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Journal of Neuroscience, Vol 11, 2655-2665, Copyright © 1991 by Society for Neuroscience
Biochemical studies of stimulus convergence during classical conditioning in Aplysia: dual regulation of adenylate cyclase by Ca2+/calmodulin and transmitter
TW Abrams, KA Karl and ER Kandel
Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
Activity-dependent facilitation is a mechanism of associative synaptic
plasticity that contributes to classical conditioning in Aplysia. Previous
studies of activity-dependent facilitation in the mechanosensory neurons of
Aplysia suggested that the Ca2+ influx during paired spike activity
enhances the transmitter-stimulated, cAMP- dependent, presynaptic
facilitation in these cells. Moreover, paired activity was found to
potentiate the activation of the adenylate cyclase by transmitter. It was
therefore proposed that the Ca2+/calmodulin-sensitive cyclase may serve as
a site of interaction between the inputs from the conditioned and
unconditioned stimuli. These studies were carried out to test whether a
Ca2+/calmodulin- sensitive adenylate cyclase in the Aplysia CNS has the
properties necessary to mediate such an associative interaction. Three
lines of evidence indicate that the same cyclase molecules that are
sensitive to Ca2+/calmodulin are also stimulated by receptor to
facilitatory transmitter via the stimulatory G-protein, Gs: First,
calmodulin inhibitors reduced stimulation of the cyclase by facilitatory
transmitter. When membranes had been preexposed to one of these inhibitors,
trifluoperazine, the addition of exogenous calmodulin partially reversed
the inhibition. Second, when Gs had been activated by GTP gamma S, so that
it persistently activated the catalytic unit of the cyclase, stimulation of
the cyclase by Ca2+ was greatly amplified, suggesting that the two inputs
interact in activating a common population of the enzyme. Third,
solubilized cyclase activity that bound to calmodulin-Sepharose in a
Ca(2+)-dependent manner was stimulated by Gs, which had been partially
purified from Aplysia CNS, as well as by Ca2+/calmodulin. Having
demonstrated dual activation of the cyclase, we have explored the
dependence of cyclase activation on the temporal pattern of Ca2+ and
transmitter addition. Optimal activation required that a pulse of Ca2+
temporally overlap the addition of facilitatory transmitter. These several
results suggested that the dually regulated adenylate cyclase might
underlie the temporal requirements for effective classical conditioning in
this system.
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