Dual mechanism of modulation of Na_V1.8 sodium channels by ouabain

In the primary sensory neuron, ouabain activates the dual mechanism that modulates the functional activity of Na_V1.8 channels. Ouabain at endogenous concentrations (EO) triggers two different signaling cascades, in which the Na,K-ATPase/Src complex is the EO target and the signal transducer. The fast EO effect is based on modulation of the Na_V1.8 channel activation gating device. EO triggers the tangential signaling cascade along the neuron membrane from Na,K-ATPase to the Na_V1.8 channel. It evokes a decrease in effective charge transfer of the Na_V1.8 channel activation gating device. Intracellular application of PP2, an inhibitor of Src kinase, completely eliminated the effect of EO, thus indicating the absence of direct EO binding to the Na_V1.8 channel. The delayed EO effect probably controls the density of Na_V1.8 channels in the neuron membrane. EO triggers the downstream signaling cascade to the neuron genome, which should result in a delayed decrease in the Na_V1.8 channels' density. PKC and p38 MAPK are involved in this pathway. Identification of the dual mechanism of the strong EO effect on Na_V1.8 channels makes it possible to suggest that application of EO to the primary sensory neuron membrane should result in a potent antinociceptive effect at the organismal level.