The transcription factor NF-κB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-α in hippocampal neurons

Tumor necrosis factor-α (TNFα) is a cytokine rapidly produced in the brain in response to vigorous neuronal activity and tissue injury. TNFα may protect neurons against excitotoxic and oxidative insults by a mechanism involving activation of the transcription factor NF-κB. Whole cell perforated patch clamp recordings in cultured rat hippocampal neurons showed that long-term treatment (24-48 h) with TNFα increases Ca²⁺ current sensitivity; pharmacological analysis indicated a major increase in current through L-type voltage-dependent calcium channels. Long-term treatment with TNFα caused a decrease in currents induced by glutamate, NMDA, AMPA, and kainate. Shorter exposure to TNFα (acute; 2 h) did not alter Ca²⁺ current or glutamate receptor agonist-induced currents. Ceramide, an intracellular messenger that activates the transcription factor NF-κB, mimicked the actions of TNFs on Ca²⁺ current density and currents induced by glutamate receptor agonists. Cotreatment with κB decoy DNA abolished the effects of TNFα on Ca²⁺ current and excitatory amino acid-induced currents, demonstrating a requirement for NF-κB activation in the actions of TNFα. Neurons pretreated with TNFα exhibited increased intracellular Ca²⁺ concentrations following membrane depolarization but reduced intracellular Ca²⁺ concentration responses to excitatory amino acids, compared with neurons in untreated control cultures or cultures cotreated with κB decoy DNA. These findings suggest important roles for the transcription factor NF- κB in modulation of voltage-dependent calcium channels and glutamate receptors and the many physiological and pathophysiological processes in which these ion channels are involved. Such signalling mechanisms may be particularly important in injury settings such as ischemia or trauma, where TNFα expression is increased and NF-κB is activated.