Trends in Endocrinology & Metabolism
ReviewFunctional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists
Section snippets
The family of CRH-related neuropeptides and their receptors
Over the past few years, the number of identified members of the CRH-related family of peptides, which includes the mammalian peptides CRH, urocortin (Ucn), urocortin II (Ucn II) and urocortin III (Ucn III), as well as fish urotensin I and frog sauvagine, has expanded rapidly 9., 10., 11., 12., 13.. It is now becoming clear that these peptides stem from an ancestral peptide precursor [14]. They are differentially distributed in the brain and periphery, and appear to be involved in an array of
Structural characteristics
The CRH receptors belong to the class II G-protein-coupled receptor superfamily, which includes receptors for parathyroid hormone (PTH), calcitonin, pituitary adenylate-cyclase-activating peptide (PACAP), growth-hormone-releasing hormone (GHRH), glucagon, glucagon-like peptide (GLP), and secretin. The CRH receptor type 1α (CRH-R1α) is a 415-amino acid protein, containing seven hydrophobic α-helices that are predicted to span the plasma membrane. CRH-R1α is widespread both within the central
G-protein coupling and second messengers
In most, but not all, tissues, stimulation of either CRH-R1 or CRH-R2 by CRH and CRH-related peptides triggers activation of adenylyl cyclase and increases cAMP levels 38., 39.. In studies using receptor overexpression in transfection systems, it has been confirmed that CRH receptors are primarily coupled to the Gs–adenylyl cyclase signaling pathway. However, in certain tissues, CRH is unable to activate this pathway, although it can activate alternative signaling cascades 40., 41.. For
Experimental and clinical uses of CRH receptor antagonists
The multifaceted actions of CRH and related peptides predict many potential uses of small molecular weight CRH-R1 and CRH-R2 antagonists that could cross the blood–brain and placental barriers and could be taken orally (Box 1). Furthermore, such compounds could be modified appropriately to allow brain function in physiological and disease states to be studied by positron emission tomography (PET) and single photon emission computerized tomogaphy (SPECT) scanning 60., 61..
CRH-R1 antagonists
The anxiogenic and possibly depressogenic actions of CRH, primarily via CRH-R1, suggest that CRH-R1 antagonists might be useful for the treatment of chronic anxiety disorder and melancholic depression [62]. Indeed, non-peptidic CRH-R1 antagonists have been tested in rat models of conditioned fear responses. One of these antagonists, antalamin [63], prevented both the establishment of fear and the expression of already established fear in these animals [64]. In rhesus monkeys, the same
CRH-R2 antagonists
In considering the potential uses of non-peptidic CRH-R2 antagonists one must be cautious, because experimental data using such antagonists are not available and species-specificities in the cardiovascular actions of Ucn have been noted. CRH-related peptides acting on CRH-R2 could, in theory, reduce stress (CRH)-induced suppression of appetite, stimulate hypothalamic CRH secretion by interrupting putative CRH-R2-mediated auto-inhibition of CRH, and block CRH-R2-mediated peripheral
Conclusions
There is little doubt that CRH and CRH-related peptides, and their receptors, form an important physiological system, influencing a wide spectrum of behavioral, cardiovascular, metabolic and immune mechanisms that allow mammals to adapt under both basal and stressful conditions. The presence of multiple CRH-related peptides and CRH receptors, capable of activating diverse signaling mechanisms in different tissues, gives this system enormous versatility and plasticity. The development of
References (84)
Neuroendocrinology of stress
Endocrinol. Metab. Clin. North Am.
(2001)- et al.
Corticotropin-releasing factor antagonists, binding-protein and receptors: implications for central nervous system disorders
Baillieres Best Pract. Res. Clin. Endocrinol. Metab.
(1999) - et al.
Role of corticotropin-releasing hormone in onset of labour
Lancet
(1999) - et al.
Evolution and physiology of the corticotropin-releasing factor (CRF) family of neuropeptides in vertebrates
Gen. Comp. Endocrinol.
(1999) A variant the human corticotropin-releasing factor (CRF) receptor: cloning, expression and pharmacology
Biochem. Biophys. Res. Commun.
(1994)A new functional isoform of the human CRF2 receptor for corticotropin-releasing factor
Biochim. Biophys. Acta
(1997)Cloning and characterization of a short variant of the corticotropin-releasing factor receptor subtype from rat amygdala
Biochem. Biophys. Res. Commun.
(1999)The human myometrial CRH receptor: G proteins and second messengers
Mol. Cell. Endocrinol.
(1994)A novel mechanism of action of corticotropin releasing factor in rat Leydig cells
J. Biol. Chem.
(1990)Corticotropin-releasing hormone (CRH) induces Fas ligand production and apoptosis in PC12 cells via activation of p38 MAPK
J. Biol. Chem.
(2002)
Corticotropin-releasing factor-like peptides increase cytosolic [Ca2+] in human epidermoid A-431 cells
Eur. J. Pharmacol.
Influence of corticotrophin releasing factor on neuronal cell death in vitro and in vivo
Brain Res.
Synthesis and biological activity of fluoro-substituted pyrrolo [2,3-d] pyrimidines: the development of potential positron emission tomography imaging agents for corticotropin-releasing hormone type 1 receptor
Bioorg. Med. Chem. Lett.
The development of a potential single photon emission computed tomography (SPECT) imaging agent for the corticotropin-releasing hormone receptor type 1
Bioorg. Med. Chem. Lett.
CRF-induced seizures and behavior: interaction with amygdala kindling
Brain Res.
Corticotropin-releasing hormone in human pregnancy and parturition
Trends Endocrinol. Metab.
Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and β-endorphin
Science
Corticotropin-releasing hormone and inflammation
Ann. New York Acad. Sci.
Stress and the gastrointestinal tract III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors
Am. J. Physiol. Gastrointest. Liver Physiol.
The role of corticotropin-releasing factor in drug addiction
Pharmacol. Rev.
The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes
Int. J. Obes. Relat. Metab. Disord.
Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor
Nature
Complete amino acid sequence of urotensin I, a hypotensive and corticotropin-releasing neuropeptide from Catostomus
Science
Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors
Proc. Natl. Acad. Sci. U. S. A.
Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor
Proc. Natl. Acad. Sci. U. S. A.
Human stesscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor
Nat. Med.
Corticotropin-releasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes
Proc. Natl. Acad. Sci. U. S. A.
Corticotropin-releasing factor receptor 2 is a tonic suppressor of vascularization
Proc. Natl. Acad. Sci. U. S. A.
Cloning and characterization of the cDNAs for human and rat corticotropin releasing factor-binding proteins
Nature
A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: implications for the design of agonists and antagonists
Proc. Natl. Acad. Sci. U. S. A.
Expression cloning of a human corticotropin-releasing-factor receptor
Proc. Natl. Acad. Sci. U. S. A.
A novel spliced variant of the type 1 corticotropin-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes
Mol. Endocrinol.
Alternative splicing of CRH-R1 receptors in human and mouse skin: identification of new variants and their differential expression
FASEB J.
Cloning and characterization of the human corticotropin-releasing factor-2 receptor complementary deoxyribonucleic acid
Endocrinology
Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: the CRF2γ receptor
Mol. Endocrinol.
CRF2α and CRF2β receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues
Endocrinology
Characterization of three corticotropin-releasing factor receptors in catfish: a novel third receptor is predominantly expressed in pituitary and urophysis
Endocrinology
Localization of ligand-binding domains of human corticotropin-releasing factor receptor: a chimeric receptor approach
Mol. Endocrinol.
The first extracellular domain of corticotropin releasing factor-R1 contains major binding determinants for urocortin and astressin
Endocrinology
Identification of amino acids in the N-terminal domain of corticotropin-releasing factor receptor 1 that are important determinants of high-affinity ligand binding
J. Neurochem.
Localization of agonist- and antagonist-binding domains of human corticotropin-releasing factor receptors
Mol. Endocrinol.
Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1
Nat. Genet.
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