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 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.

Keywords: NGF; TrkA; nociception; p75; sensory neuron; trophic.