corticotropin releasing factor

Corticotropin-releasing hormone

Corticotropin-releasing hormone (CRH), originally named corticotropin-releasing factor (CRF), and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response.

Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide derived from a 191-amino acid preprohormone. CRH is secreted by the paraventricular nucleus (PVN) of the hypothalamus in response to stress. Marked reduction in CRH has been observed in association with Alzheimer's disease, and autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially-fatal metabolic consequences including hypoglycemia and hepatitis. 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.

Hormonal actions

CRH is produced by neuroendocrine cells in the paraventricular nucleus of the hypothalamus and is released 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 corticotropin (ACTH) and other biologically-active substances (for example β-endorphin).

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

Psychopharmacy

The CRH-1 receptor antagonist pexacerfont is currently under investigation for the treatment of Generalized anxiety disorder in women. 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, abnormal levels of CRH have been found in the cerebrospinal fluid of suicide victims.

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.

Role in parturition

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

Levels rise towards birth and current theory suggests three roles of CRH in parturition:

  • Increases level so 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 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

See also

References

Further reading

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