Dual mechanism of modulation of Na1.8 sodium channels by ouabain.

In the primary sensory neuron, ouabain activates the dual mechanism that modulates the functional activity of Na1.8 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 Na1.8 channel activation gating device. EO triggers the tangential signaling cascade along the neuron membrane from Na,K-ATPase to the Na1.8 channel. It evokes a decrease in effective charge transfer of the Na1.8 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 Na1.8 channel. The delayed EO effect probably controls the density of Na1.8 channels in the neuron membrane. EO triggers the downstream signaling cascade to the neuron genome, which should result in a delayed decrease in the Na1.8 channels' density. PKC and p38 MAPK are involved in this pathway. Identification of the dual mechanism of the strong EO effect on Na1.8 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.