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Tumor necrosis factor-? downregulates sodium current in skeletal muscle by protein kinase C activation: involvement in critical illness polyneuromyopathy.

Abstract : Sepsis is involved in the decrease of membrane excitability of skeletal muscle, leading to polyneuromyopathy. This effect is mediated by alterations of the properties of voltage-gated sodium channels (Na(V)), but the exact mechanism is still unknown. The aim of the present study was to check whether tumor necrosis factor (TNF-?), a cytokine released during sepsis, exerts a rapid effect on Na(V). Sodium current (I(Na)) was recorded by macropatch clamp in skeletal muscle fibers isolated from rat peroneus longus muscle, in control conditions and after TNF-? addition. Analyses of dose-effect and time-effect relationships were carried out. Effect of chelerythrine, a PKC inhibitor, was also studied to determine the way of action of TNF-?. TNF-? induced a reversible dose- and time-dependent inhibition of I(Na). A maximum inhibition of 75% of the control current was observed. A shift toward more negative potentials of activation and inactivation curves of I(Na) was also noticed. These effects were prevented by chelerythrine pretreatment. TNF-? is a cytokine released in the early stages of sepsis. Besides a possible transcriptional role, i.e., modification of the channel type and/or number, we demonstrated the existence of a rapid, posttranscriptional inhibition of Na(V) by TNF-?. The downregulation of the sodium current could be mediated by a PKC-induced phosphorylation of the sodium channel, thus leading to a significant decrease in muscle excitability.
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01159463
Contributor : Laurent Jonchère <>
Submitted on : Wednesday, June 3, 2015 - 11:37:56 AM
Last modification on : Friday, June 12, 2020 - 5:02:04 PM

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Maïté Guillouët, Gildas Gueret, Fabrice Rannou, Marie-Agnès Giroux-Metges, Maxime Gioux, et al.. Tumor necrosis factor-? downregulates sodium current in skeletal muscle by protein kinase C activation: involvement in critical illness polyneuromyopathy.. American Journal of Physiology - Cell Physiology, American Physiological Society, 2011, 301 (5), pp.C1057--C1063. ⟨10.1152/ajpcell.00097.2011⟩. ⟨hal-01159463⟩

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