Which Na+ channel subtypes generating persistent Na+ current are present in myelinated axons? The evidence already discussed suggests that TTX-s currents play a leading role. The explanation as to how TTX-s persistent currents are generated is probably that at least some Na+ channels can lose their ability to undergo fast inactivation and/or exhibit a second open state.
While all transient Na+ channels are expected to generate a small, steady-state activation-inactivation gating (mh) overlap current, some subtypes seem particularly adept at generating a persistent current at negative membrane potentials. The persistent currents found in primary afferents have been attributed to Na^.9 (NaN) (Cummins et al., 1999; Dib-Hajj et al., 2002) and surmised to be generated by NaV1.6 (Baker and Bostock, 1998). Whereas NaV1.9 is a Na+ channel found in small diameter axons, NaV1.6 is probably the major Na+ channel isoform in both normal peripheral and central myelinated axons (Caldwell et al., 2000). NaV1.6 is a TTX-s channel, known to generate persistent and "resurgent" currents in central neurons during relatively brief voltage-clamp protocols (Raman et al., 1997). Resurgence is a kinetic property seen in voltage-clamp, characteristic of NaV1.6, in which channels apparently open from the inactivated state (into which they have previously entered during a positive prepulse) within a narrow range of membrane potentials close to the activation threshold for the current, rather than remaining nonconducting.
These properties of NaV1.6 contribute to the spontaneous and burst-firing of cerebellar Purkinje neurons (Kahliq et al., 2003). NaV1.6, when transfected and expressed in NaV1.8 null neurons, may well generate a persistent current over a wider potential range than NaV1.7 (data presented by Herzog et al. 2003a). Baker and Bostock (1997, 1998) found a low-threshold, persistent TTX-s Na+ current in large diameter DRG neurons in the rat, and Kiernan et al. (2003) found a similar current in about one third of small (<25 |im, apparent diameter) neurons. This current also exhibited "resurgence" in large neurons (unpublished observation). NaV1.6 appears to be the predominant Na+ channel at peripheral nodes of Ranvier and in optic nerve (Caldwell et al., 2000). It is also found in unmyelinated axons in the retina and the parallel fibers of the cerebellum (Caldwell et al., 2000; Schaller and Caldwell, 2003). Black et al. (2002) have provided evidence that NaV1.6 is present in unmyelinated corneal afferents and probably contributes to conduction in unmyelinated sciatic nerve axons. The distribution of NaV1.6 mRNA expression in primary sensory neurons indicates that it is widely expressed in both myelinated and unmyelinated axon cell bodies (Black et al., 1996). The channel gene includes the med locus, where med
(motor end-plate disease) is associated with loss of action potential invasion of the mouse motor nerve terminal (Duchen and Stefani, 1971). In med mutants, immunostaining for NaV1.6 is lost at nodes of Ranvier (Caldwell et al., 2000). The failure of action potential propagation into motor nerve terminals may simply reflect a reduced safety factor for action potential invasion after a general fall in Na+ channel density. Alternatively, where there is compensation for the functional loss of NaV1.6 in axons, allowing axonal conduction to continue, it is conceivable that a low-threshold, persistent current may be important in initiating an action potential within this unmyelinated, high-capacitance structure at the end of a motor nerve, and that such a current is lost in the mutant. Herzog et al. (2003b) reported that the expression of mutant NaV1.6 in peripheral neurons (from an NaV1.8 null) is dependent on calmodulin binding to the channel C-terminus, and that raised internal [Ca2+] can slow the macroscopic inac-tivation kinetics, indicating that channel open-time is probably increased by Ca2+ binding with the channel-calmodlin complex. Thus Ca2+ influx might increase the amount of persistent current by modifying channel gating.
Recently, Craner et al. (2003) have reported that in allergic encephalomyelitis, optic nerve axons not only express NaV1.6, but also NaV1.2 along apparently demeylinated internodes. These findings suggest that in central axons, NaV1.6 and NaV1.2 could contribute to the conferment of excitability in denuded internodes, although the authors believe that NaV1.2 becomes the most commonly expressed channel in demyelinated axons.
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