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1 Department of Neurology
2 Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, CT 06510
3 Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, USA
Sodium channels Nav1.2 and Nav1.6 are both normally expressed along premyelinated and myelinated axons at different stages of maturation and are also expressed in a subset of demyelinated axons, where coexpression of Nav1.6 together with the Na+/Ca2+ exchanger is associated with axonal injury. It has been difficult to distinguish the currents produced by Nav1.2 and Nav1.6 in native neurones, and previous studies have not compared these channels within neuronal expression systems. In this study, we have characterized and directly compared Nav1.2 and Nav1.6 in a mammalian neuronal cell background and demonstrate differences in their properties that may affect neuronal behaviour. The Nav1.2 channel displays more depolarized activation and availability properties that may permit conduction of action potentials, even with depolarization. However, Nav1.2 channels show a greater accumulation of inactivation at higher frequencies of stimulation (20–100 Hz) than Nav1.6 and thus are likely to generate lower frequencies of firing. Nav1.6 channels produce a larger persistent current that may play a role in triggering reverse Na+/Ca2+ exchange, which can injure demyelinated axons where Nav1.6 and the Na+/Ca2+ exchanger are colocalized, while selective expression of Nav1.2 may support action potential electrogenesis, at least at lower frequencies, while producing a smaller persistent current.
(Received 11 January 2005;
accepted after revision 7 March 2005;
first published online 10 March 2005)
Corresponding author S. G. Waxman: Department of Neurology, Yale School of Medicine, LCI 707, 333 Cedar Street, New Haven, CT 06510, USA. Email: stephen.waxman{at}yale.edu
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