Elevated expression of type II Na+ channels in hypomyelinated axons of shiverer mouse brain

Abstract

Type I and type III Na+ channels are localized mainly in neuronal cell bodies in mouse brain. Type II channels are preferentially localized in unmyelinated fiber tracts but are not detectable in normally myelinated fibers. In shiverer mice, which lack compact myelin due to a defect in the myelin basic protein gene, elevated expression of type II Na+ channels was observed in the hypomyelinated axons of large-caliber fiber tracts such as the corpus callosum, internal capsule, fimbria, fornix, corpus medullare of the cerebellum, and nigrostriatal pathway by immunocytochemical analysis with subtype-specific antibodies. No difference was observed in the localization of type I and type III Na+ channels between wild-type and shiverer mice. These findings support the hypothesis that type II Na+ channels are preferentially localized in axons of brain neurons and suggest that their density and localization are regulated by myelination. The selective increase in the number of type II channels in hypomyelinated fiber tracts may contribute to the hyperexcitable phenotype of the shiverer mouse.

Molecular changes in neurons in multiple sclerosis: Altered axonal expression of Na v 1.2 and Na v 1.6 sodium channels and Na + /Ca 2 + exchanger

“…Myelinated axons, which are sensitive to injury produced by reverse Na ϩ ͞Ca 2ϩ exchange driven by a persistent Na current (10,11), express Na v 1.6 at higher levels than other sodium channels (2,4). In contrast, dysmyelinating CNS axons, which express Na v 1.2 rather than Na v 1.6, (3,23), are substantially less sensitive than myelinated axons to this type of injury (53). Na v 1.6 channels produce a persistent current in addition to a transient current (33,37), and the persistent current produced by Na v 1.6 is much larger than the persistent current produced by Na v 1.2 (33).…”

“…In dysmyelinated axons from Shiverer mice, Na v 1.2 channels are retained, and Na v 1.6 is not expressed (3,23), and in axons from Plp͞Ϫ mice, which myelinate normally and then lose their myelin, there is a loss of Na v 1.6 clustering and increased expression of Na v 1.2 (24). Electrophysiological (25), cytochemical (26), and immunocytochemical (27)(28)(29) studies using pan-specific sodium-channel antibodies demonstrate a higher-than-normal density of sodium channels in chronically demyelinated axons but do not reveal the isoforms of the channels.…”

Regulation of NaV1.2 Channels by Brain-Derived Neurotrophic Factor, TrkB, and Associated Fyn Kinase

“…Membrane lysates (50 g) and immunoprecipitated proteins were separated by SDS-PAGE and transferred to polyvinylidene difluoride (PVDF) membrane (GE Healthcare, Piscataway, NJ). Blots were probed with antibodies against the family of Src kinases (SRC2; Santa Cruz Biotechnology, Santa Cruz, CA), Src (H-12; Santa Cruz Biotechnology), Fyn (Millipore, Billerica, MA), Lyn (H-6; Santa Cruz Biotechnology), Yes (F-7; Santa Cruz Biotechnology), or sodium channel (anti-SP20) (Westenbroek et al, 1989(Westenbroek et al, , 1992, and detected by chemiluminescence (GE Healthcare).…”

Early events in node of Ranvier formation during myelination and remyelination in the PNS

“…Transgenic mice that overexpress the proteolipid protein (Plp) develop adult onset chronic demyelination (Kagawa et al, 1994;Inoue et al, 1996). In both model animals there is a dramatic upregulation of axonal Nav1.2 (Westenbroek et al, 1992;Boiko et al, 2001;Rasband et al, 2003a). The increase in Nav1.2 is mirrored by a loss of clustered Nav1.6 from nodes (Rasband et al, 1999;Boiko et al, 2001).…”