A potential role for altered protein phosphorylation in the mediation of developmental neurotoxicity

Protein phosphorylation represents a major post-translational mechanism through which numerous physiological processes are regulated. In the central nervous system, many extracellular messengers appear to exert their effects by regulating the intracellular concentration of specific second messengers which in turn activate specific phosphoprotein kinases. The diversity of these kinases and their substrates provide the means through which the diversity of brain cell types integrate and process extracellular signals. Increasing evidence indicates that specific phosphoproteins are involved in various aspects of brain development such as gene expression, protein synthesis, and cellular differentiation (e.g. growth cone formation, synaptogenesis). There are 3 essential components to all phosphorylation systems: 1) a specific protein kinase that, in the presence of ATP and Mg++, catalyzes the phosphorylation reaction; 2) a substrate protein that exists in either a phospho- or dephospho-form and 3) a protein phosphatase that catalyzes the removal of the phosphate group. All of these components represent putative targets for developmental neurotoxicants. In the adult nervous system, protein phosphorylation recently has been show to play a role in ischemia, neurodegenerative disease and specific neurotoxic exposures. Together, these observations provide the background for a discussion of the potential role of this key signal transduction system as a mediator of developmental neurotoxicity.