Neuromodulation of Na+ channels: an unexpected form of cellular plasticity.

Voltage-gated Na+ channels set the threshold for action potential generation and are therefore good candidates to mediate forms of plasticity that affect the entire neuronal output. Although early studies led to the idea that Na+ channels were not subject to modulation, we now know that Na+ channel function is affected by phosphorylation. Furthermore, Na+ channel modulation is implicated in the control of input-output relationships in several types of neuron and seems to be involved in phenomena as varied as cocaine withdrawal, hyperalgesia and light adaptation. Here we review the available evidence for the regulation of Na+ channels by phosphorylation, its molecular mechanism, and the possible ways in which it affects neuronal function.