Figure 3. The ERK/MAP kinase cascade in the hippocampus.

The ERK/MAPK cascade can integrate a wide variety of signals and result in a final common output. The ERK cascade is initiated by the activation of Raf kinase via the small GTP-binding protein, ras, or the ras-related protein, rap-1. Activated Raf then phosphorylates MEK, a dual specific kinase. MEK phosphorylates ERK 1 and 2 on a tyrosine and threonine residue. Once activated, ERK exerts many downstream effects, including the regulation of cellular excitability and the activation of transcription factors leading to altered gene expression. Each MAP kinase cascade (ERK, JNK, and p38 MAPK) is composed of three distinct kinases activated in sequence, and despite the fact that many separate MAP kinase families exist, there is limited crosstalk between these highly homologous cascades. While many of the steps of the ERK cascade have been elucidated, the mechanisms by which the components of the MAP kinase cascade come into physical contact have not been investigated. In this context it is interesting to note that there are multiple upstream regulators of ERK in the hippocampus: NE, DA, nicotinic ACh, muscarinic ACh, histamine, estrogen, serotonin, BDNF, NMDA receptors, metabotropic glutamate receptors, AMPA receptors, voltage-gated calcium channels, reactive oxygen species, various PKC isoforms, PKA, NO, NF1, and multiple ras isoforms and homologs.