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The Biophysical Basis Underlying Gating Changes in the p.V1316A Mutant Nav1.7 Channel and the Molecular Pathogenesis of Inherited Erythromelalgia

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  • Chiung-Wei Huang
  • Hsing-Jung Lai
  • Po-Yuan Huang
  • Ming-Jen Lee
  • Chung-Chin Kuo

Abstract

The Nav1.7 channel critically contributes to the excitability of sensory neurons, and gain-of-function mutations of this channel have been shown to cause inherited erythromelalgia (IEM) with neuropathic pain. In this study, we report a case of a severe phenotype of IEM caused by p.V1316A mutation in the Nav1.7 channel. Mechanistically, we first demonstrate that the Navβ4 peptide acts as a gating modifier rather than an open channel blocker competing with the inactivating peptide to give rise to resurgent currents in the Nav1.7 channel. Moreover, there are two distinct open and two corresponding fast inactivated states in the genesis of resurgent Na+ currents. One is responsible for the resurgent route and practically existent only in the presence of Navβ4 peptide, whereas the other is responsible for the “silent” route of recovery from inactivation. In this regard, the p.V1316A mutation makes hyperpolarization shift in the activation curve, and depolarization shift in the inactivation curve, vividly uncoupling inactivation from activation. In terms of molecular gating operation, the most important changes caused by the p.V1316A mutation are both acceleration of the transition from the inactivated states to the activated states and deceleration of the reverse transition, resulting in much larger sustained as well as resurgent Na+ currents. In summary, the genesis of the resurgent currents in the Nav1.7 channel is ascribable to the transient existence of a distinct and novel open state promoted by the Navβ4 peptide. In addition, S4–5 linker in domain III where V1316 is located seems to play a critical role in activation–inactivation coupling, chiefly via direct modulation of the transitional kinetics between the open and the inactivated states. The sustained and resurgent Na+ currents may therefore be correlatively enhanced by specific mutations involving this linker and relevant regions, and thus marked hyperexcitability in corresponding neural tissues as well as IEM symptomatology.Mutations in the Nav1.7 sodium channel cause idiopathic erythromelalgia. This study shows that the pathogenic resurgent sodium currents arise via modification of gating behavior rather than via competing pore block by the Navβ4 peptide.Author Summary: The gain-of-function mutation (p.V1316A) of the Nav1.7 channel causes inherited erythromelalgia (IEM), a disease characterized by extremely enhanced activity in relevant neural tissues that results in neuropathic pain. We found that the p.V1316A mutation alters the basic gating properties of the channel, leading to increased sustained currents during membrane depolarization and resurgent currents during repolarization. Neurons expressing these mutant channels are more difficult to maintain in a hyperpolarized state and are thus more excitable. We demonstrate that there is very likely a distinct set of open/inactivated (O/I) states responsible for the genesis of resurgent currents. We show that the p.V1316A mutation chiefly accelerates the I to O transition in this set, but also decelerates the transitions between different sets of O/I states, to cause the channel gating and cellular excitability changes. Contrary to the conventional view, we find that the Navβ4 peptide, a key element responsible for sizable resurgent currents, does not seem to act as a pore blocker that competes with the inactivation peptide. Instead, we show that it acts as a gating modifier of the Nav1.7 channel. Thus, the DIII/S4–5 linker, where V1316 is located, may play a critical role not only in O/I coupling but also in the couplings between different sets of O/I in the Nav1.7 channel.

Suggested Citation

  • Chiung-Wei Huang & Hsing-Jung Lai & Po-Yuan Huang & Ming-Jen Lee & Chung-Chin Kuo, 2016. "The Biophysical Basis Underlying Gating Changes in the p.V1316A Mutant Nav1.7 Channel and the Molecular Pathogenesis of Inherited Erythromelalgia," PLOS Biology, Public Library of Science, vol. 14(9), pages 1-31, September.
  • Handle: RePEc:plo:pbio00:1002561
    DOI: 10.1371/journal.pbio.1002561
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    1. Jian Payandeh & Todd Scheuer & Ning Zheng & William A. Catterall, 2011. "The crystal structure of a voltage-gated sodium channel," Nature, Nature, vol. 475(7356), pages 353-358, July.
    2. James J. Cox & Frank Reimann & Adeline K. Nicholas & Gemma Thornton & Emma Roberts & Kelly Springell & Gulshan Karbani & Hussain Jafri & Jovaria Mannan & Yasmin Raashid & Lihadh Al-Gazali & Henan Hama, 2006. "An SCN9A channelopathy causes congenital inability to experience pain," Nature, Nature, vol. 444(7121), pages 894-898, December.
    3. Jian Payandeh & Tamer M. Gamal El-Din & Todd Scheuer & Ning Zheng & William A. Catterall, 2012. "Crystal structure of a voltage-gated sodium channel in two potentially inactivated states," Nature, Nature, vol. 486(7401), pages 135-139, June.
    4. Marcel P. Goldschen-Ohm & Deborah L. Capes & Kevin M. Oelstrom & Baron Chanda, 2013. "Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel," Nature Communications, Nature, vol. 4(1), pages 1-10, June.
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