The voltage-dependent Na+ channel of the brain is a good substrate for phosphorylation by the cAMP-dependent protein kinase (protein kinase A, or PKA), but the physiological effects of PKA on Na+ channels are poorly documented. We studied modulation by PKA of voltage-dependent Na+ channels expressed in Xenopus oocytes injected with RNA coding for the alpha-subunit of the channel protein (rat brain type IIA and its variant VA200), using the two electrode voltage-clamp technique. Intracellularly injected cAMP or catalytic subunit of PKA, or extracellularly applied forskolin, inhibited the Na+ current by 20–30%. The effect of cAMP was attenuated by prior injection of PKA inhibitors. Injection of small doses of protein phosphatase 2A increased the Na+ current by 10%, whereas larger doses of protein phosphatase 1 and alkaline phosphatase were without effect. The inhibition by PKA showed little voltage dependence, being only slightly stronger at holding potentials at which the availability of the channels was reduced. The voltage dependence of activation and inactivation processes was not altered by cAMP. Similar effects were exerted by forskolin and cAMP on the Na+ channels expressed after the injection of heterologous (total) RNA from rat brain. Thus, PKA modulates the Na+ channel by a mechanism that does not involve major changes in the voltage dependency of the current and is exerted on the channel-forming alpha-subunit.