title: Altered ion channels in an animal model of Charcot-Marie-Tooth disease type IA.
abstract: How demyelination and remyelination affect the function of myelinated axons is a fundamental aspect of demyelinating diseases. We examined this issue in Trembler-J mice, a genetically authentic model of a dominantly inherited demyelinating neuropathy of humans. The K+ channels Kv1.1 and Kv1.2 channels were often improperly located in the paranodal axon membrane, typically associated with improperly formed paranodes, and in unmyelinated segments between internodes. As in wild-type nerves, Trembler-J nodes contained Nav1.6, ankyrin-G, betaIV-spectrin, and KCNQ2, but, unlike wild-type nerves, they also contained Kv3.1b and Nav1.8. In unmyelinated segments bordered by myelin sheaths, these proteins were clustered in heminodes and did not appear to be diffusely localized in the unmyelinated segments themselves. Nodes and heminodes were contacted by Schwann cells processes that did not have the ultrastructural or molecular characteristics of mature microvilli. Despite the presence of Nav1.8, a tetrodotoxin-resistant sodium channel, sciatic nerve conduction was at least as sensitive to tetrodotoxin in Trembler-J nerves as in wild-type nerves. Thus, the profound reorganization of axonal ion channels and the aberrant expression of novel ion channels likely contribute to the altered conduction in Trembler-J nerves.
authors.affiliation: Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-6077, USA. jdevaux@mail.med.upenn.edu
authors.forename: Jérôme J
authors.initials: JJ
authors.lastname: Devaux
authors.forename: Steven S
authors.initials: SS
authors.lastname: Scherer
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001369:Axons / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005267:Femoral Nerve / Q000737:chemistry / Q000648:ultrastructure; D007473:Ion Channels / Q000032:analysis / Q000378:metabolism*; D051658:KCNQ2 Potassium Channel; D051663:Kv1.2 Potassium Channel; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D023421:Models, Animal; D020125:Mutation, Missense; D009185:Myelin Proteins / Q000737:chemistry / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D062557:NAV1.6 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism*; D009431:Neural Conduction; D017354:Point Mutation; D024642:Potassium Channels, Voltage-Gated / Q000032:analysis; D011901:Ranvier's Nodes / Q000378:metabolism / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000737:chemistry / Q000648:ultrastructure; D051670:Shaw Potassium Channels; D015222:Sodium Channels / Q000032:analysis; D013049:Spectrin / Q000032:analysis; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D007473:Ion Channels; D051658:KCNQ2 Potassium Channel; C496970:Kcna2 protein, mouse; C490839:Kcnc1 protein, mouse; C114401:Kcnq2 protein, mouse; D051663:Kv1.2 Potassium Channel; D009185:Myelin Proteins; D062557:NAV1.6 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C489545:Pmp22 protein, mouse; D024642:Potassium Channels, Voltage-Gated; C568317:SCN10A protein, human; C568318:Scn10a protein, mouse; C491046:Scn8a protein, mouse; D051670:Shaw Potassium Channels; D015222:Sodium Channels; C504042:betaIV spectrin, mouse; D013049:Spectrin; D013779:Tetrodotoxin