Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses.

Voltage-gated sodium channels perform critical roles for electrical signaling in the nervous system by generating action potentials in axons and in dendrites. At least 10 genes encode sodium channels in mammals, but specific physiological roles that distinguish each of these isoforms are not known. One possibility is that each isoform is expressed in a restricted set of cell types or is targeted to a specific domain of a neuron or muscle cell. Using affinity-purified isoform-specific antibodies, we find that Na(v)1.6 is highly concentrated at nodes of Ranvier of both sensory and motor axons in the peripheral nervous system and at nodes in the central nervous system. The specificity of this antibody was also demonstrated with the Na(v)1.6-deficient mouse mutant strain med, whose nodes were negative for Na(v)1.6 immunostaining. Both the intensity of labeling and the failure of other isoform-specific antibodies to label nodes suggest that Na(v)1.6 is the predominant channel type in this structure. In the central nervous system, Na(v)1.6 is localized in unmyelinated axons in the retina and cerebellum and is strongly expressed in dendrites of cortical pyramidal cells and cerebellar Purkinje cells. Ultrastructural studies indicate that labeling in dendrites is both intracellular and on dendritic shaft membranes. Remarkably, Na(v)1.6 labeling was observed at both presynaptic and postsynaptic membranes in the cortex and cerebellum. Thus, a single sodium channel isoform is targeted to different neuronal domains and can influence both axonal conduction and synaptic responses.

[1]  J. Trimmer,et al.  Dependence of Nodal Sodium Channel Clustering on Paranodal Axoglial Contact in the Developing CNS , 1999, The Journal of Neuroscience.

[2]  E. Peles,et al.  The Axonal Membrane Protein Caspr, a Homologue of Neurexin IV, Is a Component of the Septate-like Paranodal Junctions That Assemble during Myelination , 1997, The Journal of cell biology.

[3]  R. Wenthold,et al.  Differential Distribution of Intracellular Glutamate Receptors in Dendrites , 1999, The Journal of Neuroscience.

[4]  Clay M. Armstrong,et al.  Dendritic Function: Where does it all begin? , 1994, Current Biology.

[5]  J. Salzer Creating Barriers A New Role for Schwann Cells and Desert Hedgehog , 1999, Neuron.

[6]  S. Halegoua,et al.  Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  I. Raman,et al.  Altered Subthreshold Sodium Currents and Disrupted Firing Patterns in Purkinje Neurons of Scn8a Mutant Mice , 1997, Neuron.

[8]  J. Caldwell,et al.  Developmental and regional expression of sodium channel isoform NaCh6 in the rat central nervous system , 2000, The Journal of comparative neurology.

[9]  R. Albin,et al.  Dystonia associated with mutation of the neuronal sodium channel Scn8a and identification of the modifier locus Scnm1 on mouse chromosome 3. , 1999, Human molecular genetics.

[10]  R. Llinás,et al.  Molecular characterization of the sodium channel subunits expressed in mammalian cerebellar Purkinje cells. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[11]  W. Catterall,et al.  Elevated expression of type II Na+ channels in hypomyelinated axons of shiverer mouse brain , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[12]  K. Svoboda,et al.  Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. , 1999, Science.

[13]  Arthur J Moss,et al.  SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome , 1995, Cell.

[14]  S. Levinson,et al.  Clustering of Na+ channels and node of Ranvier formation in remyelinating axons , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[15]  W. Schreibmayer Isoform Diversity and Modulation of Sodium Channels by Protein Kinases , 1999, Cellular Physiology and Biochemistry.

[16]  H. Takeshima,et al.  Expression of functional sodium channels from cloned cDNA , 1986, Nature.

[17]  R. Eglen,et al.  Functional Analysis of a Voltage‐Gated Sodium Channel and Its Splice Variant from Rat Dorsal Root Ganglia , 1998, Journal of neurochemistry.

[18]  D. Prince,et al.  Sodium channels in dendrites of rat cortical pyramidal neurons. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Peter Shrager,et al.  Caspr2, a New Member of the Neurexin Superfamily, Is Localized at the Juxtaparanodes of Myelinated Axons and Associates with K+ Channels , 1999, Neuron.

[20]  M. Meisler,et al.  Mutation of a new sodium channel gene, Scn8a, in the mouse mutant ‘motor endplate disease’ , 1995, Nature Genetics.

[21]  A. Goldin Diversity of Mammalian Voltage‐Gated Sodium Channels , 1999, Annals of the New York Academy of Sciences.

[22]  N. Spruston,et al.  Action potential initiation and backpropagation in neurons of the mammalian CNS , 1997, Trends in Neurosciences.

[23]  H. Takeshima,et al.  Existence of distinct sodium channel messenger RNAs in rat brain , 1986, Nature.

[24]  A. L. Goldin,et al.  A rat brain na+ channel α subunit with novel gating properties , 1988, Neuron.

[25]  S. Cannon From mutation to myotonia in sodium channel disorders , 1997, Neuromuscular Disorders.

[26]  M. Meisler,et al.  Mutation Detection in the med and medJ Alleles of the Sodium Channel Scn8a , 1996, The Journal of Biological Chemistry.

[27]  A. L. Goldin,et al.  A Missense Mutation in the Sodium Channel Scn8a Is Responsible for Cerebellar Ataxia in the Mouse Mutant jolting , 1996, The Journal of Neuroscience.

[28]  P. Yarowsky,et al.  A novel, abundant sodium channel expressed in neurons and glia , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[29]  William A. Catterall,et al.  Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons , 1989, Neuron.

[30]  I. Duncan,et al.  Induction of sodium channel clustering by oligodendrocytes , 1997, Nature.

[31]  L. Duchen,et al.  Electrophysiological studies of neuromuscular transmission in hereditary ‘motor end‐plate disease’ of the mouse , 1971, The Journal of physiology.

[32]  J. Caldwell,et al.  Immunolocalization of sodium channel isoform NaCh6 in the nervous system , 2000, The Journal of comparative neurology.

[33]  William A Catterall,et al.  Persistent Sodium Currents through Brain Sodium Channels Induced by G Protein βγ Subunits , 1997, Neuron.

[34]  J. Schlessinger,et al.  Identification of a novel contactin‐associated transmembrane receptor with multiple domains implicated in protein–protein interactions , 1997, The EMBO journal.

[35]  J. Caldwell,et al.  Na channel distribution in vertebrate skeletal muscle , 1986, The Journal of general physiology.

[36]  K. Rhodes,et al.  Type I and type II Na+ channel α‐subunit polypeptides exhibit distinct spatial and temporal patterning, and association with auxiliary subunits in rat brain , 1999, The Journal of comparative neurology.

[37]  D. Johnston,et al.  Electrical and calcium signaling in dendrites of hippocampal pyramidal neurons. , 1998, Annual review of physiology.