Contrasting calcium dependencies of SAPK and ERK activations by glutamate in cultured striatal neurons

Stress-activated protein kinase (SAPK) and extracellular signal-regulated k inase (ERK), both members of the mitogen-activated protein kinase (MAPK) fa mily, may in some circumstances serve opposing functions with respect to ce ll survival. However, SAPK and ERK can also be coordinately activated in ne urons in response to glutamate stimulation of NMDA receptors. To explore th e mechanisms of these MAPK activations, we compared the ionic mechanisms me diating SAPK and ERK activations by glutamate. In primary cultures of stria tal neurons, glutamatergic activation of ERK and one of its transcription f actor targets, CREB, showed a calcium dependence typical of NMDA receptor-m ediated responses. In contrast, extracellular calcium was not required for glutamatergic, NMDA receptor-mediated activation of SAPK and phosphorylatio n of its substrate, c-Jun. Increasing extracellular calcium enhanced ERK ac tivation but reversed SAPK activation, further distinguishing the calcium d ependencies of these two NMDA receptor-mediated effects. Finally, reducing extracellular sodium prevented the glutamatergic activation of SAPK but onl y partially blocked that of ERK. These contrasting ionic dependencies sugge st a mechanism by which NMDA receptor activation may, under distinct condit ions, differentially regulate neuronal MAPKs and their divergent functions.