NF- Kappa B activation by depolarization of skeletal muscle cells depends on ryanodine and IP sub(3) receptor-mediated calcium signals

Depolarization of skeletal muscle cells by either high external K super(+) or repetitive extracellular field potential pulses induces calcium release from internal stores. The two components of this release are mediated by either ryanodine receptors or inositol 1,4,5-trisphosphate (IP sub(3)) receptors and show differences in kinetics, amplitude, and subcellular localization. We have reported that the transcriptional regulators including ERKs, cAMP/Ca super(2+)-response element binding protein, c-fos, c-jun, and egr-1 are activated by K super(+)-induced depolarization and that their activation requires IP sub(3)-dependent calcium release. We presently describe the activation of the nuclear transcription factor NF- Kappa B in response to depolarization by either high K super(+) (chronic) or electrical pulses (fluctuating). Calcium transients of relative short duration activate an NF- Kappa B reporter gene to an intermediate level, whereas long-lasting calcium increases obtained by prolonged electrical stimulation protocols of various frequencies induce maximal activation of NF- Kappa B. This activation is independent of extracellular calcium, whereas calcium release mediated by either ryanodine or IP sub(3) receptors contribute in all conditions tested. NF- Kappa B activation is mediated by I Kappa B alpha degradation and p65 translocation to the nucleus. Partial blockade by N-acetyl-L-cysteine, a general antioxidant, suggests the participation of reactive oxygen species. Calcium-dependent signaling pathways such as those linked to calcineurin and PKC also contribute to NF- Kappa B activation by depolarization, as assessed by blockade through pharmacological agents. These results suggest that NF- Kappa B activation in skeletal muscle cells is linked to membrane depolarization and depends on the duration of elevated intracellular calcium. It can be regulated by sequential activation of calcium release mediated by the ryanodine and by IP sub(3) receptors.