Linking Mitochondria and Synaptic Transmission: The CB1 Receptor

Abstract

CB1 receptors are functionally present within brain mitochondria (mtCB1), although they are usually considered specifically targeted to plasma membrane. Acute activation of mtCB1 alters mitochondrial ATP generation, synaptic transmission, and memory performance. However, the detailed mechanism linking disrupted mitochondrial metabolism and synaptic transmission is still uncharacterized. CB1 receptors are among the most abundant G protein-coupled receptors in the brain and impact on several processes, including fear coping, anxiety, stress, learning, and memory. Mitochondria perform several key physiological processes for neuronal homeostasis, including production of ATP and reactive oxygen species, calcium buffering, metabolism of neurotransmitters, and apoptosis. It is therefore possible that acute activation of mtCB1 impacts on these different mitochondrial functions to modulate synaptic transmission. In reviewing and integrating across the literature in this area, we describe the possible mechanisms involved in the regulation of brain physiology by mtCB1 receptors.

Intracellular GPCRs Play Key Roles in Synaptic Plasticity

“…As one of the most abundant GPCRs in the brain (111), CB 1 receptors are especially important in mediating either physiological and/or pathological stimuli presynaptically, postsynaptically and from within the cell (112–114). As described above, pharmacological and genetic isolation of mitochondrial CB 1 receptors have underscored their role in excitatory synaptic transmission as well as in memory performance (77).…”

“…The CB 1 -mediated memory impairment appears to be due to decreased protein kinase A (PKA)-dependent phosphorylation of complex I proteins, leading to decreased ATP and decreased mitochondrial respiration. Thus there appears to be a direct link between mitochondrial CB 1 receptors, bioenergetics and higher brain function (114). The exact mechanisms underlying this process are still unclear, but dissecting the specific proteins/pathways involved in this process may generate new therapeutic tools for brain disorders leading to memory loss.…”

GPCR Signaling From Intracellular Membranes − A Novel Concept

“…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 Djeungoue‐Petga 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 that mtCB1R activation might 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 neurotransmitters glutamate and GABA and synaptic transmission.…”

“…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.…”