title: KV1 channels identified in rodent myelinated axons, linked to Cx29 in innermost myelin: support for electrically active myelin in mammalian saltatory conduction.
abstract: Saltatory conduction in mammalian myelinated axons was thought to be well understood before recent discoveries revealed unexpected subcellular distributions and molecular identities of the K(+)-conductance pathways that provide for rapid axonal repolarization. In this study, we visualize, identify, localize, quantify, and ultrastructurally characterize axonal KV1.1/KV1.2 channels in sciatic nerves of rodents. With the use of light microscopic immunocytochemistry and freeze-fracture replica immunogold labeling electron microscopy, KV1.1/KV1.2 channels are localized to three anatomically and compositionally distinct domains in the internodal axolemmas of large myelinated axons, where they form densely packed "rosettes" of 9-nm intramembrane particles. These axolemmal KV1.1/KV1.2 rosettes are precisely aligned with and ultrastructurally coupled to connexin29 (Cx29) channels, also in matching rosettes, in the surrounding juxtaparanodal myelin collars and along the inner mesaxon. As >98% of transmembrane proteins large enough to represent ion channels in these specialized domains, ∼500,000 KV1.1/KV1.2 channels define the paired juxtaparanodal regions as exclusive membrane domains for the voltage-gated K(+)conductance that underlies rapid axonal repolarization in mammals. The 1:1 molecular linkage of KV1 channels to Cx29 channels in the apposed juxtaparanodal collars, plus their linkage to an additional 250,000-400,000 Cx29 channels along each inner mesaxon in every large-diameter myelinated axon examined, supports previously proposed K(+)conductance directly from juxtaparanodal axoplasm into juxtaparanodal myeloplasm in mammalian axons. With neither Cx29 protein nor myelin rosettes detectable in frog myelinated axons, these data showing axon-to-myelin linkage by abundant KV1/Cx29 channels in rodent axons support renewed consideration of an electrically active role for myelin in increasing both saltatory conduction velocity and maximum propagation frequency in mammalian myelinated axons.
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado; Program in Molecular, Cellular and Integrative Neurosciences, Colorado State University, Fort Collins, Colorado; and.
authors.forename: John E
authors.identifier: http://orcid.org/0000-0003-2821-5532
authors.initials: JE
authors.lastname: Rash
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado;
authors.forename: Kimberly G
authors.initials: KG
authors.lastname: Vanderpool
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado;
authors.forename: Thomas
authors.initials: T
authors.lastname: Yasumura
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado;
authors.forename: Jordan
authors.initials: J
authors.lastname: Hickman
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado;
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Beatty
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: James I
authors.initials: JI
authors.lastname: Nagy
mesh_terms: D000200:Action Potentials; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000502:physiology; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000378:metabolism* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009431:Neural Conduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D051637:Shaker Superfamily of Potassium Channels / Q000378:metabolism*
chemical_list: D017630:Connexins; C464673:Gje1 protein, mouse; D009419:Nerve Tissue Proteins; D051637:Shaker Superfamily of Potassium Channels
keywords: Cx29 channels; KV1.1/KV1.2 channels; inner mesaxon; juxtamesaxon; juxtaparanode