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Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief

Porter, Christopher J.H.; Lieu, Tina Marie; Jensen, Dane D.; Lieu, T.M.; Halls, Michelle L.; Veldhuis, Nicholas A.; Imlach, Wendy L.; Mai, Quynh N.; Poole, Daniel P.; Quach, Tim; Aurelio, Luigi; Conner, Joshua; Herenbrink, Carmen Klein; Barlow, Nicholas; Simpson, Jamie S.; Scanlon, Martin J.; Graham, Bimbil; McCluskey, Adam; Robinson, Phillip J.; Escriou, Virginie; Nassini, Romina; Materazzi, Serena; Geppetti, Pierangelo; Hicks, Gareth A.; Christie, MacDonald J.; Porter, Christopher J. H.; Canals, Meritxell; Bunnett, Nigel W.

Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief Thumbnail


Authors

Christopher J.H. Porter

Tina Marie Lieu

Dane D. Jensen

T.M. Lieu

Michelle L. Halls

Nicholas A. Veldhuis

Wendy L. Imlach

Quynh N. Mai

Daniel P. Poole

Tim Quach

Luigi Aurelio

Joshua Conner

Carmen Klein Herenbrink

Nicholas Barlow

Jamie S. Simpson

Martin J. Scanlon

Bimbil Graham

Adam McCluskey

Phillip J. Robinson

Virginie Escriou

Romina Nassini

Serena Materazzi

Pierangelo Geppetti

Gareth A. Hicks

MacDonald J. Christie

Christopher J. H. Porter

Nigel W. Bunnett



Abstract

© 2017, American Association for the Advancement of Science. 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 b-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.

Citation

Porter, C. J., Lieu, T. M., Jensen, D. D., Lieu, T., Halls, M. L., Veldhuis, N. A., …Bunnett, N. W. (2017). Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief. Science Translational Medicine, 9(392), Article eaal3447. https://doi.org/10.1126/scitranslmed.aal3447

Journal Article Type Article
Acceptance Date Mar 17, 2017
Online Publication Date May 31, 2017
Publication Date May 31, 2017
Deposit Date Mar 6, 2019
Publicly Available Date Mar 6, 2019
Journal Science Translational Medicine
Print ISSN 1946-6234
Electronic ISSN 1946-6242
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 9
Issue 392
Article Number eaal3447
DOI https://doi.org/10.1126/scitranslmed.aal3447
Keywords 3 [3,5 bis(trifluoromethyl)benzyloxy] 2 phenylpiperidine; beta arrestin; cholestanol; clathrin; dynamin; mitogen activated protein kinase; neurokinin 1 receptor; neurokinin 1 receptor antagonist; protein kinase C; beta arrestin; clathrin; dynamin; guanine
Public URL https://www.scopus.com/inward/record.uri?eid=2-s2.0-85020248318&doi=10.1126%2fscitranslmed.aal3447&partnerID=40&md5=d9f44711ab6a7177fec478f0b02c0783
Publisher URL http://stm.sciencemag.org/content/9/392/eaal3447.short
Contract Date Mar 6, 2019

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