Review
Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists

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Abstract

Corticotropin-releasing hormone (CRH) plays a major role in coordinating the behavioral, endocrine, autonomic and immune responses to stress. CRH and CRH-related peptides and their receptors are present in the central nervous system and in a wide variety of peripheral tissues, including the immune, cardiovascular and reproductive systems, and have been associated with the pathophysiology of many disease states. These observations have led to the development of several CRH receptor type-selective antagonists, which have been used experimentally to elucidate the role of CRH and related peptides in physiological and disease processes, such as anxiety and depression, sleep disorders, addictive behavior, inflammatory and allergic disorders, neurological diseases and pre-term labor. Because of the complex network of multiple CRH receptor subtypes and their tissue- and agonist-specific signaling diversity, antagonists need to be developed that can target specific CRH receptor isoform-driven signaling pathways.

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

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      Citation Excerpt :

      Both CRFR1 and CRFR2 signal by coupling to G proteins which include Gs, Gq, Gi, Go, Gi1/2 and Gz. Different G proteins binding to different CRF related peptides activated receptors activate distinct signal pathways including adenylyl cyclase - cyclic AMP - protein kinase A pathway, phospholipase C - 1,2-diacylglycerol - protein kinase C pathway, phospholipase C - inositol (1,4,5)-trisphosphate (IP3) - Ca2+ pathway, extracellular signal regulated kinase - mitogen activated protein kinase pathway and other pathways, and subsequent downstream events including gene transcription and intracellular Ca2+ mobilization (Dautzenberg and Hauger, 2002; Grammatopoulos and Chrousos, 2002; Henckens et al., 2016; Hillhouse and Grammatopoulos, 2006; Waters et al., 2015). Thus, the effects of CRF related peptides may be regulated through interaction with different types of CRF related peptides receptors and depend on CRF related peptides receptors localization and cellular context.

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