Mitogen-activated protein kinase signaling.

The mechanism by which cells respond to extracellular stimuli involves a series of signal transduction events across the cell membrane and through the cytoplasm to the nucleus. Mitogen-activated protein (MAP) kinases are important mediators of signal transduction and play a key role in the regulation of many cellular processes, such as cell growth and proliferation, differentiation, and apoptosis. In mammalian cells, three major groups of MAP kinases have been identified: extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAP kinase. It is well documented that ERK is typically stimulated by growth-related signals, whereas the JNK and p38 MAP kinase cascades are activated by various stress stimuli. Studies have indicated that MAP kinases are expressed abundantly in the central nervous system (CNS) and that ERK is involved in long-lasting neuronal plasticity, including long-term potentiation and memory consolidation. While the role of ERK in neuronal plasticity and behavioral adaptation is beginning to emerge, the role of MAP kinase signal transduction cascades in major psychiatric disorders, including schizophrenia, is not well understood. This review outlines the intermediates of this signaling cascade and downstream transcription factor targets and recent evidence implicating MAP kinases to important biological functions in the CNS. Evidence from human post-mortem studies, as well as from the phencyclidine model of schizophrenia, that different MAP kinase cascades may be involved in the pathogenesis of schizophrenia, and potentially in other psychiatric disorders, is presented. Knowledge of MAP kinase signaling will aid greatly in our ability t o understand causal changes in disease process and may lead to new therapeutic approaches in controlling or treating schizophrenia.