Calcium as a modulator of the immediate-early gene cascade in neurons.
Increases in intraneuronal free calcium result in the rapid, transient, induction of the fos and jun proto-oncogenes. In PC12 cells, induction may be elicited either by membrane depolarization or by direct activation of voltage-dependent calcium channels with BAY K 8644 both of which provoke an influx of calcium. The calmodulin pathway appears to link the elevated intracellular calcium to gene induction. In the brain, c-fos and c-jun may be induced by elevated neuronal activity such as occurs during pentylenetetrazole (PTZ) seizures. The N-methyl-D-aspartate (NMDA) form of the glutamate receptor, which can directly gate calcium, plays a role in the induction of c-fos expression in PTZ seizures. In addition, NMDA can directly stimulate c-fos in the brain. Fos and Jun form a noncovalent nucleoprotein complex that binds to the consensus recognition sequence of the AP-1 transcription factor. Thus in a larger picture we envisage Fos and Jun as members of a concerted stimulus-transcription coupling pathway that links alterations in external stimuli to long term adaptive responses. In this context Fos, Jun and the other immediate-early genes should be viewed as third messengers which are regulated by second messengers such as intracellular calcium.
Morgan
J I
JI
Department of Neuroscience, Roche Institute of Molecular Biology, Roche Research Center, Nutley, New Jersey.
Curran
T
T
D000818:Animals; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D002450:Cell Communication; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009474:Neurons / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D002118:Calcium