Glutamate receptor agonists increase the expression of Fos, Fra, and AP‐1 DNA binding activity in the mammalian brain

摘要

AbstractAdministration of convulsant doses of Metrazole (pentylenetetrazol) and picrotoxin, as well as maximal electroshock, results in a rapid but transient increase in c‐fosmRNA in mouse brain. Elevation of c‐fosmRNA is followed by the accumulation and subsequent disappearance of Fos, the protein encoded by c‐fos. In addition, immunoblots reveal the induction of two additional proteins that are antigenically related to Fos (Fra, Fos‐related antigens). Fos and the various Fra appear and disappear in a staggered manner over an 8 hour period, such that at longer times after stimulation the brain contains no Fos but relatively large amounts of Fra (the latter being designated here by their apparent molecular weights, Fra‐46K and Fra‐35K). Previous studies have established that Fos, as well as several Fra, contribute to transcription factor AP‐1 nucleoprotein complexes along with Jun, the product of thejunproto‐oncogene. The appearance in brain of Fos and Fra coincides with a protracted increase in total AP‐1 DNA binding activity, indicating that all the Fos‐like proteins can participate in AP‐1 complexes. Furthermore, the molecular composition of these complexes alters with time after stimulation. The induction of c‐fosby Metrazole is blocked or attenuated by known anticonvulsants such as diazepam and valproate as well as the N‐methyl‐D‐aspartate (NMDA) receptor antagonists, 2‐amino‐5‐phosphonovaleric acid (APV) and MK‐801. This suggests thatfosinduction might involve stimulation of a glutamate receptor. This conclusion was strengthened by the observations that two glutamate receptor agonists, kainic acid and NMDA, induced c‐fosexpression. The induction of c‐fosby NMDA had a similar kinetic and pharmacological profile to that of Metrazole. Kainic acid, in contrast, caused a protracted induction of c‐fosnot seen in any of the other paradigms. Therefore, it is likely that both the kainate and NMDA forms of the glutamate receptor may participate independently in the ind