Corticotropin-releasing hormone
Encyclopedia
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
. It belongs to corticotropin-releasing factor family
.
Its main function is the stimulation of the pituitary synthesis of ACTH.
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.
) 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 corticotrope
s to secrete adrenocorticotrophic hormone (ACTH) and other biologically-active substances β-endorphin). ACTH stimulates the synthesis of cortisol
, glucocorticoids, mineralocorticoids and DHEA; therefore high CRF levels are very common in individuals with Cushing's syndrome
.
α-helical CRH-(9–41) acts as a CRH antagonist.
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, abnormally high 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
.
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:
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.
sequence of CRH was first discovered in sheep by Vale et al. in 1981. Its full sequence is:
The rat and human peptides are identical and differ from the ovine sequence only by 7 amino acids.
with Corticotropin releasing hormone receptor 1
.
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
and neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
involved in the stress response
Stress (medicine)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
. It belongs to corticotropin-releasing factor family
Corticotropin-releasing factor family
Corticotropin-releasing factor, CRF is a family of related neuropeptides in vertebrates. This family includes corticotropin-releasing hormone, urotensin-I, urocortin and sauvagine form a family . The family can be grouped into 2 separate paralogous lineages, with urotensin-I, urocortin and...
.
Its main function is the stimulation of the pituitary synthesis of ACTH.
Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide derived from a 191-amino acid preprohormone. CRH is secreted by the paraventricular nucleus
Paraventricular nucleus
The paraventricular nucleus is a neuronal nucleus in the hypothalamus. It contains multiple subpopulations of neurons that are activated by a variety of stressful and/or physiological changes. Many PVN neurons project directly to the posterior pituitary where they release oxytocin or vasopressin...
(PVN) of the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
in response to stress. Marked reduction in CRH has been observed in association with Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, and autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
and hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
. 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
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
. In the placenta, CRH is a marker that determines the length of gestation
Gestation
Gestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time ....
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 parvocellular neuroendocrine cells (which are contained within the paraventricular nucleusParaventricular nucleus
The paraventricular nucleus is a neuronal nucleus in the hypothalamus. It contains multiple subpopulations of neurons that are activated by a variety of stressful and/or physiological changes. Many PVN neurons project directly to the posterior pituitary where they release oxytocin or vasopressin...
) of the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
and is released at the median eminence
Median eminence
The median eminence is part of the inferior boundary for the hypothalamus part of the human brain. A small swelling on the tuber cinereum posterior to the infundibulum - atop the pituitary stalk - the median eminence lies in the area roughly bounded on its posterolateral region by the cerebral...
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
Anterior pituitary
A major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland...
of the pituitary
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
, where it stimulates corticotrope
Corticotrope
Corticotropes are basophilic cells in the anterior pituitary that produce adrenocorticotropic hormone, melanocyte-stimulating hormone and lipotropin. These cells respond to corticotropin releasing hormone and make up about 20% of the cells in the anterior pituitary....
s to secrete adrenocorticotrophic hormone (ACTH) and other biologically-active substances β-endorphin). ACTH stimulates the synthesis of cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
, glucocorticoids, mineralocorticoids and DHEA; therefore high CRF levels are very common in individuals with Cushing's syndrome
Cushing's syndrome
Cushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone or CRH...
.
α-helical CRH-(9–41) acts as a CRH antagonist.
Psychopharmacology
The CRH-1 receptor antagonist pexacerfontPexacerfont
Pexacerfont is a drug developed by Bristol-Myers Squibb which acts as a CRF-1 antagonist.Corticotropin releasing factor , also known as Corticotropin releasing hormone, is an endogenous peptide hormone which is released in response to various triggers such as chronic stress...
is currently under investigation for the treatment of generalized anxiety disorder in women. Another CRH-1 antagonist antalarmin
Antalarmin
Antalarmin is a drug that acts as a CRF-1 antagonist.Corticotropin-releasing factor , also known as Corticotropin-releasing hormone, is an endogenous peptide hormone released in response to various triggers such as chronic stress and drug addiction. This, then, triggers the release of corticotropin...
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
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
of suicide victims.
Recent research has linked the activation of the CRH1 receptor
Corticotropin releasing hormone receptor 1
Corticotropin releasing hormone receptor 1 is a protein, also known as CRF1, with the latter now being the IUPHAR-recommended name...
with the euphoric feelings that accompany alcohol consumption. A CRH1 receptor antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
developed by Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
, CP-154,526
CP-154,526
CP-154,526 is a potent and selective antagonist of the corticotropin releasing hormone receptor 1 developed by Pfizer.CP-154,526 is under investigation for the potential treatment of alcoholism.- External links :...
is under investigation for the potential treatment of alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
.
Role in parturition
CRH is also synthesized by the placentaPlacenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
and seems to determine the duration of pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
.
Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition:
- Increases levels of dehydroepiandrosteroneDehydroepiandrosterone5-Dehydroepiandrosterone is a 19-carbon endogenous steroid hormone. It is the major secretory steroidal product of the adrenal glands and is also produced by the gonads and the brain. DHEA is the most abundant circulating steroid in humans....
(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 acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
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
See also
- Corticotropin-releasing hormone receptorCorticotropin-releasing hormone receptorCorticotropin-releasing hormone receptors , also known known as corticotropin-releasing factor receptors are a G protein-coupled receptor family that binds corticotropin-releasing hormone...
- ACTH
- Glucocorticoids
- ProopiomelanocortinProopiomelanocortinPro-opiomelanocortin is a precursor polypeptide with 241 amino acid residues. POMC is synthesized from the 285-amino acid long polypeptide precursor, pre-pro-opiomelanocortin , by the removal of a 44-amino acid long signal peptide sequence during translation.The POMC gene is located on chromosome...
- Hypothalamic-pituitary-adrenal axisHypothalamic-pituitary-adrenal axisThe hypothalamic-pituitary-adrenal axis , also known as thelimbic-hypothalamic-pituitary-adrenal axis and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland ,...
- CorticorelinCorticorelinCorticorelin is a diagnostic agent. It is a corticotropin-releasing hormone.The corticorelin stimulation test helps to differentiate between the etiologies of ACTH-dependent hypercortisolism...
- Cushing's syndromeCushing's syndromeCushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone or CRH...
- Addison's syndrome
Interactions
Corticotropin-releasing hormone has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Corticotropin releasing hormone receptor 1
Corticotropin releasing hormone receptor 1
Corticotropin releasing hormone receptor 1 is a protein, also known as CRF1, with the latter now being the IUPHAR-recommended name...
.