Diversity and dynamic expression challenges and opportunities

The multiplicity and diversity of Na+ channels, and the fact that their expression is dynamic rather than fixed, underscore the complexity of neurons and the electrogenic machinery that they house. Differences in the ensemble of Na+ channels produced by different types of neurons, and state-dependent changes in Na+ channel expression present daunting challenges to investigators. However, now that the open reading frames for most of these channels have been elucidated, it is possible to study their expression at the mRNA level with great precision. Moreover, an increasing number of subtype-specific antibodies are becoming available. New subtype-specific toxins are being discovered and additional subtype-specific blockers may soon be developed. These will hasten the elucidation of the physiological properties and functional roles of the various Na+ channel subtypes, so that it may soon be possible to dissect the electrogenic machinery within any given type of neuron with unprecedented precision. The complexity of Na+ channel gene expression in neurons may also present some therapeutic opportunities. In so far as abnormal Na+ channel expression contributes to hypo- and hyperexcitability and/or distorted impulse trafficking, the development of subtype-specific Na+ channel modulators may provide new therapeutic inroads for the treatment of diseases of the nervous system in which neuronal excitability is altered.

Acknowledgements

Research described in this chapter has been supported, in part, by grants from the National Multiple Sclerosis Society, and from the Rehabilitation Research Service and Medical Research Service, Department of Veterans Affairs. We also thank the Eastern Paralysed Veterans Association and the Paralysed Veterans of America for support, including a gift that supports the Yale—London Collaboration.

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