In Vitro Properties of a High Affinity Selective Antagonist of the VIP1 Receptor

Gourlet, Philippe; Neef, Philippe De; Cnudde, Johnny; Waelbroeck, Magali; Robberecht, Patrick

doi:10.1016/s0196-9781(97)00230-1

Cited by 170 publications

(98 citation statements)

References 25 publications

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“…Interestingly, VIP receptor desensitization did not affect the I sc response to capsaicin. Similarly, experiments with the VIP receptor antagonists VIP [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] (16) (14) did not affect the response to capsaicin. Indeed, in our preparations, these antagonists failed even to block the secretory response to serosally applied VIP (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves

MacNaughton

Sickle²,

Keenan³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves. Am J Physiol Gastrointest Liver Physiol 286: G863-G871, 2004. First published December 30, 2003 10.1152/ ajpgi.00482.2003.-We investigated the distribution and function of cannabinoid (CB)1 receptors in the submucosal plexus of the guinea pig ileum. CB 1 receptors were found on both types of submucosal secretomotor neurons, colocalizing with VIP and neuropeptide Y (NPY), the noncholinergic and cholinergic secretomotor neurons, respectively. CB1 receptors colocalized with transient receptor potential vanilloid-1 receptors on paravascular nerves and fibers in the submucosal plexus. In the submucosal ganglia, these nerves were preferentially localized at the periphery of the ganglia. In denervated ileal segments, CB1 receptor immunoreactivity in submucosal neurons was not modified, but paravascular and intraganglionic fiber staining was absent. Short-circuit current (I sc) was measured as an indicator of net electrogenic ion transport in Ussing chambers. In the ion-transport studies, I sc responses to capsaicin, which activates extrinsic primary afferents, and to electrical field stimulation (EFS) were reduced by pretreatment with the muscarinic antagonist atropine, abolished by tetrodotoxin, but were unaffected by VIP receptor desensitization, hexamethonium, ␣-amino-3-hydroxy-5-methlisoxazole-4-proprionic acid, or N-methyl-D-aspartate glutamate receptor antagonists. The responses to capsaicin and EFS were reduced by 47 Ϯ 12 and 30 Ϯ 14%, respectively, by the CB1 receptor agonist WIN 55,212-2. This inhibitory effect was blocked by the CB 1 receptor antagonist, SR 141716A. I sc responses to forskolin or carbachol, which act directly on the epithelium, were not affected by WIN 55,212-2. The inhibitory effect of WIN 55,212-2 on EFS-evoked secretion was not observed in extrinsically denervated segments of ileum. Taken together, these data show cannabinoids act at CB1 receptors on extrinsic primary afferent nerves, inhibiting the release of transmitters that act on cholinergic secretomotor pathways. submucosal plexus; vasoactive intestinal peptide; neuropeptide Y; transient receptor potential vanilloid-1 receptor THE ENTERIC NERVOUS SYSTEM exerts tight control over electrolyte and water transport by the intestinal epithelium (5, 7). Specifically, submucosal secretomotor neurons release vasoactive intestinal polypeptide and acetylcholine to activate cAMP-or Ca 2ϩ -dependent pathways, respectively, which control the gating of chloride transport through apically situated chloride transporters in enterocytes. The apically directed transport of chloride occurs predominantly via the cystic fibrosis transmembrane conductance regulator or a member of the calciumdependent chloride channel family (4). Whereas the intrinsic properties of these transporters have been, and continue to be, the subject of numerous studies, less well documented are the inputs that control the a...

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Section: Discussionmentioning

confidence: 99%

Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves

MacNaughton

Sickle²,

Keenan³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Table 5. Inhibitory effects of peptide analogs on the VIP-induced PRL release in the rat pituitary cell superfusion system increase VPAC 1 -R antagonistic potency, because their potent and selective VPAC 1 -R antagonist PG 97-269 contains these substitutions (29). Tyr 22 was expected to increase the binding to VPAC 2 receptors and confer enhanced VPAC 2 -R antagonistic activity to the analog, based on the published observations regarding the importance of an aromatic amino acid residue in position 22 for VPAC 2 -R agonists (35).…”

Section: Discussionmentioning

confidence: 99%

“…VIP was obtained from California Peptide Research (Napa, CA). Potent VPAC 1 -R selective antagonist (PG 97-269) was kindly provided by P. Gourlet and P. Robberecht (Université Libre de Bruxelles, Belgium) (29).…”

Section: Methodsmentioning

confidence: 99%

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Antagonistic actions of analogs related to growth hormone-releasing hormone (GHRH) on receptors for GHRH and vasoactive intestinal peptide on rat pituitary and pineal cells in vitro

Rékási¹,

Varga

Schally

et al. 2000

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

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Peptide analogs of growth hormone-releasing hormone (GHRH) can potentially interact with vasoactive intestinal peptide (VIP) receptors (VPAC1-R and VPAC2-R) because of the structural similarities of these two hormones and their receptors. We synthesized four new analogs related to GHRH (JV-1-50, JV-1-51, JV-1-52, and JV-1-53) with decreased GHRH antagonistic activity and increased VIP antagonistic potency. To characterize various peptide analogs for their antagonistic activity on receptors for GHRH and VIP, we developed assay systems based on superfusion of rat pituitary and pineal cells. Receptor-binding affinities of peptides to the membranes of these cells were also evaluated by radioligand competition assays. Previously reported GHRH antagonists JV-1-36, JV-1-38, and JV-1-42 proved to be selective for GHRH receptors, because they did not influence VIP-stimulated VPAC 2 receptordependent prolactin release from pituitary cells or VPAC 1 receptordependent cAMP efflux from pinealocytes but strongly inhibited GHRH-stimulated growth hormone (GH) release. Analogs JV-1-50, JV-1-51, and JV-1-52 showed various degrees of VPAC 1-R and VPAC 2-R antagonistic potency, although also preserving a substantial GHRH antagonistic effect. Analog JV-1-53 proved to be a highly potent VPAC 1 and VPAC2 receptor antagonist, devoid of inhibitory effects on GHRH-evoked GH release. The antagonistic activity of these peptide analogs on processes mediated by receptors for GHRH and VIP was consistent with the binding affinity. The analogs with antagonistic effects on different types of receptors expressed on tumor cells could be utilized for the development of new approaches to treatment of various human cancers.growth hormone-releasing hormone and vasoactive intestinal peptide antagonists ͉ structure-activity relationships ͉ cancer therapy

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“…Potent VIP antagonist PG 97-269 was provided by P. Gourlet and P. Robberecht (33). Na 125 I and 125 I-VIP were purchased from Amersham Pharmacia Biotech.…”

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confidence: 99%

Human renal cell carcinoma expresses distinct binding sites for growth hormone-releasing hormone

Halmos

Schally

Varga

et al. 2000

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

114

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were initially developed to block growth hormone (GH) secretion from the pituitary glands, leading to inhibition of insulin-like growth factor I (IGF-I) production in the liver and other tissues (1-6). The reduction in the levels of serum IGF-I could inhibit the proliferation of various cancers dependent on IGF-I, in view of involvement of this growth factor and of IGF-II, which is GH independent, in malignant transformation of cells, tumor progression, and metastasis (1-3). GHRH antagonists were shown to effectively inhibit the in vivo growth of various experimental human cancers, including osteosarcomas, mammary, ovarian and prostatic cancers, renal adenocarcinomas, small-cell lung cancer (SCLC) and non-SCLC, pancreatic and colorectal carcinomas, and malignant gliomas (7-17). The proliferation of some of these human cancers in vitro was also suppressed by GHRH antagonists (7-10, 12-14, 16-18). This finding and the reduction in the concentration of IGF-I and IGF-II and the suppression of the gene expression of IGF-I and -II in the tumors suggested that GHRH antagonists, in addition to indirect action mediated by inhibition of GH-IGF-I axis, might exert direct effects on tumor growth through specific yet-to-be-identified GHRH receptors (3,19).The GHRH receptor is a G-protein-coupled transmembrane receptor found predominantly in the pituitary gland, and its mRNA has also been detected in rat placenta, kidney, testis, hypothalamus, and the gastrointestinal tract (20-23). Receptors for other GHRH-related peptides, such as vasoactive intestinal peptide (VIP) and secretin, also belong to the G-protein-linked superfamily and show homology to GHRH receptor proteins (23). Although VIP receptors have been detected in various tumors and could be involved in the regulation of tumor growth (21,(24)(25)(26), recent work showed that the antiproliferative effect of GHRH antagonists is exerted through a mechanism independent of VIP receptors (27). When primers for human GHRH (hGHRH) receptor mRNA were used (27), no expression of mRNA was found in LNCaP human prostatic and MiaPaCa-2 human pancreatic cancer cells (27), in accordance with an earlier report on ovarian tumors (28). In addition, specific binding sites for radioligand [His 1 , 125 I-Tyr 10 ,Nle 27 ]hGHRH(1-32)NH 2 could not be detected in human cancers (14,17,27), although this radioligand is widely used for the characterization of pituitary GHRH receptors (29-31). These observations indicate that peptide receptors on human tumors that respond to our GHRH antagonists should be different from the classic pituitary-type GHRH receptors.In this study, we report the presence of high-affinity binding sites for GHRH antagonists on CAKI-1 human renal cell carcinoma (RCC). The binding characteristics were investigated by ligand competition assays, using 125 I-labeled GHRH antagonist JV-1-42 as a specific radioligand. These binding sites appear to be isoforms of hGHRH receptor, as demonstrated by reverse transcription (RT)-PCR, and are also distinct from the VIP receptors. In a...

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In Vitro Properties of a High Affinity Selective Antagonist of the VIP1 Receptor

Cited by 170 publications

References 25 publications

Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves

Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves

Antagonistic actions of analogs related to growth hormone-releasing hormone (GHRH) on receptors for GHRH and vasoactive intestinal peptide on rat pituitary and pineal cells in vitro

Human renal cell carcinoma expresses distinct binding sites for growth hormone-releasing hormone

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