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

Dane D. Jensen 1 Tinamarie Lieu 1 Michelle L. Halls 1 Nicholas A. Veldhuis 1 Wendy L. Imlach 2 Quynh N. Mai 1 Daniel P. Poole 1 Tim Quach 1 Luigi Aurelio 1 Joshua Conner 1 Carmen Klein Herenbrink 1 Nicholas Barlow 1 Jamie S. Simpson 1 Martin J. Scanlon 1 Bimbil Graham 1 Adam Mccluskey 3 Phillip J. Robinson 2 Virginie Escriou 4 Romina Nassini 5 Serena Materazzi 5 Pierangelo Geppetti 5 Gareth A. Hicks 6 Macdonald J. Christie 7 Christopher J. H. Porter 1 Meritxell Canals 1 Nigel W. Bunnett 1, 8
1 Monash University [Melbourne]
2 The University of Sydney
3 School of Environmental and Life Sciences - SELS (Callaghan, Australia)
4 UTCBS - UM 4 (UMR 8258 / U1022) - Unité de Technologies Chimiques et Biologiques pour la Santé
5 Università degli Studi di Firenze = University of Florence [Firenze]
6 Takeda Pharmaceuticals International GmbH
7 The University of Sydney
8 Columbia University College of Physicians and Surgeons
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 providesmore effective and sustained pain relief than conventional plasmamembrane-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.
Keywords : PROTEIN-KINASE-C SUBSTANCE-P BETA-ARRESTINS SPINAL-CORD ENDOCYTOSIS NEURONS INHIBITORS DYNAMIN CELLS NK1
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https://hal-cnrs.archives-ouvertes.fr/hal-03292054
Contributor : Colette Orange Connect in order to contact the contributor
Submitted on : Tuesday, July 20, 2021 - 10:29:51 AM
Last modification on : Tuesday, September 28, 2021 - 5:15:04 PM

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Dane D. Jensen, Tinamarie Lieu, Michelle L. Halls, Nicholas A. Veldhuis, Wendy L. Imlach, et al.. Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief. Science Translational Medicine, American Association for the Advancement of Science, 2017, 9 (392), ⟨10.1126/scitranslmed.aal3447⟩. ⟨hal-03292054⟩

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