Corticotropin-releasing hormone

Last updated

CRH
PBB Protein CRH image.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CRH , CRF, CRH1, corticotropin releasing hormone
External IDs OMIM: 122560; MGI: 88496; HomoloGene: 599; GeneCards: CRH; OMA:CRH - orthologs
Orthologs
SpeciesHumanMouse
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: 19.75 – 19.75 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress responses. It is a releasing hormone that belongs to corticotropin-releasing factor family. In humans, it is encoded by the CRH gene. [5] Its main function is the stimulation of the pituitary synthesis of adrenocorticotropic hormone (ACTH), as part of the hypothalamic–pituitary–adrenal axis (HPA axis).

Contents

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, [6] and autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia. [5]

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. [5]

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

Actions and psychopharmacology

CRH is produced in response to stress, predominantly by parvocellular neurosecretory 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. [7]

In the short term, CRH can suppress appetite, increase subjective feelings of anxiety, and perform other functions like boosting attention. [8]

During chronic stress conditions such as post-traumatic stress disorder (PTSD), blood serum levels of CRH are decreased in combat veterans with PTSD compared to healthy individuals. [9] It is believed that chronic stress enhances the negative feedback inhibition of the HPA axis, resulting in lower CRH levels and HPA function. [10] [11] [12]

Abnormally high levels of CRH have been found in people with major depression, [13] [6] and in the cerebrospinal fluid of people who have committed suicide. [14]

Corticotropin-releasing hormone has been shown to interact with its receptors, corticotropin-releasing hormone receptor 1 (CRFR1) and corticotropin-releasing hormone receptor 2 (CRFR2), in order to induce its effects. [15] [16] [17] [18] Injection of CRH into the rodent paraventricular nucleus of the hypothalamus (PVN) can increase CRFR1 expression, with increased expression leading to depression-like behaviors. [19] Sex differences have also been observed with respect to both CRH and the receptors that it interacts with. CRFR1 has been shown to exist at higher levels in the female nucleus accumbens, olfactory tubercle, and rostral anteroventral periventricular nucleus (AVPV) when compared to males, while male voles show increased levels of CRFR2 in the bed nucleus of the stria terminalis compared to females. [20]

The CRH-1 receptor antagonist pexacerfont is currently under investigation for the treatment of generalized anxiety disorder. [21] Another CRH-1 antagonist antalarmin has been researched[ citation needed ] in animal studies for the treatment of anxiety, depression and other conditions, but no human trials with this compound have been carried out.

The activation of the CRH1 receptor has been linked 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. [22] [23]

Increased CRH production has been observed to be associated with Alzheimer's disease. [6]

Although one action of CRH is immunosuppression via the action of cortisol, CRH itself can actually heighten the immune system's inflammation response, a process being investigated in multiple sclerosis research. [24]

Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia. [5]

Alpha-helical CRH-(9–41) acts as a CRH antagonist. [25]

Role in parturition

CRH is synthesized by the placenta and seems to determine the duration of pregnancy. [26]

Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition: [27]

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. [28]

Structure

The 41-amino acid sequence of CRH was first discovered in sheep by Vale et al. in 1981. [29] Its full sequence is:

The rat and human peptides are identical and differ from the ovine sequence only by 7 amino acids. [30]

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 hypothalamic–pituitary–thyroid axis (TRH has been found to be less potent than CRH in some species). [31] [32]

See also

Related Research Articles

<span class="mw-page-title-main">Hypothalamus</span> Area of the brain below the thalamus

The hypothalamus is a small part of the vertebrate brain that contains a number of nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus is located below the thalamus and is part of the limbic system. It forms the basal part of the diencephalon. All vertebrate brains contain a hypothalamus. In humans, it is about the size of an almond.

<span class="mw-page-title-main">Thyrotropin-releasing hormone</span> Hormone

Thyrotropin-releasing hormone (TRH) is a hypophysiotropic hormone produced by neurons in the hypothalamus that stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary.

<span class="mw-page-title-main">Hypothalamic–pituitary–adrenal axis</span> Set of physiological feedback interactions

The hypothalamic–pituitary–adrenal axis is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland, and the adrenal glands. These organs and their interactions constitute the HPS axis.

Corticotropin-releasing factor family, CRF family is a family of related neuropeptides in vertebrates. This family includes corticotropin-releasing hormone, urotensin-I, urocortin, and sauvagine. The family can be grouped into 2 separate paralogous lineages, with urotensin-I, urocortin and sauvagine in one group and CRH forming the other group. Urocortin and sauvagine appear to represent orthologues of fish urotensin-I in mammals and amphibians, respectively. The peptides have a variety of physiological effects on stress and anxiety, vasoregulation, thermoregulation, growth and metabolism, metamorphosis and reproduction in various species, and are all released as prohormones.

<span class="mw-page-title-main">Paraventricular nucleus of hypothalamus</span>

The paraventricular nucleus is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller amount of vasopressin, otherwise the nucleus also secretes corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH). CRH and TRH are secreted into the hypophyseal portal system and act on different targets neurons in the anterior pituitary. Dysfunctions of PVN can cause hypersomnia in mice, and dysfunction of the paraventricular nucleus can lead to drowsiness for up to 20 hours per day in humans. PVN is thought to mediate many diverse functions through different hormones, including osmoregulation, appetite,wakefulness, and the response of the body to stress.

Corticotropic cells, are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). These cells are stimulated by corticotropin releasing hormone (CRH) and make up 15–20% of the cells in the anterior pituitary. The release of ACTH from the corticotropic cells is controlled by CRH, which is formed in the cell bodies of parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and passes to the corticotropes in the anterior pituitary via the hypophyseal portal system. Adrenocorticotropin hormone stimulates the adrenal cortex to release glucocorticoids and plays an important role in the stress response.

<span class="mw-page-title-main">Ghrelin</span> Peptide hormone involved in appetite regulation

Ghrelin is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid.

<span class="mw-page-title-main">Neuropeptide Y</span> Mammalian protein found in Homo sapiens

Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. It is secreted alongside other neurotransmitters such as GABA and glutamate. 

Neuroendocrinology is the branch of biology which studies the interaction between the nervous system and the endocrine system; i.e. how the brain regulates the hormonal activity in the body. The nervous and endocrine systems often act together in a process called neuroendocrine integration, to regulate the physiological processes of the human body. Neuroendocrinology arose from the recognition that the brain, especially the hypothalamus, controls secretion of pituitary gland hormones, and has subsequently expanded to investigate numerous interconnections of the endocrine and nervous systems.

<span class="mw-page-title-main">Hypophyseal portal system</span> System of blood vessels

The hypophyseal portal system is a system of blood vessels in the microcirculation at the base of the brain, connecting the hypothalamus with the anterior pituitary. Its main function is to quickly transport and exchange hormones between the hypothalamus arcuate nucleus and anterior pituitary gland. The capillaries in the portal system are fenestrated which allows a rapid exchange between the hypothalamus and the pituitary. The main hormones transported by the system include gonadotropin-releasing hormone, corticotropin-releasing hormone, growth hormone–releasing hormone, and thyrotropin-releasing hormone.

<span class="mw-page-title-main">Urocortin</span>

Urocortin is a protein that in humans is encoded by the UCN gene. Urocortin belongs to the corticotropin-releasing factor (CRF) family of proteins which includes CRF, urotensin I, sauvagine, urocortin II and urocortin III. Urocortin is involved in the mammalian stress response, and regulates aspects of appetite and stress response.

Urocortin III, a 38–41 amino acid peptide, is a member of the CRF, also known as CRH family of peptides, with a long evolutionary lineage.

Neuromedin U is a neuropeptide found in the brain of humans and other mammals, which has a number of diverse functions including contraction of smooth muscle, regulation of blood pressure, pain perception, appetite, bone growth, and hormone release. It was first isolated from the spinal cord in 1985, and named after its ability to cause smooth muscle contraction in the uterus.

<span class="mw-page-title-main">Corticotropin-releasing hormone receptor 1</span> Protein and coding gene in humans

Corticotropin-releasing hormone receptor 1 (CRHR1) is a protein, also known as CRF1, with the latter (CRF1) now being the IUPHAR-recommended name. In humans, CRF1 is encoded by the CRHR1 gene at region 17q21.31, beside micrototubule-associated protein tau MAPT.

<span class="mw-page-title-main">Corticotropin-releasing hormone receptor 2</span> Protein found in humans

Corticotropin-releasing hormone receptor 2 (CRHR2) is a protein, also known by the IUPHAR-recommended name CRF2, that is encoded by the CRHR2 gene and occurs on the surfaces of some mammalian cells. CRF2 receptors are type 2 G protein-coupled receptors for corticotropin-releasing hormone (CRH) that are resident in the plasma membranes of hormone-sensitive cells. CRH, a peptide of 41 amino acids synthesized in the hypothalamus, is the principal neuroregulator of the hypothalamic-pituitary-adrenal axis, signaling via guanine nucleotide-binding proteins (G proteins) and downstream effectors such as adenylate cyclase. The CRF2 receptor is a multi-pass membrane protein with a transmembrane domain composed of seven helices arranged in a V-shape. CRF2 receptors are activated by two structurally similar peptides, urocortin II, and urocortin III, as well as CRH.

<span class="mw-page-title-main">CRHBP</span> Protein-coding gene in the species Homo sapiens

Corticotropin-releasing factor-binding protein is a protein that in humans is encoded by the CRHBP gene. It belongs to corticotropin-releasing hormone binding protein family.

<span class="mw-page-title-main">Antalarmin</span> Chemical compound

Antalarmin (CP-156,181) is a drug that acts as a CRH1 antagonist.

A Corticotropin-releasing hormone antagonist is a specific type of receptor antagonist that blocks the receptor sites for corticotropin-releasing hormone, also known as corticotropin-releasing factor (CRF), which synchronizes the behavioral, endocrine, autonomic, and immune responses to stress by controlling the hypothalamic-pituitary-adrenal axis. CRH antagonists thereby block the consequent secretions of ACTH and cortisol due to stress, among other effects.

Parvocellular neurosecretory cells are small neurons that produce hypothalamic releasing and inhibiting hormones. The cell bodies of these neurons are located in various nuclei of the hypothalamus or in closely related areas of the basal brain, mainly in the medial zone of the hypothalamus. All or most of the axons of the parvocellular neurosecretory cells project to the median eminence, at the base of the brain, where their nerve terminals release the hypothalamic hormones. These hormones are then immediately absorbed into the blood vessels of the hypothalamo-pituitary portal system, which carry them to the anterior pituitary gland, where they regulate the secretion of hormones into the systemic circulation.

Gonadotropin-inhibitory hormone (GnIH) is a RFamide-related peptide coded by the NPVF gene in mammals.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000049796 – Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 "Entrez Gene: CRH corticotropin releasing hormone".
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Further reading