Neurotoxic and synaptic effects of okadaic acid, an inhibitor of protein phosphatases

Protein phosphorylation and dephosphorylation reactions, catalyzed by kinas es and phosphatases, are involved in the regulation of a wide variety of ph ysiological processes. In the nervous system, such reactions seem to modula te the function of several proteins crucial in synaptic transmission, inclu ding voltage-gated and ligand-gated channels, neurotransmitter release, and neurotransmitter transporters. On the other hand, hyperphosphorylation of certain cytoskeletal proteins or receptors may lead to neuronal death. In t he present work we review the neurotoxic effect of okadaic acid (OKA), a po tent and specific inhibitor of the serine/threonine protein phosphatases 1 and 2A, as well as its action on synaptic function. We analyze recent findi ngs demonstrating that the microinjection of OKA in rat hippocampus induces neuronal stress, hyperexcitation and neurodegeneration, and discuss their possible relationships to alterations of protein phosphorylation-dephosphor ylation observed in Alzheimer's disease brain. These results suggest that p rotein hyperphosphorylation due to inhibition of phosphatases in vivo induc es neuronal stress and subsequent neurodegeneration.