THE TRANSCRIPTION FACTOR NF-KB MEDIATES INCREASES IN CALCIUM CURRENTSAND DECREASES IN NMDA-INDUCED AND AMPA KAINATE-INDUCED CURRENTS INDUCED BY TUMOR-NECROSIS-FACTOR-ALPHA IN HIPPOCAMPAL-NEURONS/

Tumor necrosis factor-alpha (TNF alpha) is a cytokine rapidly produced in the brain in response to vigorous neuronal activity and tissue inj ury. TNF alpha may protect neurons against excitotoxic and oxidative i nsults by a mechanism involving activation of the transcription factor NF-kappa B. Whole-cell perforated patch clamp recordings in cultured rat hippocampal neurons showed that long-term treatment (24-48 h) with TNF alpha increases Ca2+ current density; pharmacological analysis in dicated a major increase in current through L-type voltage-dependent c alcium channels. Longterm treatment with TNF alpha caused a decrease i n currents induced by glutamate, NMDA, AMPA, and kainate. Shorter expo sures to TNF alpha (acute; 2 h) did not alter Ca2+ current or glutamat e receptor agonist-induced currents. Ceramide, an intracellular messen ger that activates the transcription factor NF-kappa B, mimicked the a ctions of TNFs on Ca2+ current density and currents induced by glutama te receptor agonists. Cotreatment with kappa B decoy DNA abolished the effects of TNF alpha on Ca2+ current and excitatory amino acid-induce d currents, demonstrating a requirement for NF-kappa B activation in t he actions of TNF alpha. Neurons pretreated with TNF alpha exhibited i ncreased intracellular Ca2+ concentrations following membrane depolari zation but reduced intracellular Ca2+ concentration responses to excit atory amino acids, compared with neurons in untreated control cultures or cultures cotreated with kappa B decoy DNA. These findings suggest important roles for the transcription factor NF-kappa B 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 signaling mechanisms may be particularly important in injury settings such as ischemia or trauma, where TNF alp ha expression is increased and NF-kappa B is activated.