Corticotropin-releasing hormone

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

Its main function is the stimulation of the pituitary synthesis of is_associated_with::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 is_associated_with::paraventricular nucleus (PVN) of the is_associated_with::hypothalamus in response to stress. Increased CRH production has been observed to be associated with is_associated_with::Alzheimer's disease and is_associated_with::major depression, and autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including is_associated_with::hypoglycemia. In addition to being produced in the hypothalamus, CRH is also synthesized in peripheral tissues, such as is_associated_with::T lymphocytes, and is highly expressed in the is_associated_with::placenta. In the placenta, CRH is a marker that determines the length of is_associated_with::gestation and the timing of is_associated_with::parturition and delivery. A rapid increase in circulating levels of CRH occurs at the onset of is_associated_with::parturition, suggesting that, in addition to its metabolic functions, CRH may act as a trigger for parturition.

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

Psychopharmacology
The CRH-1 receptor antagonist is_associated_with::pexacerfont is currently under investigation for the treatment of is_associated_with::generalized anxiety disorder. Another CRH-1 antagonist is_associated_with::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 is_associated_with::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 is_associated_with::Pfizer, is_associated_with::CP-154,526 is under investigation for the potential treatment of is_associated_with::alcoholism.

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

Role in parturition
CRH is also synthesized by the is_associated_with::placenta and seems to determine the duration of is_associated_with::pregnancy.

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


 * Increases levels of is_associated_with::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 stimultated by is_associated_with::glucocorticoids and catecholamines, which increase prior to parturition lifting this progesterone block.

Structure
The 41-is_associated_with::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 is_associated_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.