Electrophysiological studies have revealed that the properties of voltage-gated Na+ channels can be modified by phosphorylation. Na+ channels have multiple sites for phosphorylation by protein kinases A and C (PKA and PKC). A change in the phosphorylation state of Na+ channels is an important mechanism of neuromodulation for both central and peripheral neurons. In isolated primary afferent sensory neurons, application of an inflammatory mediator, prostaglandin E2 (PGE2), causes an increase in excitability associated with a hyperpolarizing shift in the activation curve of the tetrodotoxin-resistant (TTX-R) Na+ currents. The experimental evidence indicates that the effect of PGE2 is mediated by an elevation in cAMP levels and activation of PKA. This potentiation of TTX-R Na+ channel activity is in marked contrast to the inhibitory effects of PKA and PKC on tetrodotoxin-sensitive (TTX-S) currents in central neurons. Infection of dorsal root ganglion neurons with Herpes simplex virus (HSV) results in an abolition of excitability associated with a selective loss of both TTX-S and TTX-R Na+ currents: voltage-gated Ca2+ and K+ channels are unaffected by HSV infection. The loss of Na+ current is due to a virally induced internalization process and requires extracellular Na+.