Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.
Identifieur interne : 000745 ( Main/Exploration ); précédent : 000744; suivant : 000746Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.
Auteurs : Dane D. Jensen [Australie] ; Tinamarie Lieu [Australie] ; Michelle L. Halls [Australie] ; Nicholas A. Veldhuis [Australie] ; Wendy L. Imlach [Australie] ; Quynh N. Mai [Australie] ; Daniel P. Poole [Australie] ; Tim Quach [Australie] ; Luigi Aurelio [Australie] ; Joshua Conner [Australie] ; Carmen Klein Herenbrink [Australie] ; Nicholas Barlow [Australie] ; Jamie S. Simpson [Australie] ; Martin J. Scanlon [Australie] ; Bimbil Graham [Australie] ; Adam Mccluskey [Australie] ; Phillip J. Robinson [Australie] ; Virginie Escriou [France] ; Romina Nassini [Italie] ; Serena Materazzi [Italie] ; Pierangelo Geppetti [Italie] ; Gareth A. Hicks [États-Unis] ; Macdonald J. Christie [Australie] ; Christopher J H. Porter [Australie] ; Meritxell Canals [Australie] ; Nigel W. Bunnett [Australie]Source :
- Science translational medicine [ 1946-6242 ] ; 2017.
Abstract
Typically considered to be cell surface sensors of extracellular signals, heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) control many pathophysiological processes and are the target of 30% of therapeutic drugs. Activated receptors redistribute to endosomes, but researchers have yet to explore whether endosomal receptors generate signals that control complex processes in vivo and are viable therapeutic targets. We report that the substance P (SP) neurokinin 1 receptor (NK1R) signals from endosomes to induce sustained excitation of spinal neurons and pain transmission and that specific antagonism of the NK1R in endosomes with membrane-anchored drug conjugates provides more effective and sustained pain relief than conventional plasma membrane-targeted antagonists. Pharmacological and genetic disruption of clathrin, dynamin, and β-arrestin blocked SP-induced NK1R endocytosis and prevented SP-stimulated activation of cytosolic protein kinase C and nuclear extracellular signal-regulated kinase, as well as transcription. Endocytosis inhibitors prevented sustained SP-induced excitation of neurons in spinal cord slices in vitro and attenuated nociception in vivo. When conjugated to cholestanol to promote endosomal targeting, NK1R antagonists selectively inhibited endosomal signaling and sustained neuronal excitation. Cholestanol conjugation amplified and prolonged the antinociceptive actions of NK1R antagonists. These results reveal a critical role for endosomal signaling of the NK1R in the complex pathophysiology of pain and demonstrate the use of endosomally targeted GPCR antagonists.
DOI: 10.1126/scitranslmed.aal3447
PubMed: 28566424
Affiliations:
- Australie, France, Italie, États-Unis
- Massachusetts, Nouvelle-Galles du Sud, Île-de-France
- Paris, Sydney
- Université Paris-Descartes, Université de Sydney
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000C68
- to stream PubMed, to step Curation: 000C65
- to stream PubMed, to step Checkpoint: 000C65
- to stream Ncbi, to step Merge: 004900
- to stream Ncbi, to step Curation: 004900
- to stream Ncbi, to step Checkpoint: 004900
- to stream Main, to step Merge: 000740
- to stream Main, to step Curation: 000745
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.</title><author><name sortKey="Jensen, Dane D" sort="Jensen, Dane D" uniqKey="Jensen D" first="Dane D" last="Jensen">Dane D. Jensen</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Lieu, Tinamarie" sort="Lieu, Tinamarie" uniqKey="Lieu T" first="Tinamarie" last="Lieu">Tinamarie Lieu</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Halls, Michelle L" sort="Halls, Michelle L" uniqKey="Halls M" first="Michelle L" last="Halls">Michelle L. Halls</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Veldhuis, Nicholas A" sort="Veldhuis, Nicholas A" uniqKey="Veldhuis N" first="Nicholas A" last="Veldhuis">Nicholas A. Veldhuis</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Imlach, Wendy L" sort="Imlach, Wendy L" uniqKey="Imlach W" first="Wendy L" last="Imlach">Wendy L. Imlach</name><affiliation wicri:level="4"><nlm:affiliation>Discipline of Pharmacology, University of Sydney, New South Wales 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, University of Sydney, New South Wales 2006</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Mai, Quynh N" sort="Mai, Quynh N" uniqKey="Mai Q" first="Quynh N" last="Mai">Quynh N. Mai</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Poole, Daniel P" sort="Poole, Daniel P" uniqKey="Poole D" first="Daniel P" last="Poole">Daniel P. Poole</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Quach, Tim" sort="Quach, Tim" uniqKey="Quach T" first="Tim" last="Quach">Tim Quach</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Aurelio, Luigi" sort="Aurelio, Luigi" uniqKey="Aurelio L" first="Luigi" last="Aurelio">Luigi Aurelio</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Conner, Joshua" sort="Conner, Joshua" uniqKey="Conner J" first="Joshua" last="Conner">Joshua Conner</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Herenbrink, Carmen Klein" sort="Herenbrink, Carmen Klein" uniqKey="Herenbrink C" first="Carmen Klein" last="Herenbrink">Carmen Klein Herenbrink</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Barlow, Nicholas" sort="Barlow, Nicholas" uniqKey="Barlow N" first="Nicholas" last="Barlow">Nicholas Barlow</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Simpson, Jamie S" sort="Simpson, Jamie S" uniqKey="Simpson J" first="Jamie S" last="Simpson">Jamie S. Simpson</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Scanlon, Martin J" sort="Scanlon, Martin J" uniqKey="Scanlon M" first="Martin J" last="Scanlon">Martin J. Scanlon</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Graham, Bimbil" sort="Graham, Bimbil" uniqKey="Graham B" first="Bimbil" last="Graham">Bimbil Graham</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Mccluskey, Adam" sort="Mccluskey, Adam" uniqKey="Mccluskey A" first="Adam" last="Mccluskey">Adam Mccluskey</name><affiliation wicri:level="1"><nlm:affiliation>School of Environmental and Life Sciences, University of Newcastle, New South Wales 2308, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Environmental and Life Sciences, University of Newcastle, New South Wales 2308</wicri:regionArea><wicri:noRegion>New South Wales 2308</wicri:noRegion></affiliation></author><author><name sortKey="Robinson, Phillip J" sort="Robinson, Phillip J" uniqKey="Robinson P" first="Phillip J" last="Robinson">Phillip J. Robinson</name><affiliation wicri:level="4"><nlm:affiliation>Children's Medical Research Institute, University of Sydney, New South Wales 2145, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Children's Medical Research Institute, University of Sydney, New South Wales 2145</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Escriou, Virginie" sort="Escriou, Virginie" uniqKey="Escriou V" first="Virginie" last="Escriou">Virginie Escriou</name><affiliation wicri:level="4"><nlm:affiliation>Unité de Technologies Chimiques et Biologiques pour la Sante, CNRS UMR8258, INSERM U1022, Université Paris Descartes, Chimie ParisTech, 75006 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Unité de Technologies Chimiques et Biologiques pour la Sante, CNRS UMR8258, INSERM U1022, Université Paris Descartes, Chimie ParisTech, 75006 Paris</wicri:regionArea><wicri:noRegion>75006 Paris</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation></author><author><name sortKey="Nassini, Romina" sort="Nassini, Romina" uniqKey="Nassini R" first="Romina" last="Nassini">Romina Nassini</name><affiliation wicri:level="1"><nlm:affiliation>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence</wicri:regionArea><wicri:noRegion>6-50139 Florence</wicri:noRegion></affiliation></author><author><name sortKey="Materazzi, Serena" sort="Materazzi, Serena" uniqKey="Materazzi S" first="Serena" last="Materazzi">Serena Materazzi</name><affiliation wicri:level="1"><nlm:affiliation>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence</wicri:regionArea><wicri:noRegion>6-50139 Florence</wicri:noRegion></affiliation></author><author><name sortKey="Geppetti, Pierangelo" sort="Geppetti, Pierangelo" uniqKey="Geppetti P" first="Pierangelo" last="Geppetti">Pierangelo Geppetti</name><affiliation wicri:level="1"><nlm:affiliation>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence</wicri:regionArea><wicri:noRegion>6-50139 Florence</wicri:noRegion></affiliation></author><author><name sortKey="Hicks, Gareth A" sort="Hicks, Gareth A" uniqKey="Hicks G" first="Gareth A" last="Hicks">Gareth A. Hicks</name><affiliation wicri:level="2"><nlm:affiliation>Takeda Pharmaceuticals, Boston, MA 02139, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Takeda Pharmaceuticals, Boston, MA 02139</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Christie, Macdonald J" sort="Christie, Macdonald J" uniqKey="Christie M" first="Macdonald J" last="Christie">Macdonald J. Christie</name><affiliation wicri:level="4"><nlm:affiliation>Discipline of Pharmacology, University of Sydney, New South Wales 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, University of Sydney, New South Wales 2006</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Porter, Christopher J H" sort="Porter, Christopher J H" uniqKey="Porter C" first="Christopher J H" last="Porter">Christopher J H. Porter</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. nb2733@cumc.columbia.edu chris.porter@monash.edu meri.canals@monash.edu.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Canals, Meritxell" sort="Canals, Meritxell" uniqKey="Canals M" first="Meritxell" last="Canals">Meritxell Canals</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. nb2733@cumc.columbia.edu chris.porter@monash.edu meri.canals@monash.edu.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Bunnett, Nigel W" sort="Bunnett, Nigel W" uniqKey="Bunnett N" first="Nigel W" last="Bunnett">Nigel W. Bunnett</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. nb2733@cumc.columbia.edu chris.porter@monash.edu meri.canals@monash.edu.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28566424</idno><idno type="pmid">28566424</idno><idno type="doi">10.1126/scitranslmed.aal3447</idno><idno type="wicri:Area/PubMed/Corpus">000C68</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000C68</idno><idno type="wicri:Area/PubMed/Curation">000C65</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000C65</idno><idno type="wicri:Area/PubMed/Checkpoint">000C65</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000C65</idno><idno type="wicri:Area/Ncbi/Merge">004900</idno><idno type="wicri:Area/Ncbi/Curation">004900</idno><idno type="wicri:Area/Ncbi/Checkpoint">004900</idno><idno type="wicri:Area/Main/Merge">000740</idno><idno type="wicri:Area/Main/Curation">000745</idno><idno type="wicri:Area/Main/Exploration">000745</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.</title><author><name sortKey="Jensen, Dane D" sort="Jensen, Dane D" uniqKey="Jensen D" first="Dane D" last="Jensen">Dane D. Jensen</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Lieu, Tinamarie" sort="Lieu, Tinamarie" uniqKey="Lieu T" first="Tinamarie" last="Lieu">Tinamarie Lieu</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Halls, Michelle L" sort="Halls, Michelle L" uniqKey="Halls M" first="Michelle L" last="Halls">Michelle L. Halls</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Veldhuis, Nicholas A" sort="Veldhuis, Nicholas A" uniqKey="Veldhuis N" first="Nicholas A" last="Veldhuis">Nicholas A. Veldhuis</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Imlach, Wendy L" sort="Imlach, Wendy L" uniqKey="Imlach W" first="Wendy L" last="Imlach">Wendy L. Imlach</name><affiliation wicri:level="4"><nlm:affiliation>Discipline of Pharmacology, University of Sydney, New South Wales 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, University of Sydney, New South Wales 2006</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Mai, Quynh N" sort="Mai, Quynh N" uniqKey="Mai Q" first="Quynh N" last="Mai">Quynh N. Mai</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Poole, Daniel P" sort="Poole, Daniel P" uniqKey="Poole D" first="Daniel P" last="Poole">Daniel P. Poole</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Quach, Tim" sort="Quach, Tim" uniqKey="Quach T" first="Tim" last="Quach">Tim Quach</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Aurelio, Luigi" sort="Aurelio, Luigi" uniqKey="Aurelio L" first="Luigi" last="Aurelio">Luigi Aurelio</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Conner, Joshua" sort="Conner, Joshua" uniqKey="Conner J" first="Joshua" last="Conner">Joshua Conner</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Herenbrink, Carmen Klein" sort="Herenbrink, Carmen Klein" uniqKey="Herenbrink C" first="Carmen Klein" last="Herenbrink">Carmen Klein Herenbrink</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Barlow, Nicholas" sort="Barlow, Nicholas" uniqKey="Barlow N" first="Nicholas" last="Barlow">Nicholas Barlow</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Simpson, Jamie S" sort="Simpson, Jamie S" uniqKey="Simpson J" first="Jamie S" last="Simpson">Jamie S. Simpson</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Scanlon, Martin J" sort="Scanlon, Martin J" uniqKey="Scanlon M" first="Martin J" last="Scanlon">Martin J. Scanlon</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Graham, Bimbil" sort="Graham, Bimbil" uniqKey="Graham B" first="Bimbil" last="Graham">Bimbil Graham</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Mccluskey, Adam" sort="Mccluskey, Adam" uniqKey="Mccluskey A" first="Adam" last="Mccluskey">Adam Mccluskey</name><affiliation wicri:level="1"><nlm:affiliation>School of Environmental and Life Sciences, University of Newcastle, New South Wales 2308, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Environmental and Life Sciences, University of Newcastle, New South Wales 2308</wicri:regionArea><wicri:noRegion>New South Wales 2308</wicri:noRegion></affiliation></author><author><name sortKey="Robinson, Phillip J" sort="Robinson, Phillip J" uniqKey="Robinson P" first="Phillip J" last="Robinson">Phillip J. Robinson</name><affiliation wicri:level="4"><nlm:affiliation>Children's Medical Research Institute, University of Sydney, New South Wales 2145, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Children's Medical Research Institute, University of Sydney, New South Wales 2145</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Escriou, Virginie" sort="Escriou, Virginie" uniqKey="Escriou V" first="Virginie" last="Escriou">Virginie Escriou</name><affiliation wicri:level="4"><nlm:affiliation>Unité de Technologies Chimiques et Biologiques pour la Sante, CNRS UMR8258, INSERM U1022, Université Paris Descartes, Chimie ParisTech, 75006 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Unité de Technologies Chimiques et Biologiques pour la Sante, CNRS UMR8258, INSERM U1022, Université Paris Descartes, Chimie ParisTech, 75006 Paris</wicri:regionArea><wicri:noRegion>75006 Paris</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation></author><author><name sortKey="Nassini, Romina" sort="Nassini, Romina" uniqKey="Nassini R" first="Romina" last="Nassini">Romina Nassini</name><affiliation wicri:level="1"><nlm:affiliation>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence</wicri:regionArea><wicri:noRegion>6-50139 Florence</wicri:noRegion></affiliation></author><author><name sortKey="Materazzi, Serena" sort="Materazzi, Serena" uniqKey="Materazzi S" first="Serena" last="Materazzi">Serena Materazzi</name><affiliation wicri:level="1"><nlm:affiliation>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence</wicri:regionArea><wicri:noRegion>6-50139 Florence</wicri:noRegion></affiliation></author><author><name sortKey="Geppetti, Pierangelo" sort="Geppetti, Pierangelo" uniqKey="Geppetti P" first="Pierangelo" last="Geppetti">Pierangelo Geppetti</name><affiliation wicri:level="1"><nlm:affiliation>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 6-50139 Florence</wicri:regionArea><wicri:noRegion>6-50139 Florence</wicri:noRegion></affiliation></author><author><name sortKey="Hicks, Gareth A" sort="Hicks, Gareth A" uniqKey="Hicks G" first="Gareth A" last="Hicks">Gareth A. Hicks</name><affiliation wicri:level="2"><nlm:affiliation>Takeda Pharmaceuticals, Boston, MA 02139, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Takeda Pharmaceuticals, Boston, MA 02139</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Christie, Macdonald J" sort="Christie, Macdonald J" uniqKey="Christie M" first="Macdonald J" last="Christie">Macdonald J. Christie</name><affiliation wicri:level="4"><nlm:affiliation>Discipline of Pharmacology, University of Sydney, New South Wales 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, University of Sydney, New South Wales 2006</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Porter, Christopher J H" sort="Porter, Christopher J H" uniqKey="Porter C" first="Christopher J H" last="Porter">Christopher J H. Porter</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. nb2733@cumc.columbia.edu chris.porter@monash.edu meri.canals@monash.edu.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Canals, Meritxell" sort="Canals, Meritxell" uniqKey="Canals M" first="Meritxell" last="Canals">Meritxell Canals</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. nb2733@cumc.columbia.edu chris.porter@monash.edu meri.canals@monash.edu.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author><author><name sortKey="Bunnett, Nigel W" sort="Bunnett, Nigel W" uniqKey="Bunnett N" first="Nigel W" last="Bunnett">Nigel W. Bunnett</name><affiliation wicri:level="1"><nlm:affiliation>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. nb2733@cumc.columbia.edu chris.porter@monash.edu meri.canals@monash.edu.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052</wicri:regionArea><wicri:noRegion>Victoria 3052</wicri:noRegion></affiliation></author></analytic><series><title level="j">Science translational medicine</title><idno type="eISSN">1946-6242</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Typically considered to be cell surface sensors of extracellular signals, heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) control many pathophysiological processes and are the target of 30% of therapeutic drugs. Activated receptors redistribute to endosomes, but researchers have yet to explore whether endosomal receptors generate signals that control complex processes in vivo and are viable therapeutic targets. We report that the substance P (SP) neurokinin 1 receptor (NK1R) signals from endosomes to induce sustained excitation of spinal neurons and pain transmission and that specific antagonism of the NK1R in endosomes with membrane-anchored drug conjugates provides more effective and sustained pain relief than conventional plasma membrane-targeted antagonists. Pharmacological and genetic disruption of clathrin, dynamin, and β-arrestin blocked SP-induced NK1R endocytosis and prevented SP-stimulated activation of cytosolic protein kinase C and nuclear extracellular signal-regulated kinase, as well as transcription. Endocytosis inhibitors prevented sustained SP-induced excitation of neurons in spinal cord slices in vitro and attenuated nociception in vivo. When conjugated to cholestanol to promote endosomal targeting, NK1R antagonists selectively inhibited endosomal signaling and sustained neuronal excitation. Cholestanol conjugation amplified and prolonged the antinociceptive actions of NK1R antagonists. These results reveal a critical role for endosomal signaling of the NK1R in the complex pathophysiology of pain and demonstrate the use of endosomally targeted GPCR antagonists.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Italie</li><li>États-Unis</li></country><region><li>Massachusetts</li><li>Nouvelle-Galles du Sud</li><li>Île-de-France</li></region><settlement><li>Paris</li><li>Sydney</li></settlement><orgName><li>Université Paris-Descartes</li><li>Université de Sydney</li></orgName></list><tree><country name="Australie"><noRegion><name sortKey="Jensen, Dane D" sort="Jensen, Dane D" uniqKey="Jensen D" first="Dane D" last="Jensen">Dane D. Jensen</name></noRegion><name sortKey="Aurelio, Luigi" sort="Aurelio, Luigi" uniqKey="Aurelio L" first="Luigi" last="Aurelio">Luigi Aurelio</name><name sortKey="Barlow, Nicholas" sort="Barlow, Nicholas" uniqKey="Barlow N" first="Nicholas" last="Barlow">Nicholas Barlow</name><name sortKey="Bunnett, Nigel W" sort="Bunnett, Nigel W" uniqKey="Bunnett N" first="Nigel W" last="Bunnett">Nigel W. Bunnett</name><name sortKey="Canals, Meritxell" sort="Canals, Meritxell" uniqKey="Canals M" first="Meritxell" last="Canals">Meritxell Canals</name><name sortKey="Christie, Macdonald J" sort="Christie, Macdonald J" uniqKey="Christie M" first="Macdonald J" last="Christie">Macdonald J. Christie</name><name sortKey="Conner, Joshua" sort="Conner, Joshua" uniqKey="Conner J" first="Joshua" last="Conner">Joshua Conner</name><name sortKey="Graham, Bimbil" sort="Graham, Bimbil" uniqKey="Graham B" first="Bimbil" last="Graham">Bimbil Graham</name><name sortKey="Halls, Michelle L" sort="Halls, Michelle L" uniqKey="Halls M" first="Michelle L" last="Halls">Michelle L. Halls</name><name sortKey="Herenbrink, Carmen Klein" sort="Herenbrink, Carmen Klein" uniqKey="Herenbrink C" first="Carmen Klein" last="Herenbrink">Carmen Klein Herenbrink</name><name sortKey="Imlach, Wendy L" sort="Imlach, Wendy L" uniqKey="Imlach W" first="Wendy L" last="Imlach">Wendy L. Imlach</name><name sortKey="Lieu, Tinamarie" sort="Lieu, Tinamarie" uniqKey="Lieu T" first="Tinamarie" last="Lieu">Tinamarie Lieu</name><name sortKey="Mai, Quynh N" sort="Mai, Quynh N" uniqKey="Mai Q" first="Quynh N" last="Mai">Quynh N. Mai</name><name sortKey="Mccluskey, Adam" sort="Mccluskey, Adam" uniqKey="Mccluskey A" first="Adam" last="Mccluskey">Adam Mccluskey</name><name sortKey="Poole, Daniel P" sort="Poole, Daniel P" uniqKey="Poole D" first="Daniel P" last="Poole">Daniel P. Poole</name><name sortKey="Porter, Christopher J H" sort="Porter, Christopher J H" uniqKey="Porter C" first="Christopher J H" last="Porter">Christopher J H. Porter</name><name sortKey="Quach, Tim" sort="Quach, Tim" uniqKey="Quach T" first="Tim" last="Quach">Tim Quach</name><name sortKey="Robinson, Phillip J" sort="Robinson, Phillip J" uniqKey="Robinson P" first="Phillip J" last="Robinson">Phillip J. Robinson</name><name sortKey="Scanlon, Martin J" sort="Scanlon, Martin J" uniqKey="Scanlon M" first="Martin J" last="Scanlon">Martin J. Scanlon</name><name sortKey="Simpson, Jamie S" sort="Simpson, Jamie S" uniqKey="Simpson J" first="Jamie S" last="Simpson">Jamie S. Simpson</name><name sortKey="Veldhuis, Nicholas A" sort="Veldhuis, Nicholas A" uniqKey="Veldhuis N" first="Nicholas A" last="Veldhuis">Nicholas A. Veldhuis</name></country><country name="France"><region name="Île-de-France"><name sortKey="Escriou, Virginie" sort="Escriou, Virginie" uniqKey="Escriou V" first="Virginie" last="Escriou">Virginie Escriou</name></region></country><country name="Italie"><noRegion><name sortKey="Nassini, Romina" sort="Nassini, Romina" uniqKey="Nassini R" first="Romina" last="Nassini">Romina Nassini</name></noRegion><name sortKey="Geppetti, Pierangelo" sort="Geppetti, Pierangelo" uniqKey="Geppetti P" first="Pierangelo" last="Geppetti">Pierangelo Geppetti</name><name sortKey="Materazzi, Serena" sort="Materazzi, Serena" uniqKey="Materazzi S" first="Serena" last="Materazzi">Serena Materazzi</name></country><country name="États-Unis"><region name="Massachusetts"><name sortKey="Hicks, Gareth A" sort="Hicks, Gareth A" uniqKey="Hicks G" first="Gareth A" last="Hicks">Gareth A. Hicks</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Asie/explor/AustralieFrV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000745 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000745 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Asie
|area= AustralieFrV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:28566424
|texte= Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:28566424" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a AustralieFrV1
| This area was generated with Dilib version V0.6.33. |  |