title: Altered sodium channel gating as molecular basis for pain: contribution of activation, inactivation, and resurgent currents.
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.
authors.affiliation: Institute of Physiology, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany, alampert@ukaachen.de.
authors.forename: Angelika
authors.initials: A
authors.lastname: Lampert
authors.forename: Mirjam
authors.initials: M
authors.lastname: Eberhardt
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000818:Animals; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008564:Membrane Potentials; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017288:Pain Threshold; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism*; D013577:Syndrome; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D061566:Voltage-Gated Sodium Channels; D012964:Sodium