Corticotropin-releasing hormone

Corticotropin releasing hormone
PDB rendering based on 1go9.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1GOE, 3EHT, 3EHU
Identifiers
Symbols	CRH ; CRF; CRH1
External IDs	OMIM: 122560 MGI: 88496 HomoloGene: 599 GeneCards: CRH Gene
Gene ontology Molecular function • receptor binding • hormone activity • neuropeptide hormone activity • protein binding • corticotropin-releasing hormone receptor 1 binding • corticotropin-releasing hormone receptor 2 binding Cellular component • extracellular region • extracellular space • cytoplasm • varicosity • perikaryon Biological process • positive regulation of protein phosphorylation • synaptic transmission, dopaminergic • glucocorticoid biosynthetic process • inflammatory response • signal transduction • synaptic transmission • female pregnancy • parturition • learning or memory • positive regulation of cell proliferation • associative learning • hormone-mediated apoptotic signaling pathway • positive regulation of gene expression • negative regulation of gene expression • negative regulation of norepinephrine secretion • positive regulation of circadian sleep/wake cycle, wakefulness • positive regulation of cell death • regulation of serotonin secretion • diterpenoid metabolic process • hypothalamus development • lung development • adrenal gland development • positive regulation of cAMP biosynthetic process • negative regulation of epinephrine secretion • negative regulation of luteinizing hormone secretion • locomotory exploration behavior • positive regulation of insulin secretion involved in cellular response to glucose stimulus • response to immobilization stress • negative regulation of circadian sleep/wake cycle, REM sleep • response to drug • response to estrogen • response to ethanol • response to ether • negative regulation of blood pressure • response to pain • ion homeostasis • response to corticosterone • positive regulation of corticotropin secretion • positive regulation of cortisol secretion • long-term synaptic potentiation • positive regulation of digestive system process • negative regulation of cell death • negative regulation of glucagon secretion • cellular response to cocaine • cellular response to dexamethasone stimulus • positive regulation of calcium ion import • regulation of N-methyl-D-aspartate selective glutamate receptor activity • positive regulation of corticosterone secretion • positive regulation of behavioral fear response Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1392	12918
Ensembl	ENSG00000147571	ENSMUSG00000049796
UniProt	P06850	Q8CIT0
RefSeq (mRNA)	NM_000756	NM_205769
RefSeq (protein)	NP_000747	NP_991338
Location (UCSC)	Chr 8: 66.18 – 66.18 Mb	Chr 3: 19.69 – 19.7 Mb
PubMed search	[1]	[2]

Corticotropin-releasing hormone (CRH) also known as corticotropin-releasing factor (CRF) or corticoliberin is a peptide hormone and neurotransmitter involved in the stress response. It is a releasing hormone that belongs to corticotropin-releasing factor family. In humans, it is encoded by the CRH gene.

Its main function is the stimulation of the pituitary synthesis of ACTH, as part of the HPA Axis.

Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide derived from a 196-amino acid preprohormone. CRH is secreted by the paraventricular nucleus (PVN) of the hypothalamus in response to stress. Increased CRH production has been observed to be associated with Alzheimer's disease and major depression, and autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia. In addition to being produced in the hypothalamus, CRH is also synthesized in peripheral tissues, such as T lymphocytes, and is highly expressed in the placenta. In the placenta, CRH is a marker that determines the length of gestation and the timing of parturition and delivery. A rapid increase in circulating levels of CRH occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, CRH may act as a trigger for parturition.

A recombinant version for diagnostics is called corticorelin (INN).

Hormonal actions

CRH is produced by parvocellular neuroendocrine cells within the paraventricular nucleus of the hypothalamus and is released at the median eminence from neurosecretory terminals of these neurons into the primary capillary plexus of the hypothalamo-hypophyseal portal system. The portal system carries the CRH to the anterior lobe of the pituitary, where it stimulates corticotropes to secrete adrenocorticotropic hormone (ACTH) and other biologically-active substances (β-endorphin). ACTH stimulates the synthesis of cortisol, glucocorticoids, mineralocorticoids and DHEA.

In the short term, CRH can suppress appetite, increase subjective feelings of anxiety, and perform other functions like boosting attention. Although the distal action of CRH is immunosuppression via the action of cortisol, CRH itself can actually heighten inflammation, a process being investigated in multiple sclerosis research.

Psychopharmacology

The CRH-1 receptor antagonist pexacerfont is currently under investigation for the treatment of generalized anxiety disorder. Another CRH-1 antagonist antalarmin has been researched in animal studies for the treatment of anxiety, depression and other conditions, but no human trials with this compound have been carried out.

Also, abnormally high levels of CRH have been found in the cerebrospinal fluid of people that have committed suicide.

Recent research has linked the activation of the CRH1 receptor with the euphoric feelings that accompany alcohol consumption. A CRH1 receptor antagonist developed by Pfizer, CP-154,526 is under investigation for the potential treatment of alcoholism.

Alpha-helical CRH-(9–41) acts as a CRH antagonist.

Role in parturition

CRH is also synthesized by the placenta and seems to determine the duration of pregnancy.

Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition:

• Increases levels of dehydroepiandrosterone (DHEA) directly by action on the fetal adrenal gland, and indirectly via the mother's pituitary gland. DHEA has a role in preparing for and stimulating cervical contractions.
• Increases prostaglandin availability in uteroplacental tissues. Prostaglandins activate cervical contractions.
• Prior to parturition it may have a role inhibiting contractions, through increasing cAMP levels in the myometrium.

In culture, trophoblast CRH is inhibited by progesterone, which remains high throughout pregnancy. Its release is stimulated by glucocorticoids and catecholamines, which increase prior to parturition lifting this progesterone block.

Structure

The 41-amino acid sequence of CRH was first discovered in sheep by Vale et al. in 1981. Its full sequence is:

• SQEPPISLDLTFHLLREVLEMTKADQLAQQAHSNRKLLDIA

The rat and human peptides are identical and differ from the ovine sequence only by 7 amino acids.

• SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII

Role in non-mammalian vertebrates

In mammals, studies suggest that CRH has no significant thyrotropic effect. However, in representatives of all non-mammalian vertebrates, it has been found that, in addition to its corticotropic function, CRH has a potent thyrotropic function, acting with TRH to control the thyroid axis (TRH has been found to be less potent than CRH in some species).

Interactions

Corticotropin-releasing hormone has been shown to interact with corticotropin-releasing hormone receptor 1.

See also

• Corticotropin-releasing hormone receptor
• ACTH
• Glucocorticoids
• Proopiomelanocortin
• Hypothalamic-pituitary-adrenal axis
• Cushing's syndrome
• Addison's disease