Neuropilin-1 is a co-receptor for NGF and TrkA-evoked pain

Abstract

AbstractNerve growth factor (NGF) monoclonal antibodies (mAb) are one of the few patient-validated non-opioid treatments for chronic pain, despite failing to gain FDA approval due to worsened joint damage in some osteoarthritis patients. Herein, we demonstrate that neuropilin-1 (NRP1) is a nociceptor-enriched co-receptor for NGF that is necessary for tropomyosin-related kinase A (TrkA) signaling of pain. NGF binds NRP1 with nanomolar affinity. NRP1 and G Alpha Interacting Protein C-terminus 1 (GIPC1), a NRP1/TrkA adaptor, are coexpressed with TrkA in human and mouse nociceptors. NRP1 small molecule inhibitors and blocking mAb prevent NGF-stimulated action potential firing and activation of Na+and Ca2+channels in human and mouse nociceptors and abrogate NGF-evoked and inflammatory nociception in mice. NRP1 knockdown blunts NGF-stimulated TrkA phosphorylation, kinase signaling and transcription, whereas NRP1 overexpression enhances NGF and TrkA signaling. As well as interacting with NGF, NRP1 forms a heteromeric complex with TrkA. NRP1 thereby chaperones TrkA from the biosynthetic pathway to the plasma membrane and then to signaling endosomes, which enhances NGF-induced TrkA dimerization, endocytosis and signaling. Knockdown of GIPC1, a PDZ-binding protein that scaffolds NRP1 and TrkA to myosin VI, abrogates NGF-evoked excitation of nociceptors and pain-like behavior in mice. We identify NRP1 as a previously unrecognized co-receptor necessary for NGF/TrkA pain signaling by direct NGF binding and by chaperoning TrkA to the plasma membrane and signaling endosomesviathe adaptor protein GIPC1. Antagonism of NRP1 and GIPC1 in nociceptors offers a long-awaited alternative to systemic sequestration of NGF with mAbs for the treatment of pain.Significance StatementAlthough monoclonal antibodies to nerve growth factor (NGF) reduce pain in patients with osteoarthritis, they failed to gain FDA approval due to the deleterious consequences of sequestrating NGF throughout the body. We report that neuropilin 1 (NRP1) is an alternative target for the treatment of NGF-dependent pain. NRP1 and the NGF receptor, tropomyosin-related kinase A (TrkA), are coexpressed in neurons that that detect painful stimuli in humans and mice. NRP1 binds NGF and escorts TrkA to the surface of pain-sensing nerves. NRP1 antagonism prevents NGF-and TrkA-mediated pain. The identification of NRP1 as an NGF receptor that is enriched in pain-sensing nerves reveals an alternate and much-needed target for treatment of the multiple forms of NGF-evoked pain.