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Altered Sodium Channel Gating as Molecular Basis for Pain: Contribution of Activation, Inactivation, and Resurgent Currents

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Voltage Gated Sodium Channels

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 221))

Abstract

Mutations in voltage-gated sodium channels, especially Nav1.7, can cause the genetic pain syndromes inherited erythromelalgia, small fiber neuropathy, paroxysmal extreme pain disorder, and chronic insensitivity to pain. Functional analysis of these mutations offers the possibility of understanding the potential pathomechanisms of these disease patterns and also may help to explicate the molecular mechanisms underlying pain in normal conditions. The mutations are distributed over the whole channel protein, but nevertheless induce similar changes for each pain syndrome. In this review we focus on their impact on sodium channel gating, which may be conferred via modulation of (1) conformation (affecting all gating characteristics); (2) the amount of voltage-sensing charges (affecting mainly activation); (3) interaction within the protein (e.g., binding of the inactivation linker); and (4) interaction with other proteins (e.g., for generation of resurgent currents). Understanding the molecular basis for each gating mode and its impact on cellular excitability and nociception in each disease type may provide a basis for development of more specific and effective therapeutic tools.

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Authors and Affiliations

  1. Institute of Physiology, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany

    Angelika Lampert

  2. Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

    Mirjam Eberhardt

  3. Center for Neuroscience and Regeneration/Neurorehabilitation Research, Yale University School of Medicine, West Haven, CT, USA

    Stephen G. Waxman

  4. VA Neuroscience Research Center, Bldg. 34, VA Connecticut (127A), 950 Campbell Avenue, West Haven, CT, 06516, USA

    Stephen G. Waxman

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  1. Angelika Lampert
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  2. Mirjam Eberhardt
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  3. Stephen G. Waxman
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Correspondence to Angelika Lampert .

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Editors and Affiliations

  1. Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada

    Peter C. Ruben

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Lampert, A., Eberhardt, M., Waxman, S.G. (2014). Altered Sodium Channel Gating as Molecular Basis for Pain: Contribution of Activation, Inactivation, and Resurgent Currents. In: Ruben, P. (eds) Voltage Gated Sodium Channels. Handbook of Experimental Pharmacology, vol 221. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-41588-3_5

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