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

Nerve growth factor (NGF) monoclonal antibodies are one of the few patient-validated non-opioid treatments for chronic pain, despite failing to gain FDA approval. Herein, we demonstrate that neuropilin-1 (NRP1) is a co-receptor for NGF that potentiates tropomyosin-related kinase A (TrkA) signaling. NGF binds NRP1 with nanomolar affinity. NRP1 and its associated adaptor protein GIPC1 are coexpressed with TrkA in nociceptors, particularly in human tissues. NRP1 inhibitors prevent NGF-stimulated action potential firing of 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 signaling. As well as interacting with NGF, NRP1 forms a heteromeric complex that chaperones TrkA from the biosynthetic pathway to the plasma membrane and signaling endosomes. NRP1 thereby enhances NGF-induced TrkA dimerization, endocytosis and signaling. Knockdown of GIPC1, a PDZ-binding protein that scaffolds NRP1 and TrkA cargo to myosin VI, abrogates NGF-evoked nociception. We identify NRP1 as a previously unrecognized co-receptor necessary for NGF/TrkA pain signaling by direct NGF binding and chaperoning TrkA to the plasma membrane and signaling endosomes via the adaptor protein GIPC1 - a discovery that offers a long-awaited alternative to block NGF-evoked pain.