DOCSLIB.ORG

Neurotensin Receptor 1 Antagonist SR48692 Improves Response To

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Neurotensin Receptor 1 Antagonist SR48692 Improves Response To Published OnlineFirst August 8, 2017; DOI: 10.1158/1078-0432.CCR-17-0861 Cancer Therapy: Preclinical Clinical Cancer Research Neurotensin Receptor 1 Antagonist SR48692 Improves Response to Carboplatin by Enhancing Apoptosis and Inhibiting Drug Efflux in Ovarian Cancer Jin Liu1, Mikael€ Agopiantz2,3,Joel€ Poupon4, Zherui Wu1, Pierre-Alexandre Just5, Bruno Borghese6, Evelyne Segal-Bendirdjian 1, Guillaume Gauchotte3,7, Anne Gompel1,8, and Patricia Forgez1 Abstract Purpose: The high affinity receptor 1 (NTSR1) and its agonist, Results: SR48692 enhanced the response to carboplatin in neurotensin (NTS), are correlated with tumor cell aggressiveness ovarian cancer cells and experimental tumors. When SR48692 in most solid tumors. As chemoresistance and tumor aggres- is combined with carboplatin, we noted a major improvement siveness are often related, we decided to study the role of the of platinum-induced DNA damage and cell death, as well as a NTSR1 complex within platinum-based chemotherapy responses. decrease in tumor growth. The relationship of these results In an ovarian model, we studied carboplatin because it is the main to clinical studies was made by the detection of NTS and standard of care for ovarian cancer. NTSR1 in 72% and 74% of ovarian cancer, respectively. Fur- Experimental Design: Experimental tumors and in vitro studies thermore, in a large series of high-grade ovarian cancer, NTSR1 were performed using SKOV3 and A2780 cells treated with mRNA was shown to correlate with higher stages and platinum carboplatin, with or without a very specific NTSR1 antagonist, resistance. SR48692. We measured the effects of these treatments on cell Conclusions: This study strongly suggests that the addition apoptosis and apoptosis-related proteins, platinum accumula- of NTSR1 inhibitor in combination with platinum salt–based tion in the cell and nucleus, and the expression and localization of therapy will improve the response to the drug. Clin Cancer Res; platinum transporters. NTS and NTSR1 labeling was measured in 23(21); 6516–28. Ó2017 AACR. patients with ovarian cancer. Introduction obvious specific symptoms, the majority of females with ovarian cancer are diagnosed at advanced stages, and the 5-year survival Ovarian cancer is the seventh most common cancer in the rate is 46.2% (2). Consequently, ovarian cancer is one of the most world and the eighth most frequent cause of cancer-related death lethal gynecologic malignancies in women. among women (1). In the United States, 22,280 new cases and The standard treatment for advanced ovarian cancer patients is 14,270 deaths were estimated for 2016. This represents about primarily debulking surgery and platinum-based chemotherapy 2.4% of all cancer-related deaths. Because this disease has no combined with taxane (3, 4). The combination of carboplatin plus paclitaxel results in a complete response rate in 40% to 60% of the cases. However, more than 90% of these patients relapse 1 2 INSERM UMRS 1007, Paris Descartes University, Paris, France. Department after 2 years, and patients with recurrence become incurable due œ of Medical Gynecology, CHRU Nancy, University of Lorraine, Vand uvre to the development of chemoresistance (5). Ovarian cancer -les-Nancy, France. 3INSERM U 954, Faculty of Medicine, University of Lorraine, Vandœuvre-les-Nancy, France. 4Toxicology Laboratory, Lariboisiere Hospital, remains a real clinical challenge, and despite the development AP-HP, Paris, France. 5Department of Pathology, Paris Descartes University, of new therapeutic strategies, there is an urgent need to optimize AP-HP, HUPC, Paris, France. 6Department of Gynecology Obstetrics II and the current treatment. To this regard, we suggest the use of Reproductive Medicine, Paris Descartes University, AP-HP, Paris, France. neurotensin blockage to improve the sensitivity to platinum- 7 Department of Pathology, CHRU Nancy, University of Lorraine, France. based chemotherapy. 8 Department of Gynecological Endocrinology, Paris Descartes University, APHP, Neurotensin (NTS) is a 13-amino acid peptide acting as a HUPC, Paris, France. neurotransmitter in the central nervous system and local hor- Note: Supplementary data for this article are available at Clinical Cancer mone in gastrointestinal tract (6). NTS activates three subtypes of Research Online (http://clincancerres.aacrjournals.org/). receptors. NTSR1 and NTSR2 belong to G-protein–coupled recep- Corresponding Author: Patricia Forgez, INSERM UMR-S 1007, Universite Paris tor family (7). NTSR3 (gp95/sortilin) is a sorting protein member Descartes, 45 rue des Saints-Peres, Paris 75270, France. Phone: 331-428-622; 33 of the family of Vps10p-domain receptor family (8). The complex 142 862 227; E-mail: [email protected] of Neurotensin (NTS) and its high affinity receptor 1 (NTSR1) was doi: 10.1158/1078-0432.CCR-17-0861 shown to contribute to cancer progression (9). NTSR1 was found Ó2017 American Association for Cancer Research. overexpressed in several types of solid cancers (10), in association 6516 Clin Cancer Res; 23(21) November 1, 2017 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst August 8, 2017; DOI: 10.1158/1078-0432.CCR-17-0861 NTSR1 Blockade Improves Platinum Response in Ovarian Cancer from normal ovary samples, whereas these makers are present in Translational Relevance approximately 70% of ovarian cancer. Platinum salt–based therapy is used to treat almost 50% of cancer patients. It is proposed as an adjuvant, first-line, or in Materials and Methods palliative therapy. Unfortunately, many patients relapse Cell culture because of intrinsic, acquired resistance, or a weak sensitivity Ovarian adenocarcinoma cells SKOV3 was purchased from to the treatment. New therapeutic strategies to optimize the ATCC and A2780 was purchased from European Collection current treatment will add a real benefit to patient therapy. of Authenticated Cell Cultures (ECACC). Cells were cultured Neurotensin receptor 1 (NTSR1) is overexpressed in a large in RPMI 1640 supplemented with 10% FBS (Gibco) and number of solid cancers, and contributes to tumor aggres- 2 mmol/L glutamine. SKOV3 was used at passages between siveness. We report that blocking NTS/NTSR1 complex 38 and 48 and A2780 was used at passages between 25 and 35. improves the effect of carboplatin in ovarian cancer by enhanc- The corresponding NTSR1-overexpressing clone A2780-R1 was ing the drug-to-target ratio (platinum binding to DNA), and cultured in RPMI 1640 supplemented with 10% FBS, 2 mmol/L consequently the toxic effect of the drug. A combined plati- glutamine, and 0.5 mg/mL G418. All cells used in our research num salt–based therapy with NTS/NTSR1 inhibitor would be were mycoplasma-free as confirmed by the EZ-PCR Mycoplas- a suitable alternative to the current standard of care without ma Test Kit (Biological Industries). adding toxicity to the treatment. Transfection procedure A2780 cells were transfected with NTSR1 expressing pcDNA3 vectors using Lipofectamine 2000 (Invitrogen) according to the manufacturer's protocol. Selection was performed with 1 mg/mL with the dysregulation of the b-catenin pathway or epigenetic of G418 (Invitrogen). Stable transfectants were screened for NTS – regulation (11 13). Moreover, the presence of NTS/NTSR1 com- and NTSR1 expression by RT-PCR and immunofluorescence. plex enhanced the tumor growth and metastasis process in many – solid cancers (7, 14 19). Our group demonstrated that this cell Cell viability assay aggressiveness was due to the establishment of the EGFR autocrine Tumor cell growth was evaluated by PrestoBlue Cell Viability activation, occurring under the sustained stimulation of NTSR1 Reagent (Invitrogen). Cell suspension (100 mL) containing 8,000 (7, 12, 14). cells were seeded in 96-well plates, and the cells were treated Independently of the contribution of NTS/NTSR1 complex to accordingly. After 72 hours, 10-mL Presto blue was added to each cancer progression, it was recently shown that NTS plasma con- well and the cells were incubated for 2 hours at 37C. The centration is increased in rats treated with cisplatin and oxaliplatin fluorescence was measured by a multimode plate reader (EnSpire, fi for several weeks, causing speci c damage of the sciatic nerve, and PerkinElmer). producing variable effects in motor and behavioral tests (20). We hypothesized that NTS/NTSR1 complex may contribute to che- Tumor xenografts motherapy resistance and that the blockage of NTS/NTSR1 may A2780 cells (2.5  106) were suspended in PBS and Matrigel improve the response to platinum salt–based chemotherapy. (50%) (BD Biosciences) then inoculated in the right flank of Until now, the most studied approach to antagonize NTSR1 nude mice (NMRI-Nude Foxn1). All the procedures were in activation is the use of the nonpeptidic component meclinertant accordance with the Guide of the Care and Use of laboratory (SR48692; ref. 21). This drug was developed to counteract the Animals. Institutional Review Board approval was obtained by action of NTS on neurotransmitters in the brain (22). Mecliner- Le Comite d'Ethique en Experimentation Animale Charles tant exhibits a nanomolar affinity for different tissues and cells Darwin # B751201. Fourteen days after injection, four groups from various species (21). This compound crosses the blood– of six to seven mice were randomized as follows: 116 Æ 10 mm3 brain barrier. It was reported to reverse most intracellular medi- for control group, 120 Æ 11 mm3 for SR48692
Load more

Recommended publications
  • Neurotensin Activates Gabaergic Interneurons in the Prefrontal Cortex
    The Journal of Neuroscience, February 16, 2005 • 25(7):1629–1636 • 1629 Behavioral/Systems/Cognitive Neurotensin Activates GABAergic Interneurons in the Prefrontal Cortex Kimberly A. Petrie,1 Dennis Schmidt,1 Michael Bubser,1 Jim Fadel,1 Robert E. Carraway,2 and Ariel Y. Deutch1 1Departments of Pharmacology and Psychiatry, Vanderbilt University Medical Center, Nashville, Tennessee 37212, and 2Department of Physiology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655 Converging data suggest a dysfunction of prefrontal cortical GABAergic interneurons in schizophrenia. Morphological and physiological studies indicate that cortical GABA cells are modulated by a variety of afferents. The peptide transmitter neurotensin may be one such modulator of interneurons. In the rat prefrontal cortex (PFC), neurotensin is exclusively localized to dopamine axons and has been suggested to be decreased in schizophrenia. However, the effects of neurotensin on cortical interneurons are poorly understood. We used in vivo microdialysis in freely moving rats to assess whether neurotensin regulates PFC GABAergic interneurons. Intra-PFC administra- tion of neurotensin concentration-dependently increased extracellular GABA levels; this effect was impulse dependent, being blocked by treatment with tetrodotoxin. The ability of neurotensin to increase GABA levels in the PFC was also blocked by pretreatment with 2-[1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazole-3-yl)carbonylamino]tricyclo(3.3.1.1.3.7)decan-2-carboxylic acid (SR48692), a high-affinity neurotensin receptor 1 (NTR1) antagonist. This finding is consistent with our observation that NTR1 was localized to GABAergic interneurons in the PFC, particularly parvalbumin-containing interneurons. Because neurotensin is exclusively localized to dopamine axons in the PFC, we also determined whether neurotensin plays a role in the ability of dopamine agonists to increase extracellular GABA levels.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 7,723,342 B2 Palani Et Al
    US007723342B2 (12) United States Patent (10) Patent No.: US 7,723,342 B2 Palani et al. (45) Date of Patent: *May 25, 2010 (54) HETEROCYCLES AS NICOTINIC ACID FOREIGN PATENT DOCUMENTS RECEPTORAGONSTS FOR THE TREATMENT OF DYSLIPIDEMA DE 263 891 A3 1, 1989 DE 265 760 A3 3, 1989 (75) Inventors: Anandan Palani, Bridgewater, NJ (US); FR 256223 * 10, 1985 Jing Su, Scotch Plains, NJ (US); Dong WO WOOO698.29 A1 11, 2000 WO WO 02/084.298 A2 10, 2002 Xiao, Warren, NJ (US); Xianhai Huang, WO WO 2004037159 * 10/2003 Warren, NJ (US); Ashwin U. Rao, WO WO 2004/O37159 A2 5, 2004 Avenel, NJ (US); Xiao Chen, Edison, NJ WO WO 2004/047755 A2 6, 2004 (US); Haiqun Tang, Belle Mead, NJ WO WO 2004/083388 A2 9, 2004 (US); Jun Qin, Edison, NJ (US); Ying WO WO 2004f1 10368 A2 12/2004 Huang, Berkeley Heights, NJ (US); WO WO 2004f1 10375 A2 12/2004 Robert G. Aslanian, Rockaway, NJ WO WO 2005/OOO217 A2 1, 2005 (US); Brian A. McKittrick, New WO WO 2006O78834 * 1 2005 Vernon, NJ (US) WO WO 2005, O7795O A2 8, 2005 WO WO 2005,105097 A2 11/2005 (73) Assignee: Schering Corporation, Kenilworth, NJ WO WO 2006/045564 A1 5, 2006 (US) WO WO 2006/045565 A1 5, 2006 Notice: WO WO 2006/078834 A1 T 2006 (*) Subject to any disclaimer, the term of this WO WO 2006/089009 A2 8, 2006 patent is extended or adjusted under 35 WO WO 2006/092430 A1 9, 2006 U.S.C. 154(b) by 10 days.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • Structure and Dynamics of a Constitutively Active Neurotensin Receptor Received: 26 August 2016 Brian E
    www.nature.com/scientificreports OPEN Structure and dynamics of a constitutively active neurotensin receptor Received: 26 August 2016 Brian E. Krumm1,†, Sangbae Lee2, Supriyo Bhattacharya2, Istvan Botos3, Courtney F. White1, Accepted: 03 November 2016 Haijuan Du1, Nagarajan Vaidehi2 & Reinhard Grisshammer1 Published: 07 December 2016 Many G protein-coupled receptors show constitutive activity, resulting in the production of a second messenger in the absence of an agonist; and naturally occurring constitutively active mutations in receptors have been implicated in diseases. To gain insight into mechanistic aspects of constitutive activity, we report here the 3.3 Å crystal structure of a constitutively active, agonist-bound neurotensin receptor (NTSR1) and molecular dynamics simulations of agonist-occupied and ligand-free receptor. Comparison with the structure of a NTSR1 variant that has little constitutive activity reveals uncoupling of the ligand-binding domain from conserved connector residues, that effect conformational changes during GPCR activation. Furthermore, molecular dynamics simulations show strong contacts between connector residue side chains and increased flexibility at the intracellular receptor face as features that coincide with robust signalling in cells. The loss of correlation between the binding pocket and conserved connector residues, combined with altered receptor dynamics, possibly explains the reduced neurotensin efficacy in the constitutively active NTSR1 and a facilitated initial engagement with G protein in the absence of agonist. G protein-coupled receptors (GPCRs) are highly dynamic and versatile signalling molecules that mediate second messenger responses within the cell. Binding of an extracellular agonist causes conformational changes in the receptor, triggering activation of signalling partners such as G proteins or arrestin molecules on the intracellu- lar side of the membrane.
    [Show full text]
  • G Protein-Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
    [Show full text]
  • Axon Medchem
    Understanding Communication Satisfaction “Together we are stronger!” Axon Medchem - A top-line chemistry service platform specialized in contract research in medicinal chemistry and Contract Research Organization high-quality synthesis of bio-active and/or drug-like molecules. in Medicinal Chemistry Providing Axon Ligands™ for Pharmaceutical Research - Proven track record in developing novel drug candidates and achieving excellence for a decade by collaborating with partners and serving research scientists all over the world. Prime Source High Value - Prime source of highest performance and up-to-date life science reagents, providing Axon High Quality Ligands™ for advanced pharmaceutical research. Axon Ligands™ - Reagents for over 500 Biological Targets - A unique collection of biologically active molecules, as world-wide recognized research tools and drug standards in diversified application fields such as neurological disorders, cardiovascular Axon Medchem BV The Netherlands disease, pain and inflammation, epigenetics, stem cell biology, apoptosis and many more on cell Tel: +31-50-3118007 signaling and oncology research. Fax: +31-50-3600390 [email protected] - Featured products with our expertise including CNS reagents, ion channel modulators, signal transduction regulators (such as kinase inhibitors) and much more … Axon Medchem LLC USA Axon Ligands™ are widely used by research institutes and Axon Medchem has been cited in Tel: (888) 703-9861 numerous publications as their supplier of drugs. Fax: (703) 596-8062 [email protected]
    [Show full text]
  • Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors
    Journal of Nuclear Medicine, published on September 4, 2014 as doi:10.2967/jnumed.114.142000 CONTINUING EDUCATION Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors Clément Morgat1–3, Anil Kumar Mishra2–4, Raunak Varshney4, Michèle Allard1,2,5, Philippe Fernandez1–3, and Elif Hindié1–3 1CHU de Bordeaux, Service de Médecine Nucléaire, Bordeaux, France; 2University of Bordeaux, INCIA, UMR 5287, Talence, France; 3CNRS, INCIA, UMR 5287, Talence, France; 4Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, DRDO, New Delhi, India; and 5EPHE, Bordeaux, France Learning Objectives: On successful completion of this activity, participants should be able to list and discuss (1) the presence of bombesin receptors, neurotensin receptors, or neuropeptide-Y receptors in some major tumors; (2) the perspectives offered by radiolabeled peptides targeting these receptors for imaging and therapy; and (3) the choice between agonists and antagonists for tumor targeting and the relevance of various PET radionuclides for molecular imaging. Financial Disclosure: The authors of this article have indicated no relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through October 2017.
    [Show full text]
  • G Protein‐Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology (2019) 176, S21–S141 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors Stephen PH Alexander1 , Arthur Christopoulos2 , Anthony P Davenport3 , Eamonn Kelly4, Alistair Mathie5 , John A Peters6 , Emma L Veale5 ,JaneFArmstrong7 , Elena Faccenda7 ,SimonDHarding7 ,AdamJPawson7 , Joanna L Sharman7 , Christopher Southan7 , Jamie A Davies7 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia 3Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK 4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 5Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 6Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 7Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website.
    [Show full text]
  • Identification of Neuropeptide Receptors Expressed By
    RESEARCH ARTICLE Identification of Neuropeptide Receptors Expressed by Melanin-Concentrating Hormone Neurons Gregory S. Parks,1,2 Lien Wang,1 Zhiwei Wang,1 and Olivier Civelli1,2,3* 1Department of Pharmacology, University of California Irvine, Irvine, California 92697 2Department of Developmental and Cell Biology, University of California Irvine, Irvine, California 92697 3Department of Pharmaceutical Sciences, University of California Irvine, Irvine, California 92697 ABSTRACT the MCH system or demonstrated high expression lev- Melanin-concentrating hormone (MCH) is a 19-amino- els in the LH and ZI, were tested to determine whether acid cyclic neuropeptide that acts in rodents via the they are expressed by MCH neurons. Overall, 11 neuro- MCH receptor 1 (MCHR1) to regulate a wide variety of peptide receptors were found to exhibit significant physiological functions. MCH is produced by a distinct colocalization with MCH neurons: nociceptin/orphanin population of neurons located in the lateral hypothala- FQ opioid receptor (NOP), MCHR1, both orexin recep- mus (LH) and zona incerta (ZI), but MCHR1 mRNA is tors (ORX), somatostatin receptors 1 and 2 (SSTR1, widely expressed throughout the brain. The physiologi- SSTR2), kisspeptin recepotor (KissR1), neurotensin cal responses and behaviors regulated by the MCH sys- receptor 1 (NTSR1), neuropeptide S receptor (NPSR), tem have been investigated, but less is known about cholecystokinin receptor A (CCKAR), and the j-opioid how MCH neurons are regulated. The effects of most receptor (KOR). Among these receptors, six have never classical neurotransmitters on MCH neurons have been before been linked to the MCH system. Surprisingly, studied, but those of most neuropeptides are poorly several receptors thought to regulate MCH neurons dis- understood.
    [Show full text]
  • Structural Prerequisites for G-Protein Activation by the Neurotensin Receptor
    ARTICLE Received 28 Jan 2015 | Accepted 23 Jun 2015 | Published 24 Jul 2015 DOI: 10.1038/ncomms8895 OPEN Structural prerequisites for G-protein activation by the neurotensin receptor Brian E. Krumm1, Jim F. White1, Priyanka Shah1 & Reinhard Grisshammer1 We previously determined the structure of neurotensin receptor NTSR1 in an active-like conformation with six thermostabilizing mutations bound to the peptide agonist neurotensin. This receptor was unable to activate G proteins, indicating that the mutations restricted NTSR1 to relate agonist binding to G-protein activation. Here we analyse the effect of three of those mutations (E166A3.49, L310A6.37, F358A7.42) and present two structures of NTSR1 able to catalyse nucleotide exchange at Ga. The presence of F3587.42 causes the conserved W3216.48 to adopt a side chain orientation parallel to the lipid bilayer sealing the collapsed Na þ ion pocket and linking the agonist with residues in the lower receptor part implicated in GPCR activation. In the intracellular receptor half, the bulkier L3106.37 side chain dictates the position of R1673.50 of the highly conserved D/ERY motif. These residues, together with the presence of E1663.49 provide determinants for G-protein activation by NTSR1. 1 Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Rockville, Maryland 20852, USA. Correspondence and requests for materials should be addressed to R.G. (email: [email protected]). NATURE COMMUNICATIONS | 6:7895 | DOI: 10.1038/ncomms8895 | www.nature.com/naturecommunications 1 & 2015 Macmillan Publishers Limited.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2008/0019978A1 Palani Et Al
    US 200800 19978A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0019978A1 Palani et al. (43) Pub. Date: Jan. 24, 2008 (54) NITROGEN-CONTAINING HETEROCYCLIC (57) ABSTRACT COMPOUNDS AND METHODS OF USE The present invention provides compounds of Formula (I): THEREOF (75) Inventors: Anandan Palani, Bridgewater, NJ (US); Jing Su, Scotch Plains, NJ (US); (I) Dong Xiao, Warren, NJ (US); Xianhai Huang, Warren, NJ (US); Ashwin U. Rao, Avenel, NJ (US); Xiao Chen, Edison, NJ (US); Haiqun Tang, Belle Mead, NJ (US); Jun Qin, Edison, NJ (US); Ying R. Huang, Berkeley Heights, NJ (US); Robert G. Aslanian, Rockaway, NJ (US); Brian A. and pharmaceutically acceptable salts, Solvates, esters, and McKittrick, New Vernon, NJ (US); tautomers thereof, wherein: Sylvia J. Degrado, Scotch Plains, NJ Q is selected from the group consisting of: (US) Correspondence Address: SCHERING-PLOUGH CORPORATION PATENT DEPARTMENT (K-6-1, 1990) 2000 GALLOPNG HILL ROAD KENILWORTH, NJ 07033-0530 (US) (73) Assignee: Schering Corporation (21) Appl. No.: 11/771.538 (22) Filed: Jun. 29, 2007 (b) Related U.S. Application Data (63) Continuation-in-part of application No. 1 1/600,216, filed on Nov. 15, 2006, which is a continuation-in-part of application No. 11/432,133, filed on May 11, 2006. (60) Provisional application No. 60/681,848, filed on May 17, 2005. Provisional application No. 60/715,565, filed on Sep. 9, 2005. Provisional application No. 60/731,039, filed on Oct. 28, 2005. (c) Publication Classification (51) Int. Cl. A 6LX 3/59 (2006.01) A 6LX 3L/397 (2006.01) A6 IK 3/56 (2006.01) A6 IK 3L/60 (2006.01) A6 IK 38/16 (2006.01) A 6LX 39/395 (2006.01) (d) A6IP I/00 (2006.01) A6IP II/00 (2006.01) A6IP 3/00 (2006.01) A6IP 3/10 (2006.01) A6IP 35/00 (2006.01) A6IP 9/00 (2006.01) C07D 239/70 (2006.01) (52) U.S.
    [Show full text]
  • The Anti-Apoptotic Role of Neurotensin
    Cells 2013, 2, 124-135; doi:10.3390/cells2010124 OPEN ACCESS cells ISSN 2073-4409 www.mdpi.com/journal/cells Review The Anti-Apoptotic Role of Neurotensin Christelle Devader, Sophie Béraud-Dufour, Thierry Coppola and Jean Mazella * Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 7275, Université de Nice-Sophia Antipolis, 660 route des Lucioles, Valbonne 06560, France; E-Mails: [email protected] (C.D.); [email protected] (S.B.-D.); [email protected] (T.C.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +33-4-93-95-77-61; Fax: +33-4-93-95-77-08. Received: 24 January 2013; in revised form: 15 February 2013 / Accepted: 26 February 2013 / Published: 4 March 2013 Abstract: The neuropeptide, neurotensin, exerts numerous biological functions, including an efficient anti-apoptotic role, both in the central nervous system and in the periphery. This review summarizes studies that clearly evidenced the protective effect of neurotensin through its three known receptors. The pivotal involvement of the neurotensin receptor-3, also called sortilin, in the molecular mechanisms of the anti-apoptotic action of neurotensin has been analyzed in neuronal cell death, in cancer cell growth and in pancreatic beta cell protection. The relationships between the anti-apoptotic role of neurotensin and important physiological and pathological contexts are discussed in this review. Keywords: neurotensin; receptor; apoptosis; sortilin 1. Introduction The tridecapeptide neurotensin (NT) was isolated from bovine hypothalami on the basis of its ability to induce vasodilatation [1]. NT is synthesized from a precursor protein following excision by prohormone convertases [2].
    [Show full text]