Corticotropin-releasing hormone receptor 1

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.[8] Excision of exon 6 yields in the mRNA for the primary functional CRF₁,[8] which is a peptide composed of 415 amino acids, arranged in seven hydrophobic alpha-helices.[9][10]

The CRHR1 gene is alternatively spliced into a series of variants.[8][11] 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.[8][10] 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.[10] Such structural changes suggest that the alternate CRF₁ receptors have different degrees of capacity and efficiency in binding CRF and its agonists.[8][10][11] Though the functions of these CRF₁ receptors is yet unknown, they are suspected to be biologically significant.[10]

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.[8][10]

CRF₁ is activated through the binding of CRF or a CRF-agonist.[8][9][10] The ligand binding and subsequent receptor conformational change depends on three different sites in the second and third extracellular domains of CRF₁.[10]

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.[8][10] However, the signal can be transmitted along multiple signal transduction cascades, according to the structure of the receptor and the region of its expression.[10] Alternate signaling pathways activated by CRF₁ include PKC and MAPK.[8] This wide variety of cascades suggests that CRF₁ mediates tissue-specific responses to CRF and CRF-agonists.[8][10]

CRF₁ is expressed widely throughout both the central and peripheral nervous systems.[10] 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.[12][8][9][13] 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.[8] 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.[8][9][11]

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.[8][13] However, the effect of CRF₁appears 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.[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.[13]

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]

Corticotrophin releasing hormone (CRH) evolved ~500 million years ago in an organism that subsequently gave rise to both chordates and arthropods.[16] 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.[17]

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.[18][19]

Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn.[20]

Corticotropin-releasing hormone receptor 1 has been shown to interact with Corticotropin-releasing hormone[10][21] and urocortin.[22]

• Corticotropin-releasing hormone
• Corticotropin-releasing hormone receptor
• Corticotropin-releasing hormone antagonist
• Antalarmin
• Pexacerfont
• Verucerfont

• "Corticotropin-releasing Factor Receptors: CRF₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Corticotropin-releasing+hormone+receptors at the US National Library of Medicine Medical Subject Headings (MeSH)
• CRF+receptor+type+1 at the US National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P34998 (Corticotropin-releasing factor receptor 1) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.