Biphasic modulation of voltage-dependent currents of retinal cones by cannabinoid CB1 receptor agonist WIN 55212-2.

Endogenous cannabinoids modulate neurotransmitter action and release in the brain. The effects are exerted on membrane permeability to Ca2+ and K+ via protein kinase A (PKA). Cannabinoid CB1 receptors are present at the synaptic terminals of cones in goldfish retina. We investigated the effects of CB1 receptor agonist WIN 55212-2 on voltage-gated currents of goldfish cones. Whole-cell currents were recorded with conventional-patch-clamp methods in goldfish retinal slices. Depolarizing pulses elicited inward I(Ca) and I(outward) that contained several components: I(K), I(A), and I(Cl). WIN 55212-2 (< 1 microM) enhanced I(K), I(Cl), and I(Ca), while at > 1 microM, I(K), I(Cl), and I(Ca) were suppressed. The voltage-activation ranges of these currents were not affected. All effects of WIN 55212-2 were blocked by the CB1 receptor antagonist SR 141716A as well as the PKA inhibitor Wiptide. The enhancing effect of WIN 55212-2 was blocked selectively by 0.5 nM cholera toxin and the suppressive effect was blocked by pertussis toxin. The results obtained from long and short single cones and double cones were basically the same. Cannabinoids, via CB1 receptor and PKA, dose-dependently enhance I(K), I(Cl), and I(Ca) by a pertussis-toxin insensitive Gs and suppress these currents by a pertussis-toxin sensitive Gi/o in cones. This biphasic regulation may provide a mechanism to inhibit constitutively active CB1 receptors in the presence of a high concentration of ligand. Thus, neuronal excitability appears to be affected by cannabinoids at the first synapse of the visual pathway and could account for some of the visual effects of marijuana.