Swedish Nerve Growth Factor Mutation (NGFR100W) Defines a Role for TrkA and p75NTR in Nociception

Abstract

Nerve growth factor (NGF) exerts multiple functions on target neurons throughout development. The recent discovery of a point mutation leading to a change from arginine to tryptophan at residue 100 in the mature NGF{beta} sequence (NGFR100W) in patients with hereditary sensory and autonomic neuropathy, type V (HSAN V), made it possible to distinguish the signaling mechanisms that lead to two functionally different outcomes of NGF: trophic versus nociceptive. We performed extensive biochemical, cellular and live imaging experiments to examine the binding and signaling properties of NGFR100W. Our results show that, similar to the wildtype NGF (wtNGF), the naturally occurring NGFR100W mutant was capable of binding to and activating the TrkA receptor and its downstream signaling pathways to support neuronal survival and differentiation. However, NGFR100W failed to bind and stimulate the 75kD neurotrophic factor receptor (p75NTR)-mediated signaling cascades (i.e. the RhoA-Cofilin pathway). Intraplantar injection of NGFR100W into adult rats induced neither TrkA-mediated thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia based on agonism for TrkA signaling. Taken together, our studies provide evidence that NGFR100W retains trophic support capability through TrkA and one aspect of its nociceptive signaling, but fails to engage p75NTR signaling pathways. Our findings suggest that wtNGF acts through TrkA to regulate the delayed priming of nociceptive responses. The integration of both TrkA and p75NTR signaling thus appears to regulate neuroplastic effects of NGF in peripheral nociception.\n\nSignificance StatementIn the present study, we characterized the naturally occurring NGFR100W mutant that is associated with hereditary sensory and autonomic neuropathy, type V. We have demonstrated for the first time that NGFR100W retains trophic support capability through TrkA but fails to engage p75NTR signaling pathways. Furthermore, following Intraplantar injection into adult rats, NGFR100W induced neither thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia. We have also provided evidence that the integration of both TrkA-and p75NTR-mediated signaling thus appears to regulate neuroplastic effects of NGF in peripheral nociception. Our study with NGFR100W suggests that it is possible to uncouple trophic effect from nociceptive function, both induced by wildtype NGF.\n\nAbbreviations