Cannabinoid receptor agonists modulate calcium channels in rat retinal müller cells

- CaV3.1, CaV3.2, CaV3.3 and CaV1.2 are expressed in rat Müller cells.
- CB1R agonist WIN55212-2 dose-dependently suppresses Ca2+ currents in Müller cells.
- WIN55212-2-induced suppression of Ca2+ currents is independent of CB1R/CB2R.
- Endocannabinoids 2-AG/AEA suppress Ca2+ currents in a CB1R-independent manner.
- The 2-AG effect is not, but the AEA effect is partially mediated by CB2Rs.

While activation of cannabinoid CB1 receptor (CB1R) regulates a variety of retinal neuronal functions by modulating ion channels in these cells, effect of activated cannabinoid receptors on Ca2+ channels in retinal Müller cells is still largely unknown. In the present work we show that three subunits of T-type Ca2+ channels, CaV3.1, CaV3.2 and CaV3.3, as well as one subunit of L-type Ca2+ channels, CaV1.2, were expressed in rat Müller cells by immunofluorescent staining. Consistently, nimodipine- and mibefradil-sensitive Na+ currents through L- and T-type Ca2+ channels could be recorded electrophysiologically. The cannabinoid receptor agonist WIN55212-2 significantly suppressed Ca2+ channel currents, mainly the T-type one, in acutely isolated rat Müller cells in a dose-dependent manner, with an IC50 of 3.98 μM. The WIN55212-2 effect was not blocked by AM251/SR141716, specific CB1R antagonists. Similar suppression of the currents was observed when anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), endogenous ligands of cannabinoid receptors, were applied. Moreover, even though CB2 receptors (CB2Rs) were expressed in rat Müller cells, the effects of WIN55212-2 and 2-AG on Ca2+ channel currents were not blocked by AM630, a selective CB2R antagonist. However, the effect of AEA could be partially rescued by AM630. These results suggest that WIN55212-2 and 2-AG receptor-independently suppressed the Ca2+ channel currents in Müller cells, while AEA suppressed the currents partially through CB2Rs. The existence of receptor-dependent and -independent mechanisms suggests that cannabinoids may modulate Müller cell functions through multiple pathways.