Activation of NMDA receptors induces rapid dephosphorylation of the cytoskeletal protein MAP2.

Hippocampal slices were preincubated with 32P-orthophosphate and used to study the effect of glutamate analogs on protein phosphorylation. NMDA induced a rapid, 70% decrease in the phosphorylation of the microtubule-associated protein MAP2, with no change in the total amount of MAP2. Both competitive and noncompetitive NMDA antagonists blocked the effect of NMDA, but a glutamate antagonist acting at non-NMDA receptors did not. Kainate and quisqualate were less potent than NMDA in stimulating dephosphorylation of MAP2. Other forebrain regions (necortex, striatum, and olfactory bulb) also showed dephosphorylation of MAP2 in response to NMDA. These and other results suggest that NMDA receptor activation induces the dephosphorylation of MAP2 by stimulating a protein phosphatase, possibly the calcium/calmodulin-dependent protein phosphatase calcineurin. Moreover, they indicate that alteration in the properties of a microtubule-associated protein may account for some of the effects of glutamate on postsynaptic neurons.