Analysis of a decreased Na⁺ conductance by tumor necrosis factor in identified neurons of Aplysia kurodai

Abstract

The ionic mechanisms of the effect of extracellularly ejected recombinant human tumor necrosis factor-alpha (rhTNF-alpha) on the membrane of identified neurons R9 and R10 of Aplysia kurodai was investigated with conventional voltage-clamp, micropressure ejection, and ion substitution techniques. Micropressure-ejected rhTNF caused a marked hyperpolarization in the unclamped neuron. Clamping the same neuron at it resting potential level (-60 mV) and reejecting rhTNF-alpha with the same dose produced a slow outward current [Io (TNF)] associated with a decrease in input membrane conductance. Io (TNF) was decreased by depolarization and increased by hyperpolarization. The extrapolated reversal potential of Io (TNF) was approximately +10 mV. Ion substitution and pharmacological experiments suggest that Io (TNF) in identified neurons R9 and R10 of A. kurodai is due to a decreased Na+ conductance but not due to an activation of the Na(+)-K+ pump. Our results demonstrate that the immunomodulator TNF can act directly on the nervous system as well as on the immune system.

Tumor Necrosis Factor‐α Regulates Nicotinic Responses in Mixed Cultures of Sympathetic Neurons and Nonneuronal Cells

“…Prolonged exposure to TNF-a results in increased Ca 2+ current density in sympathetic neurons (Soliven and Albert, 1992b) but induces a decrease in K + currents in cultured oligodendrocytes (Soliven et al ., 1991) . Brief exposure to TNF-a decreases a K + conductance and a Na' conductance in Aplysia neurons (Sawada et al, 1990(Sawada et al, , 1991 . Therefore, cytokines regulate the functional output of neurons and other cell types by differential modulation of transmitter receptors and voltage-dependent ion channels .…”

Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents

“…Unsurprisingly, therefore, every organ, including the brain, has proved to be influenced by this cytokine. By 1987, TNF had been shown to be a necessary part of the chain of events that control normal sleep [25], and a few years later, current conductance in neurons of a sea slug, Aplysia kurodai , was observed to be reduced by human TNF [26, 27]. Next, physiological levels of TNF had been reasoned to be necessary for normal mammalian neuronal function, with a loss or gain of TNF beyond homeostatic limits being pathological [28].…”

Signal transduction pathways in oligodendrocytes: Role of tumor necrosis factor‐α

“…1°8,114 Brief exposure to TNF-et decreases a K + conductance and a Na + conductance in Aplysia neurons. 93,94 Other electrophysiological effects of TNF-et include depolarization of muscle cells 125 and inhibition of long-term potentiation in rat hippocampal slices. 119 Taken together, the data suggest that TNF-ot and other cytokines regulate the functional output of glial cells and neurons by differential modulation of voltage-dependent ion channels and transmitter receptors.…”