title: Tumor necrosis factor-α 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-α), 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-α 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-α. TNF-α 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-α 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-α. 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.
authors.affiliation: Faculté de Médecine et des Sciences de la Santé, Laboratoire de Physiologie, Université de Brest, Brest, France.
authors.forename: Maité
authors.initials: M
authors.lastname: Guillouet
authors.forename: Gildas
authors.initials: G
authors.lastname: Gueret
authors.forename: Fabrice
authors.initials: F
authors.lastname: Rannou
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Giroux-Metges
authors.forename: Maxime
authors.initials: M
authors.lastname: Gioux
authors.forename: Charles C
authors.initials: CC
authors.lastname: Arvieux
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pennec
mesh_terms: D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D016638:Critical Illness; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000201:enzymology*; D011115:Polyneuropathies / Q000201:enzymology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D015222:Sodium Channels; D014409:Tumor Necrosis Factor-alpha; D012964:Sodium; C016299:chelerythrine; D011493:Protein Kinase C