Molecular Properties of the CRF Receptor

Spiess, Joachim; Dautzenberg, Frank M.; Sydow, Sabine; Hauger, Richard L.; Rühmann, Andreas; Blank, Thomas; Radulovic, Jelena

doi:10.1016/s1043-2760(98)00037-x

Cited by 46 publications

(42 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The fact that urocortin, an agonist, binds to bNT-CRFR1 is consistent with the observation that urocortin displays some antagonist binding characteristics. For example, guanyl nucleotides do not modulate the binding of urocortin to the wild type receptor (19,48), as they do the binding of CRF (49). In addition, ligands like sauvagine and CRF may require other extracellular or transmembrane domains for their high affinity binding.…”

Section: Discussionmentioning

confidence: 99%

Expression, Purification, and Characterization of a Soluble Form of the First Extracellular Domain of the Human Type 1 Corticotropin Releasing Factor Receptor

Perrin¹,

Fischer²,

Kunitake³

et al. 2001

Journal of Biological Chemistry

108

View full text Add to dashboard Cite

Corticotropin releasing factor (CRF), 1 a 41-amino acid peptide, was identified initially on the basis of its primary role in the activation of the hypothalamic-pituitary-adrenal in response to stress. The CRF family of ligands includes sauvagine from frog and urotensin from fish as well as the additional mammalian family members, urocortin (1, 2), urocortin II (3, 4), and urocortin III (4, 5). Broader roles for CRF and its ligand family now involve effects on the cardiovascular, reproductive, gastrointestinal, immune, and central nervous systems (6 -8).The action of CRF and related ligands is initiated by binding to their receptors, which transduce an increase in intracellular cAMP. Thus far, two receptors, CRFR1 and CRFR2, have been cloned in mammals (9 -15). Homologous receptors have been identified in chicken (16), fish (17), and Xenopus (18) and a third receptor, CRFR3, with high levels of sequence identity to CRFR1, has recently been cloned in catfish (17). Both CRFR1 and CRFR2 exist as multiple splice variants and belong to the type B 7-transmembrane receptor family that includes receptors for growth hormone releasing factor, secretin, calcitonin, vasoactive intestinal peptide, glucagon, glucagon-like peptide, and parathyroid hormone (PTH). Receptors for the CRF ligand family have been characterized in the central nervous system, pituitary, gastrointestinal tract, epididymis, heart, gonads, and adrenals (6).The affinities of CRF and urocortin in binding to CRFR1 are nearly the same but in binding to CRFR2, urocortin is ϳ10 times more potent than CRF (19). Both urocortins II and III are highly selective in binding and activating CRFR2 compared with CRFR1 (4, 5). A synthetic peptide antagonist, astressin, binds with equally high affinity to CRFR1 and CRFR2 (19,20).The CRF receptor family consists of proteins with a relatively large first extracellular domain (ECD-1). Mutagenesis studies have identified regions of the CRF receptors that are implicated in differential recognition of agonists and antagonists, as well as in governing the ligand selectivity of the two types of receptors (21-25). We showed that a chimeric receptor in which the ECD-1 of CRFR1 replaced the ECD of the activin receptor, a single transmembrane receptor kinase (26), was capable of high affinity binding to both astressin and urocortin (21). The mode of receptor activation was explored by our study of a tethered peptide-receptor chimera in which the first 16 amino acids of CRF were substituted for the ECD-1 of CRFR1 (CRF (1-16)/R1 ⌬N ) (27). This chimera displayed continual signaling suggesting that the N-terminal third of CRF, when presented in proximity to the receptor, is able to cause activation.Biochemical characterizations of soluble ECD-1s include those of receptors for follicle stimulating hormone (28), luteinizing hormone/human chorionic gonadotropin (29), calcium (30), PTH (31), glucagon-like peptide-1 (32), and glutamate (33). The ECD-1 of the metabotropic glutamate receptor has

show abstract

Section: Discussionmentioning

confidence: 99%

Expression, Purification, and Characterization of a Soluble Form of the First Extracellular Domain of the Human Type 1 Corticotropin Releasing Factor Receptor

Perrin¹,

Fischer²,

Kunitake³

et al. 2001

Journal of Biological Chemistry

108

View full text Add to dashboard Cite

show abstract

“…[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%

“…The TMD and ICD regions have greater than 80% homology, while the third IC loop is identical between all CRH receptors and is responsible for the G-protein interaction, as highlighted in Fig (1). [5,7,20] CRHR 1 Primarily found in the brain, [5,6,11,12] CRHR 1 is composed of 415 amino acids (α splice variant). It has 8 variants; α, β, c, d, e, f, g, h, however α is believed to be the only active form.…”

Section: Crh Receptor (Crhr)mentioning

confidence: 99%

“…It has 8 variants; α, β, c, d, e, f, g, h, however α is believed to be the only active form. [20,23] From mutant and chimera studies of CRHR 1 , it has been shown that the N-terminus controls peptide ligand binding to the receptor [7,11,24] by binding to the C-terminus of the ligand. The ECD1 and 3 and the ECD2-TMD5 junction are also believed to be involved in binding.…”

Section: Crh Receptor (Crhr)mentioning

confidence: 99%

See 1 more Smart Citation

Corticotropin Releasing Hormone - A GPCR Drug Target

Hemley

McCluskey²,

Keller³

2007

CDT

View full text Add to dashboard Cite

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.

show abstract

“…It exhibits its biologic actions through G protein-dependent receptors. To date, mainly two subtypes of CRF receptors (CRFRs) (5,6), CRFR1 and CRFR2, have been identified. The central actions of CRF-like peptides are also modulated by the water-soluble CRF binding protein (CRFBP) (7,8).…”

mentioning

confidence: 99%

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

Eckart

Jahn

Radulovic

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

In view of the observation that corticotropin-releasing factor (CRF) affects several brain functions through at least two subtypes of G protein-dependent receptors and a binding protein (CRFBP), we have developed synthetic strategies to provide enhanced binding specificity. Human͞rat CRF (h͞rCRF) and the CRF-like peptide sauvagine (Svg), differing in their affinities to CRFBP by two orders of magnitude, were used to identify the residues determining binding to CRFBP. By amino acid exchanges, it was found that Ala 22 of h͞rCRF was responsible for this peptide's high affinity to CRFBP, whereas Glu 21 located in the equivalent position of Svg prevented high affinity binding to CRFBP. Accordingly, [Glu 22 ]h͞rCRF was not bound with high affinity to CRFBP in contrast to [Ala 21 ]Svg, which exhibited such high affinity. Furthermore, the affinity of both peptides to either CRF receptor (CRFR) subtype was not reduced by these replacements, and their subtype preference was not changed. Thus, exchange of Ala and Glu and vice versa in positions 22 and 21 of h͞rCRF and Svg, respectively, serves as a switch discriminating between CRFBP and CRFR. On the basis of this switch function, development of new specific CRF agonists and antagonists is expected to be facilitated. One application was the modification of the CRF antagonist astressin (Ast), whose employment in animal experiments is limited by its low solubility in cerebrospinal fluid. Introduction of Glu residues into Ast generated with [Glu 11,16 ]Ast an acidic astressin, which efficiently antagonized in vivo the CRFR1-dependent reduction of locomotion induced by ovine CRF without detectable binding to CRFBP.

show abstract

Molecular Properties of the CRF Receptor

Cited by 46 publications

References 46 publications

Expression, Purification, and Characterization of a Soluble Form of the First Extracellular Domain of the Human Type 1 Corticotropin Releasing Factor Receptor

Expression, Purification, and Characterization of a Soluble Form of the First Extracellular Domain of the Human Type 1 Corticotropin Releasing Factor Receptor

Corticotropin Releasing Hormone - A GPCR Drug Target

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

Contact Info

Product

Resources

About