Mechanisms underlying cannabinoid inhibition of presynaptic Ca2+ influx at parallel fibre synapses of the rat cerebellum.
Activation of CB1 cannabinoid receptors in the cerebellum acutely depresses excitatory synaptic transmission at parallel fibre-Purkinje 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 Ca(2+) influx controlling glutamate release at these synapses. Using rat cerebellar frontal slices and fluorometric measures of presynaptic Ca(2+) 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 Ca(2+) influx. The present study demonstrates that the molecular mechanisms underlying the CB1 inhibitory effect involve the activation of the PTX-sensitive G(i)/G(o) subclass of G proteins, independently of any direct effect on presynaptic Ca(2+) 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 (Ba(2+)- and tertiapin Q-sensitive) K(+) channels, in addition to 4-aminopyridine-sensitive K(+) channels.
Daniel
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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. herve.daniel@snv.jussieu.fr
Rancillac
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A
Crepel
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D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000814:Aniline Compounds; D000818:Animals; D048588:Benzoxazines; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003864:Depression, Chemical; D004594:Electrophysiology; D005470:Fluorometry; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000378:metabolism*; D014966:Xanthenes
D000067956:Adenylyl Cyclase Inhibitors; D000814:Aniline Compounds; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002186:Cannabinoids; C409648:Fluo 4; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D017661:Receptors, Presynaptic; D014966:Xanthenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D037342:Pertussis Toxin; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases; D002118:Calcium