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ResearchIn-Press PreviewCell biologyNeuroscience Open Access | 10.1172/JCI183873

NEUROPILIN-1 INHIBITION SUPPRESSES NERVE-GROWTH FACTOR SIGNALING AND NOCICEPTION IN PAIN MODELS

Chloe J. Peach,1 Raquel Tonello,1 Elisa Damo,1 Kimberly Gomez,1 Aida Calderon-Rivera,1 Renato Bruni,1 Harsh Bansia,1 Laura Maile,2 Ana-Marie Manu,1 Hyunggu Hahn,1 Alex R.B. Thomsen,1 Brian L. Schmidt,1 Steve Davidson,2 Amedee des Georges,1 Rajesh Khanna,1 and Nigel W. Bunnett1

1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

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1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

Find articles by Tonello, R. in: JCI | PubMed | Google Scholar |

1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

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1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

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1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

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1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

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1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

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1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

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1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

Find articles by Manu, A. in: JCI | PubMed | Google Scholar

1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

Find articles by Hahn, H. in: JCI | PubMed | Google Scholar

1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

Find articles by Thomsen, A. in: JCI | PubMed | Google Scholar

1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

Find articles by Schmidt, B. in: JCI | PubMed | Google Scholar

1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

Find articles by Davidson, S. in: JCI | PubMed | Google Scholar |

1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

Find articles by des Georges, A. in: JCI | PubMed | Google Scholar

1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

Find articles by Khanna, R. in: JCI | PubMed | Google Scholar

1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

2Department of Anesthesiology, College of Medicine, University of Cincinnati, Cincinnati, United States of America

Find articles by Bunnett, N. in: JCI | PubMed | Google Scholar

Published November 26, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI183873.
Copyright © 2024, Peach et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 26, 2024 - Version history
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Abstract

Nerve growth factor (NGF) monoclonal antibodies inhibit chronic pain yet failed to gain approval due to worsened joint damage in osteoarthritis patients. We report that neuropilin-1 (NRP1) is a co-receptor for NGF and tropomyosin-related kinase A (TrkA) pain signaling. NRP1 was coexpressed with TrkA in human and mouse nociceptors. NRP1 inhibitors suppressed NGF-stimulated excitation of human and mouse nociceptors and NGF-evoked nociception in mice. NRP1 knockdown inhibited NGF/TrkA signaling, whereas NRP1 overexpression enhanced signaling. NGF bound NRP1 with high affinity and interacted with and chaperoned TrkA from the biosynthetic pathway to the plasma membrane and endosomes, enhancing TrkA signaling. Molecular modeling suggested that C-terminal R/KXXR/K NGF motif interacts with extracellular “b” NRP1 domain within a plasma membrane NGF/TrkA/NRP1 of 2:2:2 stoichiometry. G Alpha Interacting Protein C-terminus 1 (GIPC1), which scaffolds NRP1 and TrkA to myosin VI, colocalized in nociceptors with NRP1/TrkA. GIPC1 knockdown abrogated NGF-evoked excitation of nociceptors and pain-like behavior. Thus, NRP1 is a nociceptor-enriched co-receptor that facilitates NGF/TrkA pain signaling. NRP binds NGF and chaperones TrkA to the plasma membrane and signaling endosomes via GIPC1 adaptor. NRP1 and GIPC1 antagonism in nociceptors offers a long-awaited non-opioid alternative to systemic antibody NGF sequestration for the treatment of chronic pain.

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