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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 NGFβ sequence (NGF R100W ) 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 NGF R100W Our results show that, similar to the wild-type NGF (wtNGF), the naturally occurring NGF R100W mutant was capable of binding to and activating the TrkA receptor and its downstream signaling pathways to support neuronal survival and differentiation. However, NGF R100W failed to bind and stimulate the 75 kDa neurotrophic factor receptor (p75 NTR )-mediated signaling cascades (i.e., the RhoA-Cofilin pathway). Intraplantar injection of NGF R100W 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. Together, our studies provide evidence that NGF R100W retains trophic support capability through TrkA and one aspect of its nociceptive signaling, but fails to engage p75 NTR signaling pathways. Our findings suggest that wtNGF acts via TrkA to regulate the delayed priming of nociceptive responses. The integration of both TrkA and p75 NTR signaling thus appears to regulate neuroplastic effects of NGF in peripheral nociception. SIGNIFICANCE STATEMENT In the present study, we characterized the naturally occurring nerve growth factor NGF R100W mutant that is associated with hereditary sensory and autonomic neuropathy type V. We have demonstrated for the first time that NGF R100W retains trophic support capability through TrkA, but fails to engage p75 NTR signaling pathways. Furthermore, after intraplantar injection into adult rats, NGF R100W 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 p75 NTR -mediated signaling appears to regulate neuroplastic effects of NGF in peripheral nociception. Our study with NGF R100W suggests that it is possible to uncouple trophic effect from nociceptive function, both induced by wild-type NGF.

Swedish Nerve Growth Factor Mutation (NGFR100W) Defines a Role for TrkA and p75NTRin Nociception

Swedish Nerve Growth Factor Mutation (NGF^R100W) Defines a Role for TrkA and p75^NTRin Nociception