albright's hereditary osteodystrophy Gnas alcohol dependence Arrb2 alcohol use disorder Crh , Crhr1 Alcohol-Related Disorders Crh alopecia Crh Alzheimer's disease Crh , Gnas amphetamine abuse Arrb2 amyotrophic lateral sclerosis type 8 Gnas Anorexia Crh , Crhr1 , Crhr2 , Ucn2 anxiety disorder Crh , Crhr1 , Crhr2 , Ucn Arteriovenous Fistula Arrb1 , Arrb2 asthma Crhr1 , Crhr2 , Ucn atherosclerosis Ucn2 autosomal dominant nocturnal frontal lobe epilepsy Crh B-Cell Chronic Lymphocytic Leukemia Gnas benign familial infantile seizures 6 Crh Binge Drinking Crhr1 bipolar disorder Grk3 brachydactyly Gnas Bradycardia Crh brain edema Crh brain infarction Arrb2 brain ischemia Crh Breast Neoplasms Crhr1 , Gnas Burns Ucn Cafe-au-Lait Spots Gnas Cardiomegaly Grk3 Charcot-Marie-Tooth disease type 2 Crhr2 Charcot-Marie-Tooth disease type 2EE Ucn Chest Pain Crh cholangiocarcinoma Gnas chronic obstructive pulmonary disease Crhr1 Cocaine-Related Disorders Crh , Crhbp , Crhr1 , Crhr2 , Grk3 cognitive disorder Crh colitis Arrb1 , Crhr2 , Ucn , Ucn2 Colorectal Neoplasms Gnas congestive heart failure Arrb1 , Grk3 , Ucn , Ucn2 contact dermatitis Crhr1 Cushing Syndrome Crh , Gnas Delayed Puberty Crh depressive disorder Crh , Crhbp , Crhr1 , Crhr2 Diabetic Nephropathies Grk3 , Grk6 dilated cardiomyopathy Ucn disease of cellular proliferation Gnas drug psychosis Arrb2 Drug-Induced Dyskinesia Grk6 Duane retraction syndrome Gnas Dyspepsia Crh Ehlers-Danlos syndrome dermatosparaxis type Grk6 Ehlers-Danlos syndrome kyphoscoliotic type 2 Crhr2 Ehlers-Danlos syndrome spondylodysplastic type 2 Grk6 endocrine system disease Gnas Experimental Arthritis Arrb1 , Arrb2 , Crhr1 Experimental Diabetes Mellitus Crh Experimental Liver Cirrhosis Arrb2 Experimental Liver Neoplasms Arrb2 extrahepatic cholestasis Crh fetal alcohol spectrum disorder Crhr1 Fetal Hypoxia Crh , Crhr1 , Crhr2 Fever Crh frontotemporal dementia Crhr1 functional colonic disease Crhr1 , Crhr2 Gallstones Gnas gastric adenocarcinoma Gnas genetic disease Gnas glioblastoma Arrb2 growth hormone secreting pituitary adenoma Gnas head and neck squamous cell carcinoma Gnas hemorrhagic disease Gnas hepatocellular carcinoma Arrb2 , Crhbp , Gnas hereditary breast ovarian cancer syndrome Crhr1 hereditary spastic paraplegia 4 Gnas Hermansky-Pudlak syndrome 2 Crhbp heroin dependence Arrb2 Heterotopic Ossification Gnas Hyperalgesia Crhr1 Hyperkinesis Crhr1 hypertension Arrb2 , Crhr1 , Crhr2 , Gnas , Grk3 , Ucn , Ucn2 hypertrophic cardiomyopathy Ucn hypoglycemia Crh hypoparathyroidism-deafness-renal disease syndrome Ucn3 Hypotension Crh , Crhr2 , Ucn hypothyroidism Grk3 Hypoxia Gnas Inflammation Crhr2 , Ucn , Ucn3 Insulin Resistance Gnas intellectual disability Arrb1 , Crhr1 , Gnas irritable bowel syndrome Crhr1 , Crhr2 ischemia Crhr2 Koolen de Vries syndrome Crhr1 Left Ventricular Hypertrophy Crhr2 , Ucn liver cirrhosis Arrb1 , Arrb2 lung adenocarcinoma Gnas lung disease Crhr2 , Ucn3 major depressive disorder Arrb1 , Crhr1 Marfanoid Mental Retardation Syndrome, Autosomal Grk6 McCune Albright syndrome Gnas melanoma Gnas Metabolic Bone Diseases Gnas metabolic dysfunction and alcohol associated liver disease Arrb2 middle cerebral artery infarction Crh mitochondrial DNA depletion syndrome 6 Ucn movement disease Crh muscular atrophy Crhr2 Myocardial Reperfusion Injury Arrb2 , Ucn neuroblastoma Gnas Neurodevelopmental Disorders Crhbp nicotine dependence Arrb2 obesity Crh , Crhbp , Crhr1 , Gnas , Ucn opiate dependence Arrb2 , Grk6 Orthostatic Hypotension Gnas Osteoarthritis, Hip Crhr1 Pain Crh pain agnosia Arrb2 pancreatic adenocarcinoma Gnas pancreatic cancer Gnas panic disorder Crh Parasitic Liver Diseases Gnas Parkinson's disease Crh , Grk3 , Grk6 Parkinsonism Ucn pituitary adenoma 3 Gnas pituitary apoplexy Crh Pituitary Neoplasms Gnas pleomorphic xanthoastrocytoma Crhr2 Pneumococcal Pneumonia Crhr1 , Crhr2 pneumonia Crhr2 polycystic kidney disease Gnas polycystic ovary syndrome Gnas polymyalgia rheumatica Crh portal hypertension Arrb2 Postoperative Pain Crhr1 Precocious Puberty Gnas Prenatal Exposure Delayed Effects Crhr1 primary hyperaldosteronism Crh , Gnas Progressive Microcephaly with Seizures and Cerebral and Cerebellar Atrophy Ucn2 progressive osseous heteroplasia Gnas pseudohypoaldosteronism Gnas pseudohypoparathyroidism Gnas pseudohypoparathyroidism type IB Gnas Pseudohypoparathyroidism Type IC Gnas pseudopseudohypoparathyroidism Gnas Psychomotor Disorders Crh renal fibrosis Arrb2 Respiration Disorders Gnas retinal degeneration Crh RETINAL DYSTROPHY WITH INNER RETINAL DYSFUNCTION AND GANGLION CELL ABNORMALITIES Crh retinitis Crh rheumatoid arthritis Grk6 rhinitis Crhr1 , Crhr2 schizophrenia Gnas , Ucn3 sciatic neuropathy Crh Sepsis Crh sex cord-gonadal stromal tumor Gnas skin melanoma Gnas Sleep Deprivation Crh Sotos syndrome Grk6 Spinal Cord Injuries Crh , Grk6 status epilepticus Crh stereotypic movement disorder Crh stress-related disorder Crhr1 Tachycardia Gnas Tatton-Brown-Rahman syndrome Ucn temporal arteritis Crh temporal lobe epilepsy Crh , Crhbp thromboangiitis obliterans Crhr1 , Ucn Transplant Rejection Arrb1 , Arrb2 type 2 diabetes mellitus Arrb2 , Crhr1 Uterine Cervical Neoplasms Gnas Weight Loss Crh West syndrome Crh withdrawal disorder Crh , Gnas
