Dm. Chetkovich et Jd. Sweatt, NMDA RECEPTOR ACTIVATION INCREASES CYCLIC-AMP IN AREA CA1 OF THE HIPPOCAMPUS VIA CALCIUM-CALMODULIN STIMULATION OF ADENYLYL-CYCLASE, Journal of neurochemistry, 61(5), 1993, pp. 1933-1942
We observed previously that activation of N-methyl-D-aspartate (NMDA)
receptors in area CA1 of the hippocampus, through either NMDA applicat
ion or long-term potentiation (LTP)-inducing high-frequency stimulatio
n (HFS), results in an increase in cyclic AMP. In the present study, w
e performed experiments to determine the mechanism by which NMDA recep
tor activation causes this increase in cyclic AMP. As the NMDA recepto
r-mediated increase in cyclic AMP is dependent upon extracellular calc
ium, we hypothesized that NMDA receptors are coupled to adenylyl cycla
se (AC) via calcium/calmodulin. In membranes prepared from area CA1, A
C was stimulated by calcium in the presence of calmodulin, and the eff
ect of calcium/calmodulin on AC in membranes was blocked by the calmod
ulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W
-7) and trifluoperazine (TFP). In intact hippocampal slices, W-7 and T
FP blocked the increase in cyclic AMP levels caused by both NMDA appli
cation and HFS of Schaffer collateral fibers. Exposure of hippocampal
slices to elevated extracellular potassium to induce calcium influx al
so caused increased cyclic AMP levels; the increase in cyclic AMP caus
ed by high potassium was also blocked by W-7 and TFP. These data suppo
rt the hypothesis that NMDA receptor activation is positively coupled
to AC via calcium/calmodulin and are consistent with a role for cyclic
AMP metabolism in the induction of NMDA receptor-dependent LTP in are
a CA1 of the hippocampus.