Corticotropin-releasing hormone receptors

Hillhouse, E. W.; Randeva, Harpal S.; Ladds, Graham; Grammatopoulos, Dimitris K.

doi:10.1042/bst0300428

Cited by 55 publications

(44 citation statements)

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“…The most abundant and prevalent receptor forms are glycosylated that have high molecular weight (mw) (60-70 kD), although a 55 kD form has been found in normal melanocytes and in selected cancer and melanoma lines (22). Exposure of skin cells to CRH or related peptides results in the rapid activation of the CRH-R1alpha receptor, coupling to G alpha s followed by cAMP synthesis or coupling to G alpha q with activation of IP 3 signaling (6,22,23), similarly to other systems (1,2). Ligand activation of CRH-R1alpha in skin cells also induces Ca 2+ influx (24); this requires opening of voltage-activated Ca 2+ ion channels separate from the cyclic nucleotide-gated ion channels (25).…”

Section: Membrane Bound Receptorsmentioning

confidence: 99%

“…In humans the gene coding for CRH-R1 generate at least 7 alternatively spliced CRH-R1 transcripts (1,2,6,15,16); it contains 14 exons with exon 6 being unique in that it is only present in CRH-R1beta (that contains all 14 exons). In the main functional isoform, CRH-R1alpha, exon 6 is spliced out; in other isoforms there are additional splicing sites, for example, CRHR1c (exon 3 is spliced out), CRH-R1d (exons 13 is absent), CRH-R1e (exons 3, 4 are absent, which cause frame shift and early stop codon in exon 8), CRH-R1f (exon 12 is absent resulting in frame shift), CRH-R1g (exons 11, 27 bp of exon 10 and 28 bp of exon 12 are absent), and CRH-R1h (insertion of cryptic exon between exons 4 and 5 cause frame shift and early termination codon in exon 5).…”

Section: Alternatively Spliced Crh-rs Isoforms: An Overviewmentioning

confidence: 99%

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Corticotropin releasing hormone and the skin

Słomiński¹

2006

Front Biosci

139

228

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Cotricotropin-releasing hormone (CRH) and related peptides are produced in skin that is dependent on species and anatomical location. Local peptide production is regulated by ultraviolet radiation (UVR), glucocorticoids and phase of the hair cycle. The skin also expresses the corresponding receptors (CRH-R1 and CRH-R2), with CRH-R1 being the major receptor in humans. CRH-R1 is expressed in epidermal and dermal compartments, and CRH-R2 predominantly in dermal structures. The gene coding for CRH-R1 generates multiple isoforms through a process modulated by UVR, cyclic adenosine monophosphate (cAMP) and phorbol 12-myristate 13-acetate. The phenotypic effects of CRH in human skin cells are largely mediated by CRH-R1alpha through increases in concentrations of cAMP, inositol triphosphate (IP 3 ), or Ca 2+ with subsequent activation of protein kinases A (PKA) and C (PKC) dependent pathways. CRH also modulates the activity of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kappaB), activator protein 1 (AP-1) and cAMP responsive element binding protein (CREB). The cellular functions affected by CRH depend on cell type and nutritional status and include modulation of differentiation program(s), proliferation, viability and immune activity. The accumulated evidence indicates that cutaneous CRH is also a component of a local structure organized similarly to the hypothalamo-pituitary-adrenal axis. KeywordsHuman Skin; Hormone; Corticotropin; CRH; CRH-R1; CRH-R2; Urocortin; Review INTRODUCTIONCRH is the central trigger of HPA axis, and together with related peptides urocortin I-III also regulate behavioral, autonomic, endocrine, reproductive, cardiovascular, gastro-intestinal, metabolic and immune systemic functions (1-11). Other actions include local immunomodulatory (predominantly proinflammatory) effects (12)(13)(14), differing from a central immunosuppressive activity (through the HPA axis) (3). Of note, locally produced CRH can directly regulate steroid hormone production by adrenals and gonads (1,2). Furthermore, CRH in the immune cells can induce production and release of proopiomelanocortin (POMC) derived adrenocorticotropin (ACTH) and beta-endorphin peptides. NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2007 April 2. Published in final edited form as:Front Biosci. ; 11: 2230-2248. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn vertebrates these peptides interact with membrane-bound CRH-R1 and CRH-R2 (1,2). Both receptor types belong to the group II subfamily of G protein-coupled receptors (GPCRs). CRH-R1 binds CRH and urocortin I with high affinity; it does not bind urocortin II (strescopin related protein). CRH-R2 shows preferential affinity for urocortin II, although it also binds CRH, however, with lower affinity than CRH-R1. Signal transduction through CRH-Rs is coupled to the activation of adenylate cyclase (AC), phospholipase C (PLC) and calcium channels (1, 2,5,6). ALTERNATIVELY SPLICED CRH-RS ISOFORMS: AN OVER...

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Section: Membrane Bound Receptorsmentioning

confidence: 99%

Section: Alternatively Spliced Crh-rs Isoforms: An Overviewmentioning

confidence: 99%

Corticotropin releasing hormone and the skin

Słomiński¹

2006

Front Biosci

139

228

View full text Add to dashboard Cite

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“…[5][6][7][8][9][10] It is a 41 amino acid polypeptide (Fig. 1a), [5][6][7][8][9][10][11][12][13][14] formed from the 196 amino acid CRH precursor by the cleavage of the C-terminus. [5] The CRH peptide can be segmented into three functional parts as shown in Fig.…”

Section: Crhmentioning

confidence: 99%

“…CRH has wide distribution throughout the CNS and periphery, including the reproductive system. [9,10,12] CRH is the key regulator of the hypothalamus-pituitary-adrenal (HPA) axis. [6,8,9,13] The HPA axis influences a multitude of vital bodily functions, the driving force being the variety of stress responses.…”

Section: Crhmentioning

confidence: 99%

Corticotropin Releasing Hormone - A GPCR Drug Target

Hemley

McCluskey²,

Keller³

2007

CDT

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Corticotrophin Releasing Hormone (CRH) is a primary hormone in the fight or flight response targeting a membrane bound G-protein coupled receptor (GPCR). Many people worldwide stand to benefit by the development of CRH agonists and antagonists for the treatment of anxiety and depression, with additional therapeutic targets including Alzheimer's, pain and the prevention of premature birth: so why the delay in development? In this review, we will discuss not only CRH, related proteins, receptors and ligands, but some of the obstacles that have arisen, as well as strategies being pursued to overcome these problems in the pursuit of this GPCR targeted therapeutic. Several key proteins influence the complex and intrinsic regulation of CRH, including its receptors (CRHR), of which 3 types have been categorised, CRHR1, CRHR2, CRHR3, each containing active and inactive splice variants. Additionally, the CRH binding protein (CRHBP) is believed to moderate the effects of CRH at the receptor, whether it is as a molecular mop, or a delivery vessel, or both, is still being investigated. Homology based receptor modelling is a technique that has only recently become available with the crystallisation of bovine rhodopsin (a GPCR), [1] and the application of this technique to the CRH receptors is still in the early stages of development. Therefore, the medicinal chemist has previously had to rely on ligand-based strategies, specifically, the development of pharmacophores. Thus, an extensive number of both CRH peptide analogues and small ligands that show nanomolar antagonism have been developed with SAR libraries being integral to the iterative drug design process. Alzheimer's, pain and the prevention of premature birth: so why the delay in development? In this review, we will discuss not only CRH, related proteins, receptors and ligands, but some of the obstacles that have arisen, as well as strategies being pursued to overcome these problems in the pursuit of this GPCR targeted therapeutic.Several key proteins influence the complex and intrinsic regulation of CRH, including its receptors (CRHR), of which 3 types have been categorised, CRHR 1 , CRHR 2 , CRHR 3, each containing active and inactive splice variants. Additionally, the CRH binding protein (CRHBP) is believed to moderate the effects of CRH at the receptor, whether it is as a molecular mop, or a delivery vessel, or both, is still being investigated.Homology based receptor modelling is a technique that has only recently become available with the crystallisation of bovine rhodopsin (a GPCR), [1] and the application of this technique to the CRH receptors is still in the early stages of development. Therefore, the medicinal chemist has previously had to rely on ligand-based strategies, specifically, the development of pharmacophores. Thus, an extensive number of both CRH peptide analogues and small ligands that show nanomolar antagonism have been developed with SAR libraries being integral to the iterative drug design process.

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“…Furthermore, CRH in the immune cells can induce production and release of POMC derived ACTH and betaendorphin peptides. In vertebrates these peptides interact with membrane-bound CRH-R1 and CRH-R2 (Hillhouse et al, 2002). Both receptor types belong to the group II subfamily of G protein-coupled receptors (GPCRs).…”

Section: Hpa Axis and Crh: Response To Local Stressmentioning

confidence: 99%