Corticotropin-releasing hormone receptor 1 (CRHR1) is a protein, also known as CRF1, with the latter (CRF1) now being the IUPHAR-recommended name. [4] In humans, CRF1 is encoded by the CRHR1 gene at region 17q21.31, beside micrototubule-associated protein tau MAPT. [5] [6]
The human CRHR1 gene contains 14 exons over 20 kb of DNA, and its full gene product is a peptide composed of 444 amino acids. [7] Excision of exon 6 yields in the mRNA for the primary functional CRF1, [7] which is a peptide composed of 415 amino acids, arranged in seven hydrophobic alpha-helices. [8] [9]
The CRHR1 gene is alternatively spliced into a series of variants. [7] [10] These variants are generated through deletion of one of the 14 exons, which in some cases causes a frame-shift in the open reading frame, and encode corresponding isoforms of CRF1. [7] [9] Though these isoforms have not been identified in native tissues, the mutations of the splice variants of mRNA suggest the existence of alternate CRF receptors, with differences in intracellular loops or deletions in N-terminus or transmembrane domains. [9] Such structural changes suggest that the alternate CRF1 receptors have different degrees of capacity and efficiency in binding CRF and its agonists. [7] [9] [10] Though the functions of these CRF1 receptors is yet unknown, they are suspected to be biologically significant. [9]
CRF1 is 70% homologous with the second human CRF receptor family, CRF2; the greatest divergence between the two lies at the N-terminus of the protein. [7] [9]
CRF1 is activated through the binding of CRF or a CRF-agonist. [7] [8] [9] The ligand binding and subsequent receptor conformational change depends on three different sites in the second and third extracellular domains of CRF1. [9]
In the majority of tissues, CRF1 is coupled to a stimulatory G-protein that activates the adenylyl cyclase signaling pathway, and ligand-binding triggers an increase in cAMP levels. [7] [9] However, the signal can be transmitted along multiple signal transduction cascades, according to the structure of the receptor and the region of its expression. [9] Alternate signaling pathways activated by CRF1 include PKC and MAPK. [7] This wide variety of cascades suggests that CRF1 mediates tissue-specific responses to CRF and CRF-agonists. [7] [9]
CRF1 is expressed widely throughout both the central and peripheral nervous systems. [9] In the central nervous system, CRF1 is particularly found in the cortex, cerebellum, amygdala, hippocampus, olfactory bulb, ventral tegmental area, brainstem areas, paraventricular hypothalamus, and pituitary. [11] [7] [8] [12] In the pituitary, CRF1 stimulation triggers the activation of the POMC gene, which in turn causes the release of ACTH and β-endorphins from the anterior pituitary. [7] In the peripheral nervous system, CRF1 is expressed at low levels in a wide variety of tissues, including the skin, spleen, heart, liver, adipose tissue, placenta, ovary, testis, and adrenal gland. [7] [8] [10]
In CRF1 knockout mice, and mice treated with a CRF1 antagonist, there is a decrease in anxious behavior and a blunted stress response, suggesting that CRF1 mechanisms are anxiogenic. [7] [12] However, the effect of CRF1 appears to be regionally specific and cell-type specific, likely due to the wide variety of cascades and signaling pathways activated by the binding of CRF or CRF-agonists. [12] In mice, offspring born to CRF1 -/- knockout mothers typically die within a few days of birth from lung dysplasia, likely due to low glucocorticoid levels. [13] In the central nervous system, CRF1 activation mediates fear learning and consolidation in the extended amygdala, stress-related modulation of memory formation in the hippocampus, and brainstem regulation of arousal. [12]
The corticotropin-releasing hormone receptor binds corticotropin-releasing hormone, a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress. [14]
CRF1 receptors in mice mediate ethanol enhancement of GABAergic synaptic transmission. [15]
Postpartum CRF1 knockout mice spend less time nursing and less time licking and grooming their offspring than their wildtype counterparts during the first few days postpartum. [13] These pups weighed less as a result. This pattern of maternal behavior indicates that CRF1 may be needed for early postpartum mothers to display typical mothering behaviors. Maternal aggression is attenuated by increases in CRF and urocortin 2, which bind to CRF1. [16]
Corticotrophin releasing hormone (CRH) evolved ~ 500 million years ago in an organism that subsequently gave rise to both chordates and arthropods. [17] The binding site for this was single CRH like receptor. In vertebrates this gene was duplicated leading to the extant CRH1 and CRH2 forms. Additionally four paralogous ligands developed including CRH, urotensin-1/urocortin, urocortin II and urocortin III.
Variations in the CRHR1 gene is associated with enhanced response to inhaled corticosteroid therapy in asthma. [18]
CRF1 triggers cells to release hormones that are linked to stress and anxiety [original reference missing]. Hence CRF1 receptor antagonists are being actively studied as possible treatments for depression and anxiety. [19] [20]
Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn. [21]
Corticotropin-releasing hormone receptor 1 has been shown to interact with Corticotropin-releasing hormone [9] [22] and urocortin. [23]
Corticotropin-releasing hormone (CRH) 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. Its main function is the stimulation of the pituitary synthesis of adrenocorticotropic hormone (ACTH), as part of the hypothalamic–pituitary–adrenal 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.
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 2 (Ucn2) is an endogenous peptide in the corticotrophin-releasing factor (CRF) family.
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.
Corticotropin-releasing hormone receptors (CRHRs), also known as corticotropin-releasing factor receptors (CRFRs) are a G protein-coupled receptor family that binds corticotropin-releasing hormone (CRH). There are two receptors in the family, designated as type 1 and 2, each encoded by a separate gene.
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.
Interleukin 10 receptor, beta subunit is a subunit for the interleukin-10 receptor. IL10RB is its human gene.
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.
Urocortin-2 is a protein that in humans is encoded by the UCN2 gene.
Urocortin-3 is a protein that, in humans, is encoded by the UCN3 gene. It belongs to the corticotropin-releasing hormone family.
Antalarmin (CP-156,181) is a drug that acts as a CRH1 antagonist.
Pexacerfont (INN, previously known as BMS-562,086) is a drug developed by Bristol-Myers Squibb which acts as a CRF1 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.
Corticotropin-releasing hormone binding protein (CRH-BP) binds corticotropin-releasing hormone (CRH) and several related peptide hormones. It is an ancient, highly conserved protein whose origin predates the divergence of protostomes and deuterostomes.
Astressin-B is a nonselective corticotropin releasing hormone antagonist that reduces the synthesis of adrenocorticotropic hormone and cortisol.
Verucerfont (GSK-561,679) is a drug developed by GlaxoSmithKline which acts as a CRF-1 antagonist. Corticotropin releasing factor (CRF), also known as Corticotropin releasing hormone, is an endogenous peptide hormone which is released in response to various triggers such as chronic stress, and activates the two corticotropin-releasing hormone receptors CRH-1 and CRH-2. This then triggers the release of corticotropin (ACTH), another hormone which is involved in the physiological response to stress.
Sauvagine is a neuropeptide from the corticotropin-releasing factor (CRF) family of peptides and is orthologous to the mammalian hormone, urocortin 1, and the teleost fish hormone, urotensin 1. It is 40 amino acids in length, and has the sequence XGPPISIDLSLELLRKMIEIEKQEKEKQQAANNRLLLDTI-NH2, with a pyrrolidone carboxylic acid modification at the N-terminal and amidation of the C-terminal isoleucine residue. It was originally isolated from the skin of the frog Phyllomedusa sauvagii. Given its relation to other CRF-related peptides, it exerts similar physiological effects as corticotropin-releasing hormone.
Emicerfont (GW-876,008) is a drug developed by GlaxoSmithKline which acts as a CRF-1 antagonist. Corticotropin releasing factor (CRF), also known as Corticotropin releasing hormone, is an endogenous peptide hormone which is released in response to various triggers such as chronic stress, and activates the two corticotropin-releasing hormone receptors: CRF1 and CRF2. This then triggers the release of corticotropin (ACTH), another hormone which is involved in the physiological response to stress.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
