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Journal of Neuroscience, Vol 14, 1320-1331, Copyright © 1994 by Society for Neuroscience
Differential regulation of calcium/calmodulin-dependent protein kinase II and p42 MAP kinase activity by synaptic transmission
TH Murphy, LA Blatter, RV Bhat, RS Fiore, WG Wier and JM Baraban
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2185.
Calcium/calmodulin-dependent protein kinase II (CaMK) and p42 mitogen-
activated protein kinase (MAPK) are enriched in neurons and possess the
capacity to become persistently active, or autonomous, following removal of
the activating stimulus. Since persistent kinase activation may be a
mechanism for information storage, we have used primary cultures of
cortical neurons to investigate whether kinase autonomy can be triggered by
bursts of spontaneous synaptic activity. We and others have found that both
these kinases respond to synaptic stimulation, but differ markedly in their
kinetics of activation and inactivation, as well as in their sensitivity to
NMDA receptor blockade. While 90% of maximal CaMK activation was observed
after only 10 sec of synaptic bursting, MAPK activity was unaffected at
this early time and rose to only 30% of maximal after 2 min of stimulation.
Following blockade of synaptic stimulation, CaMK activity decreased by 50%
in 10-30 sec, while MAPK activity decayed by 50% within 6-10 min. Although
MAPK exhibited relatively slow activation, short periods of synaptic
activity could trigger the MAPK activation process, which persisted in the
absence of synaptic stimulation. Comparison of the effect of NMDA receptor
blockade on synaptic activation of these kinases revealed that CaMK
activity is preferentially suppressed. As previous immunocytochemical
studies indicate that CaMK is concentrated in dendritic processes in the
vicinity of synapses, we measured synaptic calcium transients in fine
dendritic processes (approximately 1 microns diameter) to assess their
sensitivity to NMDA receptor blockade. Calcium transients in these fine
processes were reduced by up to 90% by NMDA receptor blockade, possibly
accounting for the profound sensitivity of CaMK to this treatment. The
sharp contrast between the regulation of CaMK and MAPK by synaptic activity
indicates that they may mediate neuronal responses to different patterns of
afferent stimulation. The relatively slow activation and inactivation of
MAPK suggests that it may be able to integrate information from multiple,
infrequent bursts of synaptic activity.
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