(R)-methanandamide as an opener of large conductance Ca2+ activated K+ channel

The endocannabinoid anandamide and its metabolically stable analog (R) -methanandamide have been reported as modulators of some ion channels. In this study, we examined effects of (R) -methanandamide on large-conductance Ca2+ activated K+ (BK) channels heterologously expressed in human embryonic kidney (HEK) 293 cells using patch clamp techniques. BKα subunit (BKα) alone, both BKα and β1 subunit or both BKα and β4 subunit were stably expressed in HEK293 cells. Application of (R) -methanandamide increased BKα current amplitude. Because co-expression of β1 or β4 subunit with α-subunit did not affect the enhancement of BKα current by (R) -methanandamide, the site of action for (R) -methanandamide is suggested to be BKα subunit. Single channel recordings of BKα in inside-out patches showed the lack of (R) -methanandamide-induced enhancement. In contrast, in cellattached patches, (R) -methanandamide increased the channel activity. In conclusion, (R) -methanandamide leads to the activation of BKα subunits not directly but via the activation of cell surface receptors and/or intracellular signaling.