Calcium and Proto-Oncogene Involvement in the Immediate-Early Response in the Nervous System

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Abstract
Depolarization of neurons either in culture or in vivo results in the rapid, calcium-dependent induction of several, so-called, immediate-early genes; the prototypes being c-fos and c-jun. The proteins encoded by c-jun, c-fos, and several fos-related genes all participate in a complex that interacts with the AP-1 consensus DNA sequence, previously shown to be important for the "transcriptional activation" of certain genes. Thus it is proposed that neuronal stimulation, via elevated intracellular calcium, leads to the induction of a series of genes, some of which encode proteins involved in transcriptional regulation, that contribute to long-term adaptive and plastic responses. Surprisingly, the molecular composition of the brain AP-1 binding complex varies with time after stimulation. This is because some of the inducible Fos-related proteins accumulate with much slower kinetics than Fos itself and only appear in significant amounts when Fos has disappeared. Of some considerable interest is the result these compositional alterations have upon the transcriptional activity of the AP-1 complex. Given the foregoing findings we consider some of the possible implications this might have for aging and neurodegenerative disorders particularly with regard to alterations in cellular calcium homeostasis.