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S-F Fan, S Yazulla; Cannabinoid Receptor CB1 Agonist WIN 55212-2 Modulates IOut(V) and ICa in Retinal Cones . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3749.
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Purpose: Endogeneous cannabinoid receptor ligands have modulatory effects on neurotransmitter action and release in the brain. The effects are exerted via modulating neuronal membrane permeability to Ca2+ and K+ and the activity of adenylate cyclase. Cannabinoid CB1 receptors have been localized immunocytochemically at the synaptic terminals of cone photoreceptors in goldfish retina (Yazulla et al., '00 Vis. Neurosci. 17:391). Here we investigated the effects of CB1 receptor agonists on the membrane ionic permeability of goldfish cones. Methods: Whole-cell currents were recorded from cones with conventional-patch-clamp methods in goldfish retinal slices. Results: 1) Depolarizing pulses elicited inward ICa and Ioutward. ICa was regularly elicited and maintained only when the pipette solution contained the ATP regenerating system (phosphocreatine and creatine phosphokinase). Otherwise ICa either was not observed or ran down. Ioutward contained several components: IK(V), IA and ICl(V). The latter was the algebraic sum carried by the influx and outflux of Cl- as can be shown by the effect of niflumic acid, which only blocks Cl- outflux. 2) WIN 55212-2, 1-2 µM, suppressed IK(V), IA and ICa but increased ICl, while lower concentrations (0.1-0.5 µM) increased IK(V) and ICa but not IA. The voltage-activation ranges of both IK(V) and ICa were not affected. The effects of WIN 55212-2, at all concentrations, were blocked by the CB1 receptor antagonist SR 131716A (2 µM) as well as the PKA inhibitor Wiptide (10 µM) . 3) The results obtained from long and short single cones as well as from double cones were basically the same. Conclusion: Cannabinoids dose-dependently enhance or suppress IK(V) and ICa via CB1 receptor and PKA in cone photoreceptors. An increase or decrease in ICa will correspondingly change glutamate release, which effectively changes the excitability of the secondary neurons. An increase or decrease of IK(V) should shorten or lengthen the recovery time of photoreceptors at the offset of a light stimulus.
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