Neuropilin-1 inhibition suppresses nerve growth factor signaling and nociception in pain models
Chloe J. Peach, … , Rajesh Khanna, Nigel W. Bunnett
Chloe J. Peach, … , Rajesh Khanna, Nigel W. Bunnett
Published November 26, 2024
Citation Information: J Clin Invest. 2025;135(4):e183873. https://doi.org/10.1172/JCI183873.
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Research Article Cell biology Neuroscience

Neuropilin-1 inhibition suppresses nerve growth factor signaling and nociception in pain models

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 coreceptor 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 the C-terminal R/KXXR/K NGF motif interacts with the extracellular “b” NRP1 domain within a plasma membrane NGF/TrkA/NRP1 of 2:2:2 stoichiometry. G α 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 coreceptor that facilitates NGF/TrkA pain signaling. NRP binds NGF and chaperones TrkA to the plasma membrane and signaling endosomes via the GIPC1 adaptor. NRP1 and GIPC1 antagonism in nociceptors offers a long-awaited nonopioid alternative to systemic antibody NGF sequestration for the treatment of chronic pain.

Authors

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

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Figure 10

Hypothesized mechanism by which NRP1 mediates NGF/TrkA pain signaling.

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Hypothesized mechanism by which NRP1 mediates NGF/TrkA pain signaling. i...
i. NGF is released from diseased tissues (e.g., sites of injury, inflammation, cancer) in close proximity to the peripheral endings of nociceptors. ii. At the surface of nociceptors, NGF binds to both NRP1 and TrkA, forming a ternary NGF/NRP1/TrkA complex with a 2:2:2 stoichiometry. iii. TrkA signals from the plasma membrane and endosomes to activate kinases and ion channels. iv. Activation and sensitization of TRPV1 and Na+ and Ca2+ channels lead to increased excitability of nociceptors. v. NRP1 chaperones TrkA from the biosynthetic pathway to the plasma membrane and to signaling endosomes, which further enhances excitability of nociceptors. vi. GIPC1 interacts with NRP1 and TrkA, linking the complex to the myosin VI molecular motor to amplify pain signaling. As such, by binding NGF and interacting with TrkA, NRP1 is a coreceptor that facilitates NGF/TrkA signaling of pain.