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Neurobiologie des Processus Adaptatifs UMR CNRS 7102-UPMC, Laboratoire de Neurobiologie et Pharmacologie de la Synapse - case n° 8, 7 quai St Bernard, 75005 Paris, France
Activation of CB1 cannabinoid receptors in the cerebellum acutely depresses excitatory synaptic transmission at parallel fibrePurkinje cell synapses by decreasing the probability of glutamate release. This depression involves the activation of presynaptic 4-aminopyridine-sensitive K+ channels by CB1 receptors, which in turn inhibits presynaptic Ca2+ influx controlling glutamate release at these synapses. Using rat cerebellar frontal slices and fluorometric measures of presynaptic Ca2+ influx evoked by stimulation of parallel fibres with the fluorescent dye fluo-4FF, we tested whether the CB1 receptor-mediated inhibition of this influx also involves a direct inhibition of presynaptic voltage-gated calcium channels. Since various physiological effects of CB1 receptors appear to be mediated through the activation of PTX-sensitive proteins, including inhibition of adenylate cyclases, activation of mitogen-activated protein kinases (MAPK) and activation of G protein-gated inwardly rectifying K+ channels, we also studied the potential involvement of these intracellular signal transduction pathways in the cannabinoid-mediated depression of presynaptic Ca2+ influx. The present study demonstrates that the molecular mechanisms underlying the CB1 inhibitory effect involve the activation of the PTX-sensitive Gi/Go subclass of G proteins, independently of any direct effect on presynaptic Ca2+ channels (N, P/Q and R (SNX-482-sensitive) types) or on adenylate cyclase or MAPK activity, but do require the activation of G protein-gated inwardly rectifying (Ba2+- and tertiapin Q-sensitive) K+ channels, in addition to 4-aminopyridine-sensitive K+ channels.
(Received 23 February 2004;
accepted after revision 15 March 2004;
first published online 19 March 2004)
Corresponding author H. Daniel: Neurobiologie des Processus Adaptatifs UMR CNRS 7102-UPMC, Laboratoire de Neurobiologie et Pharmacologie de la Synapse - case n° 8, 7 quai St Bernard, 75005 Paris, France. Email: herve.daniel{at}snv.jussieu.fr
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