Dual mechanism of modulation of NaV1.8 sodium channels by ouabain

In the primary sensory neuron, ouabain activates the dual mechanism that modulates the functional activity of Na 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 f...

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Bibliographic Details
Published in:Canadian journal of physiology and pharmacology 2020, Vol.98 (11), p.785-802
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:
Channel gating
culture de tissu nerveux organotypique
Enzyme inhibitors
Genomes
MAP kinase
méthode de patch-clamp
Na+/K+-exchanging ATPase
Na,K-ATPase
neurone sensoriel
nociception
organotypic nerve tissue culture
Ouabain
Pain perception
patch-clamp method
Protein kinase C
sensory neuron
Sodium channels (voltage-gated)
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Summary:In the primary sensory neuron, ouabain activates the dual mechanism that modulates the functional activity of Na 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 V 1.8 channel activation gating device. EO triggers the tangential signaling cascade along the neuron membrane from Na,K-ATPase to the Na V 1.8 channel. It evokes a decrease in effective charge transfer of the Na 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 V 1.8 channel. The delayed EO effect probably controls the density of Na 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 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 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.
ISSN:0008-4212
1205-7541
DOI:10.1139/cjpp-2020-0197