1. (S)Pot on Mitochondria: Cannabinoids Disrupt Cellular Respiration to Limit Neuronal Activity 
Tibor Harkany, Tamas L. Horvath 
Cell Metabolism 
Volume 25, Issue 1, Pages 8-10 (January 2017)
DOI: /j.cmet
Copyright © 2017 Elsevier Inc. Terms and Conditions

2. Figure 1
CB1 Cannabinoid Receptors in Mitochondria Control Neuronal Bioenergetics
The classical GPCR processing pathway relies on gene transcription in nucleus, protein translation, and processing on polyribosomes and in the ER-trans-Golgi complex, respectively. Protein orientation but not intermediate steps on small transport vesicles is shown. Upon insertion in the plasma membrane with their N terminus facing extracellularly, CB1Rs can initiate manifold signaling pathways through Gi/o proteins. This typically involves the sequential inhibition of adenylyl cyclase (AC) and protein kinase A (PKA). Less-frequent Gs coupling is not shown. Recently, Marsicano and colleagues proposed (Bénard et al., 2012; Hebert-Chatelain et al., 2016) that a subcellular pool of CB1Rs (1) target to mitochondria (“mtCB1Rs”) with its N1-22 sequence facilitating mitochondrial import. Whether CB1Rs naturally lacking N1-22 exist remains unknown. The exact mitochondrial import machinery for CB1Rs is also elusive (2) even if a Mim1-dependent mechanism might be prioritized. mtCB1Rs localize to the outer mitochondrial membrane (Bénard et al., 2012). However, whether they form homo- or heteromultimers, like plasmalemmal CB1Rs, is another open question (3). Δ9-tetrahydrocannabinol (THC) acts on mtCB1Rs and reduces cellular ATP availability, and thus respiration. (4) Mitochondrial Gi proteins co-immunoprecipitate with and are released upon mtCB1R activation, and inhibit soluble AC (sAC), suggesting signaling in the intermembrane space. How partitioning of key signal proteins changes upon cell state and mtCB1R activity to support signaling needs further analysis (5). Cannabinoids then decrease PKA-dependent phosphorylation of complex I proteins, particularly NDUFS2. Dissecting mtCB1R signal specificity on complex I proteins will be critical to exploit this pathway for therapeutic benefit. Considering that constitutively active PKA as well as phosphomimetic NDUFS2 rescue the effects of cannabinoids on mitochondrial respiration and block cannabinoid-induced amnesia in vivo, a direct link between mtCB1Rs, neuronal bioenergetics, and higher brain functions emerges.
Cell Metabolism  , 8-10DOI: ( /j.cmet )
Copyright © 2017 Elsevier Inc. Terms and Conditions