Control of Ca(2+) influx by cannabinoid and metabotropic glutamate receptors in rat cerebellar cortex requires K(+) channels.
1. In the rodent cerebellum, both presynaptic CB1 cannabinoid receptors and presynaptic mGluR4 metabotropic glutamate receptors acutely depress excitatory synaptic transmission at parallel fibre-Purkinje cell synapses. Using rat cerebellar slices, we have analysed the effects of selective CB1 and mGluR4 agonists on the presynaptic Ca(2+) influx which controls glutamate release at this synapse. 2. Changes in presynaptic Ca(2+) influx were determined with the Ca(2+)-sensitive dyes fluo-4FF AM or fluo-3 AM. Five stimulations delivered at 100 Hz or single stimulations of parallel fibres evoked rapid and reproducible transient increases in presynaptic fluo-4FF or fluo-3 fluorescence, respectively, which decayed to prestimulus levels within a few hundred milliseconds. Bath application of the selective CB1 agonist WIN55,212-2 (1 microM) markedly reduced the peak amplitude of these fluorescence transients. This effect was fully reversed by the selective CB1 antagonist SR141716-A (1 microM). 3. Bath application of the selective mGluR4 agonist L-AP4 (100 microM) also caused a transient decrease in the peak amplitude of the fluorescence transients evoked by parallel fibre stimulation. 4. Bath application of the potassium channel blocker 4-AP (1 mM) totally prevented both the WIN55,212-2- and the L-AP4-induced inhibition of peak fluorescence transients evoked by parallel fibre stimulation. 5. The present study demonstrates that activation of CB1 and mGluR4 receptors inhibits presynaptic Ca(2+) influx evoked by parallel fibre stimulation via the activation of presynaptic K(+) channels, suggesting that the molecular mechanisms underlying this inhibition involve an indirect inhibition of presynaptic voltage-gated Ca(2+) channels rather than their direct inhibition.
Daniel
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Laboratoire de Neurobiologie et Pharmacologie de la Synapse FRE 2371, CNRS-UPMC, case no. 8, 7, quai St Bernard, 75005 Paris, France. herve.daniel@snv.jussieu.fr
Crepel
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F
D015761:4-Aminopyridine / Q000494:pharmacology; D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines; D002118:Calcium / Q000378:metabolism*; D002525:Cerebellar Cortex / Q000378:metabolism*; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology*
D000613:Aminobutyrates; D048588:Benzoxazines; D018690:Excitatory Amino Acid Agonists; D009025:Morpholines; D009281:Naphthalenes; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D018094:Receptors, Metabotropic Glutamate; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D015761:4-Aminopyridine; C012729:2-amino-4-phosphonobutyric acid; D002118:Calcium; C108823:metabotropic glutamate receptor 4