Dual mechanism of modulation of [Na.sub.V]1.8 sodium channels by ouabain

• Published in: Canadian journal of physiology and pharmacology 2020-11, Vol.98 (11), p.785
• Main Authors: Plakhova, Vera B, Penniyaynen, Valentina A, Rogachevskii, Ilia V, Podzorova, Svetlana A, Khalisov, Maksim M, Ankudinov, Alexander V, Krylov, Boris V
• Format: Article
• Language: English
• Subjects: Ouabain; Physiological aspects; Sodium channels
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2020-0197

In the primary sensory neuron, ouabain activates the dual mechanism that modulates the functional activity of [Na.sub.V]1.8 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.sub.V]1.8 channel activation gating device. EO triggers the tangential signaling cascade along the neuron membrane from Na,K-ATPase to the [Na.sub.V]1.8 channel. It evokes a decrease in effective charge transfer of the [Na.sub.V]1.8 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.sub.V]1.8 channel. The delayed EO effect probably controls the density of [Na.sub.V]1.8 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.sub.V]1.8 channels' density. PKC and p38 MAPK are involved in this pathway. Identification of the dual mechanism of the strong EO effect on [Na.sub.V]1.8 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.