STIMULATION OF P42 AND P44 MITOGEN-ACTIVATED PROTEIN-KINASES BY REACTIVE OXYGEN SPECIES AND NITRIC-OXIDE IN HIPPOCAMPUS

Reactive oxygen species (ROS) have been suggested to act as cellular m essengers that mediate signal transduction cascades in various cell ty pes. However, little is known about their role in this capacity in the nervous system. We have begun to investigate the role of ROS, and tha t of nitric oxide (NO), in mediating mitogen-activated protein kinase (MAPK) signaling in rat hippocampal slices. Our studies have revealed that direct exposure of hippocampal slices to hydrogen peroxide, xanth ine/xanthine oxidase (a superoxide-generating system), sodium nitropru sside (an NO donor compound), S-nitroso-N-acetylpenicillamine (an NO d onor compound), or 3-morpholinosydnonimine (a compound that produces N O and superoxide) results in an enhancement in tyrosine phosphorylatio n of several proteins, including proteins with apparent molecular mass es of 42 and 44 kDa. We investigated the possibility that these protei ns correspond to the active forms of p42 MAPK and p44 MAPK. Hippocampa l slices exposed to Various ROS and NO donors resulted in increases in levels of the active forms of both p42 MAPK and p44 MAPK. The ROS- an d NO-enhanced tyrosine phosphorylation and activation of p42 MAPK and p44 MAPK were inhibited by pretreatment with the antioxidant N-acetyl- L-cysteine. Our observations indicate that ROS and NO can mediate prot ein tyrosine phosphorylation and MAPK signaling in the hippocampus via a redox-sensitive mechanism and suggest a potential cellular mechanis m for their effects in the nervous system.