Regulation of Neuronal PP1 and PP2A During Development.

A variety of studies in recent years have indicated that modulation of protein phosphatases perturbs brain function. For example, a mutation in PP1 is associated with defective habituation and associative learning in drosophila (1), and the activity of PPl and/or PP2A is essential for induction and maintenance of long term depression (LTD) in hippocampal neurons (2). Recent studies link reduced PP2A activity with hyperphosphorylation of Tau in Alzheimer's disease (3). A number of studies using inhibitors of PP1 and PP2A have also implicated a role for PP1 and PP2A in regulating neurotransmitter release. Studies from this laboratory suggest a role for these enzymes in priming or modulation rather than triggering of release (4. At the molecular level, regulation of PP1 and PP2A has been implicated in modulating the activity of several receptors and ion channels. For example, inhibition with okadaic acid leads to stimulation of non-NMDA-type glutamate receptors (5) and activation of NMDA-type receptors induces specific dephosphorylation and inactivation of DARPP-32, a neuronal homolog of PPl-inhibitor 1 (6). Given the ubiquitous distribution and substrate overlap of the catalytic subunits of PP1 and PP2A, both between cell types and within cells, the current challenge is to delineate and localize the individual mechanisms regulating PP1 and PP2A in the nervous system. [ABSTRACT FROM AUTHOR]