Abstract
Regulation of Ca^2+^ homeostasis plays a critical role in oligodendrocyte function and survival. Cannabinoid CB~1~ and CB~2~ receptors have been shown to regulate Ca^2+^ levels and/or K^+^ currents in a variety of cell types. In this study we investigated the effect of cannabinoid compounds on the Ca^2+^ influx elicited in cultured oligodendrocytes by transient membrane depolarization with an elevated extracellular K^+^ concentration (50 mM). The CB~1~ receptor agonist arachidonoyl‐chloro‐ethanolamide (ACEA) elicited a concentration‐dependent inhibition of depolarization‐evoked Ca^2+^ transients in oligodendroglial somata with a maximal effect (94 ± 3)% and an EC~50~ of 1.3 ± 0.03 μM. This activity was mimicked by the CB~1~/CB~2~ agonist CP55,940, as well as by the endocannabinoids N‐arachidonoyl‐ethanolamine (anandamide, AEA) and 2‐arachidonoylglycerol (2‐AG), whereas the CB~2~ receptor selective agonist JWH133 was ineffective. The CB~1~ receptor antagonist AM251 (1 μM) also reduced the Ca^2+^ response evoked by high extracellular K^+^ and did not prevent the inhibition elicited by ACEA (3 μM). Nevertheless, the ability of ACEA and AEA to reduce depolarization‐evoked Ca^2+^ transients was significantly reduced in oligodendrocytes from CB~1~ receptor knockout mice, as well as by pretreatment with pertussis toxin. Bath application of the inwardly rectifying K^+^ channels (Kir channels) blockers BaCl~2~ (300 μM) and CsCl~2~ (1 mM) reduced the size of voltage‐induced Ca^2+^ influx and partially prevented the inhibitory effect of ACEA. Our results indicate that cannabinoids inhibit depolarization‐evoked Ca^2+^ transients in oligodendrocytes via CB~1~ receptor‐independent and ‐dependent mechanisms that involve the activation of PTX‐sensitive G~i/o~ proteins and the blockade of Kir channels. © 2008 Wiley‐Liss, Inc.