Inhibitory interaction of cannabinoid CB1 receptor and dopamine D2 receptor agonists on voltage-gated currents of goldfish cones

Dopamine is a light-adaptive signal that desensitizes the retina, while cannabinoids reportedly increase photosensitivity. The presynaptic membrane of goldfish retinal cones has dopamine D2 receptors and cannabinoid CB1 receptors. This work focused on whether dopamine D2 receptor agonist quinpirole and cannabinoid CB1 receptor agonist WIN 55212-2 (WIN) interacted to modulate voltage-dependent membrane currents of cones. A conventional patch-clamp method was used to record depolarization evoked whole-cell outward currents (I-out) and an inward calcium current (I-Ca) from the inner segment of cones in goldfish retinal slices. WIN had biphasic actions: low concentrations (<1 muM) increased the currents via Gs, while higher concentrations (>1 muM) decreased the currents via Gi/Go. Neither dopamine nor the D2 agonist quinpirole (1-20 muM) had a significant effect on either I-out or I-Ca. Quinpirole at 50 muM had a mild suppressive (similar to20%) effect on I-out. However, quinpirole (<10 muM) completely blocked the enhancement of both currents seen with 0.7 muM WIN. The effect of quinpirole was blocked by sulpiride and by pertussis toxin, indicating that quinpirole was acting via a D2 receptor-Gi/o coupled mechanism. The suppressive action of 50 muM quinpirole (similar to20%) was not additive with the suppressive effect of 3 muM WIN (similar to40%). D2 agonists via Gi/o oppose the action of low concentrations of CB1 agonists acting via Gs to modulate cone membrane currents, suggesting a role in shaping the cone light response and/or sensitivity to changes in ambient light conditions. The nonadditive effect of high concentrations of WIN and quinpirole suggests that both decrease membrane currents via the same transduction pathway, Gi/Go protein kinase A (PKA).