Neuropilin-1 inhibition suppresses nerve growth factor signaling and nociception in pain models
Year: 2024
Type: article
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 is coexpressed with TrkA in human and mouse nociceptors. NRP1 inhibitors suppress NGF-stimulated excitation of human and mouse nociceptors and NGF-evoked nociception in mice. NRP1 knockdown inhibits NGF/TrkA signaling, whereas NRP1 overexpression enhances signaling. NGF binds NRP1 with high affinity and interacts with and chaperones TrkA from the biosynthetic pathway to the plasma membrane and endosomes, enhancing TrkA signaling. Molecular modeling suggests 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) scaffolds NRP1 and TrkA to myosin VI and colocalizes in nociceptors with NRP1/TrkA. GIPC1 knockdown abrogates NGF-evoked excitation of nociceptors and pain-like behavior. 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 the 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. Summary: Neuropilin-1 and G Alpha Interacting Protein C-terminus 1 are necessary for nerve growth factor-evoked pain and are non-opioid therapeutic targets for chronic pain.
DOI: 10.1172/jci183873
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
Institutions: New York University, University of Cincinnati
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Defense, University of Cincinnati, York University, National Institutes of Health, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Dental and Craniofacial Research
Awards: CRMP2, mitochondria, and Huntington’s disease, Trafficking-Dependent Signaling of Pain by Protease-Activated Receptors, Endosomal mechanisms signaling oral cancer pain, G2266079415, Protease/PAR2/TRPV4 Axis and Oral Cancer Pain, Targeting Endosomal Receptors for Treatment of Chronic Pain, CRMP2, Nav1.7 sodium channel, and chronic pain, RECEPTORS IN ENDOSOMES MEDIATE CHRONIC PAIN ASSOCIATED WITH TRAUMA AND STRESS: NON-OPIOID TARGETS FOR PAIN, Lymphocyte Antigen 6 (Ly6) Proteins: New Players in Chronic Pain, Genetic and Pharmacological Validation of CRMP2 Phosphorylation as a Novel therapeutic Target for Neuropathic Pain, RECEPTORS IN ENDOSOMES MEDIATE CHRONIC PAIN ASSOCIATED WITH TRAUMA, INFLAMMATION, AND STRESS: NON-OPIOID TARGETS FOR SUSTAINED RELIEF OF PAIN, Endosomal Platforms for Signaling Pain, Understanding membrane proteins’ allosteric modulation with cryo-EM, Spatiotemporal Regulation of GPCR Signaling by Different Beta-Arrestin Conformations
OpenAlex ID: W4404745306