Control of Ca(2+) Influx by Cannabinoid and Metabotropic Glutamate Receptors in Rat Cerebellar Cortex Requires K(+) Channels

J Physiol. 2001 Dec 15;537(Pt 3):793-800. doi: 10.1111/j.1469-7793.2001.00793.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / pharmacology
  • Aminobutyrates / pharmacology
  • Animals
  • Benzoxazines
  • Calcium / metabolism*
  • Cerebellar Cortex / metabolism*
  • Electric Stimulation
  • Excitatory Amino Acid Agonists / pharmacology
  • In Vitro Techniques
  • Male
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Potassium Channel Blockers / pharmacology
  • Potassium Channels / physiology*
  • Presynaptic Terminals / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cannabinoid
  • Receptors, Drug / agonists
  • Receptors, Drug / physiology*
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / physiology*

Substances

  • Aminobutyrates
  • Benzoxazines
  • Excitatory Amino Acid Agonists
  • Morpholines
  • Naphthalenes
  • Potassium Channel Blockers
  • Potassium Channels
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Receptors, Metabotropic Glutamate
  • Win 55212-2
  • 4-Aminopyridine
  • 2-amino-4-phosphonobutyric acid
  • Calcium
  • metabotropic glutamate receptor 4