Abstract
The effects of the cannabinoid receptor agonist Win55,212 on Ca 2+ channels were studied in rat hippocampal neurons grown in primary culture. Win55,212-2 inhibited whole-cell Ba 2+ currents through Ca 2+ channels by both CB1 receptor-mediated and direct mechanisms. The concentration dependent inhibition of the current showed two clear phases, a high-affinity receptor-mediated phase (IC 50=14±2 nM) that was stereoselective and sensitive to a CB1 receptor antagonist, 300 nM SR141716, and a non-saturating phase that was neither stereoselective nor inhibited by SR141716. These concentration-dependent effects were paralleled by Win55212-induced inhibition of glutamatergic synaptic transmission. Win55,212-2 (100 nM) inhibited both ω-agatoxin IVA- and ω-conotoxin GVIA-sensitive currents. Thus, activation of cannabinoid receptors inhibits N- and P/Q-type Ca 2+ channels. Activation of cannabinoid receptors inhibited only a fraction of the whole-cell Ca 2+ channel current (17±2%) even though more than half of the whole-cell Ba 2+ current was carried by N- and P/Q-type Ca 2+ channels. Concentrations of agonist greater than 1 μM inhibited Ca 2+ channels directly.
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