LAUSR

The properties of the main psychoactive compound of the Cannabis plant, namely Δ-tetrahydrocannabinol (THC), have been recognized for a long time. Ever since the discovery of cannabinoid receptors (CB1R and CB2R) and the characterization of endogenous ligands acting at these receptors (endocannabinoids) they have been studied intensely and shown to be crucial regulators of brain and peripheral functions. CB1R is a G protein-coupled receptor (GPCR) with high and abundant cell surface expression in the central nervous system. Evidence of functional CB1R in brain mitochondria (mtCB1R) made it necessary to revisit the physiological impact of CB1R signaling in brain and to discuss possible downstream effects of mtCB1R activation. In their comprehensive overview DjeungouePetga et al. summarize the potential impact of mtCB1R on the regulation of brain physiology. CB1R regulates numerous brain tasks, including synaptic activity, perception and memory performance, and at least some of these functions might be mediated by mtCB1R. It is well established that cannabinoid administration impacts on mitochondrial structure. Djeungoue-Petga et al. hypothesize thatmtCB1Ractivationmight have a crucial role in this process, and showed that mtCB1R activation decreases mitochondrial mobility, an outcome that is probably linked to the reduced mitochondrial metabolism. Moreover, activation of mtCB1R decreases flux through the electron transport chain and thus mitochondrial oxygen consumption and energy production, which likely impacts on ATP generation, the production of the central neurotransmittersglutamateandGABAandsynaptic transmission. The classical concept of GPCR function and signaling includes the expression of the receptor exclusively on the plasma membrane and the recognition of extracellular agonists. This concept was recently challenged by accumulating evidence for signaling of GPCRs from intracellular membranes (reviewed in Ref. ) of endosomes, mitochondria (as discussed in the current issue of BioEssays for CB1R), the endoplasmatic reticulum (ER), the Golgi apparatus, and the nucleus. G-proteins and G protein-related signaling components have also been shown to be present in intracellular organelles including mitochondria (reviewed in Ref. ). One of the first examples