Phyto and endocannabinoids exert complex actions on calcium and zinc signaling in mouse cortical neurons.

Live-cell imaging experiments were performed with the fluorescent Ca and Zn probes Fluo-4 and FluoZin-3 on cultured cortical neurons dissociated from embryonic mice to investigate the effects of the cannabinoids anandamide (AEA), cannabidiol (CBD), and N-arachidonoyl glycine (NAGly) on neuronal store-operated Ca entry (SOCE). When tested individually AEA, CBD or NAGly inhibited SOCE. CBD and NAGly also released Ca from the endoplasmic reticulum. Furthermore, NAGly mobilized Zn from a store distinct from the endoplasmic reticulum and mitochondria, and up-regulated the thapsigargin-evoked Ca release. All these effects developed in a cannabinoid receptor CB1/2 independent manner via an intracellular pathway sensitive to the GPR55 antagonist ML193. Evidence is presented that cannabinoids influence Ca and Zn signaling in central nervous system neurons. The lipid sensing receptor GPR55 seems to be a central actor governing these responses. In addition, the alteration of the cytosolic Zn levels produced by NAGly provides support for the existence of a connection between endocannabinoids and Zn signaling in the brain.