DIFFERENTIAL REGULATION OF CALCIUM CALMODULIN-DEPENDENT PROTEIN-KINASE-II AND P42 MAP KINASE-ACTIVITY BY SYNAPTIC TRANSMISSION/

Calcium/calmodulin-dependent protein kinase II (CaMK) and p42 mitogen- activated protein kinase (MAPK) are enriched in neurons and possess th e capacity to become persistently active, or autonomous, following rem oval of the activating stimulus. Since persistent kinase activation ma y be a mechanism for information storage, we have used primary culture s of cortical neurons to investigate whether kinase autonomy can be tr iggered by bursts of spontaneous synaptic activity. We and others have found that both these kinases respond to synaptic stimulation, but di ffer markedly in their kinetics of activation and inactivation, as wel l as in their sensitivity to NMDA receptor blockade. While 90% of maxi mal CaMK activation was observed after only 10 sec of synaptic burstin g, MAPK activity was unaffected at this early time and rose to only 30 % of maximal after 2 min of stimulation. Following blockade of synapti c stimulation, CaMK activity decreased by 50% in 10-30 sec, while MAPK activity decayed by 50% within 6-10 min. Although MAPK exhibited rela tively slow activation, short periods of synaptic activity could trigg er the MAPK activation process, which persisted in the absence of syna ptic stimulation. Comparison of the effect of NMDA receptor blockade o n synaptic activation of these kinases revealed that CaMK activity is preferentially suppressed. As previous immunocytochemical studies indi cate that CaMK is concentrated in dendritic processes in the vicinity of synapses, we measured synaptic calcium transients in fine dendritic processes(similar to 1 mu m diameter) to assess their sensitivity to NMDA receptor blockade. Calcium transients in these fine processes wer e reduced by up to 90% by NMDA receptor blockade, possibly accounting for the profound sensitivity of CaMK to this treatment. The sharp cont rast between the regulation of CaMK and MAPK by synaptic activity indi cates that they may mediate neuronal responses to different patterns o f afferent stimulation. The relatively slow activation and inactivatio n of MAPK suggests that it may be able to integrate information from m ultiple, infrequent bursts of synaptic activity.