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 (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 wild-type 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 75 kDa 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. 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 via 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.SIGNIFICANCE STATEMENT In the present study, we characterized the naturally occurring nerve growth factor 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, after 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 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 wild-type NGF.

• Authors: Kijung Sung, Luiz F Ferrari, Wanlin Yang, ChiHye Chung, Xiaobei Zhao, Yingli Gu, Suzhen Lin, Kai Zhang, Bianxiao Cui, Matthew L Pearn, Michael T Maloney, William C Mobley, Jon D Levine, Chengbiao Wu
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 38 Issue 14 Pg. 3394-3413 (04 04 2018) ISSN: 1529-2401 [Electronic] United States
• PMID: 29483280 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 the authors 0270-6474/18/383395-20$15.00/0.

Chemical References

• Nerve Tissue Proteins
• Receptors, Growth Factor
• Receptors, Nerve Growth Factor
• Ngfr protein, rat
• Nerve Growth Factor
• Receptor, trkA

Topics

• 3T3 Cells
• Animals
• Cells, Cultured
• HEK293 Cells
• Hereditary Sensory and Autonomic Neuropathies (genetics, metabolism, physiopathology)
• Humans
• Male
• Mice
• Mutation, Missense
• Nerve Growth Factor (genetics, metabolism)
• Nerve Tissue Proteins
• Nociception
• PC12 Cells
• Protein Binding
• Rats
• Rats, Sprague-Dawley
• Receptor, trkA (metabolism)
• Receptors, Growth Factor
• Receptors, Nerve Growth Factor (metabolism)
• Signal Transduction