Harvesting Benefits from Cannabinoids
2016; Cell Press; Volume: 167; Issue: 7 Linguagem: Inglês
10.1016/j.cell.2016.12.001
ISSN1097-4172
Autores Tópico(s)GABA and Rice Research
ResumoWith the ongoing liberalization of cannabis laws in many parts of the United States that are decriminalizing its recreational and/or medical use, there is much discussion about the benefits of cannabinoids and how to mitigate potential negative societal repercussions of increased access to them. At risk of being overshadowed amidst this debate is the fascinating biology coming to light about how cannabinoids mediate their effects, including the crystal structures of human CB1 cannabinoid receptors (Hua et al., 2016Hua T. Vemuri K. Pu M. Qu L. Han G.W. Wu Y. Zhao S. Shui W. Li S. Korde A. et al.Cell. 2016; 167: 750-762.e14Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, Shao et al., 2016Shao Z. Yin J. Chapman K. Grzemska M. Clark L. Wang J. Rosenblum D.M. Nature. 2016; (Published online November 16, 2016)https://doi.org/10.1038/nature20613Crossref Scopus (263) Google Scholar), and surprising insights about where in the cell they act (Herbert-Chatelain et al., 2016Herbert-Chatelain E. Desprez T. Serrat R. Bellocchio L. Soria-Gomez E. Busquets-Garcia A. Zottola A.C.P. Delamarre A. Cannich A. Vincent P. et al.Nature. 2016; (Published online November 9, 2016)https://doi.org/10.1038/nature20127Crossref Scopus (249) Google Scholar, Younts et al., 2016Younts T.J. Monday H.R. Dudok B. Klein M.E. Jordan B.A. Katona I. Castillo P.E. Neuron. 2016; 92: 479-492Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Both plant-based and synthetic cannabinoids piggyback their pharmacology on a collection of endogenous molecules and their receptors together known as the endocannabinoid system. In broad strokes, endocannabinoids are neuromodulatory and have central roles in memory, mood, pain, inflammation, and appetite. Because of these attributes, this system has been an attractive target for therapeutic development. In this context, the recent failed phase I safety trial of a small-molecule inhibitor of fatty acid amide hydrolase, aimed at boosting endocannabinoid levels, highlights the need for a better understanding of both the basic biology of the endocannabinoid system and specific therapeutic targets (Kerbrat et al., 2016Kerbrat A. Ferré J.C. Fillatre P. Ronzière T. Vannier S. Carsin-Nicol B. Lavoué S. Vérin M. Gauvrit J.Y. Le Tulzo Y. Edan G. N. Engl. J. Med. 2016; 375: 1717-1725Crossref PubMed Scopus (126) Google Scholar). Although in this case it is surmised that the severe neurologic symptoms, and in one case fatality, that occurred with high dosing of the experimental compound were due to off-target effects, the tragic outcome and open questions underscore the desirability of pursuing highly specific compounds. The recent crystal structures of the human CB1 receptor should accelerate this effort. CB1 is the main target for both psychoactive ligands (such as trans-Δ9-tetrahydrocannabinol [THC] from cannabis) and endogenous ones (such as anandamide and 2-arachidonyl glycerol [2-AG]). It is a class A G-protein-coupled receptor (GPCR), and consistent with its many roles, it is thought to be the most common GPCR in the central nervous system. The structures from the two groups, respectively, capture the receptor in an inactive state bound to taranabant (Shao et al., 2016Shao Z. Yin J. Chapman K. Grzemska M. Clark L. Wang J. Rosenblum D.M. Nature. 2016; (Published online November 16, 2016)https://doi.org/10.1038/nature20613Crossref Scopus (263) Google Scholar) and a derivative of rimonabant called AM6538 (Hua et al., 2016Hua T. Vemuri K. Pu M. Qu L. Han G.W. Wu Y. Zhao S. Shui W. Li S. Korde A. et al.Cell. 2016; 167: 750-762.e14Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar). Both taranabant and rimonabant are inverse agonists developed for the treatment of obesity that failed to attain regulatory approval due to side effects, including depression. Although pharmacologically distinct from receptor activators, the structures nevertheless permit modeling of the binding pocket for THC and endogenous ligands. The insights into the unique features of the CB1 pocket will aid in the computational design of new inhibitors and activators. And given that THC is known to have wide safety margins, it can be hoped that the new structures will provide insights into the reasons for this, which might assist in developing new compounds with better safety and fewer side effects. A frequent undesirable effect of cannabinoid intoxication is memory impairment, and understanding the specific mechanisms underlying this may inform new ways of mitigating this problem while maintaining other potential benefits. A study by Herbert-Chatelain et al., 2016Herbert-Chatelain E. Desprez T. Serrat R. Bellocchio L. Soria-Gomez E. Busquets-Garcia A. Zottola A.C.P. Delamarre A. Cannich A. Vincent P. et al.Nature. 2016; (Published online November 9, 2016)https://doi.org/10.1038/nature20127Crossref Scopus (249) Google Scholar suggests surprisingly that an important cellular locus of cannabinoid action in memory is mitochondria. It has been known that cannabinoids can activate CB1 at the plasma membrane and also at mitochondrial membranes, although the specific function of the latter has been unclear. Through the deletion of its first 22 amino acids, the authors disrupt trafficking of CB1 to mitochondria in mouse hippocampal neurons. This intervention makes the mice unresponsive to the amnesia-inducing effects of CB1 receptor agonist. The signaling pathway triggered by cannabinoids in mitochondria leads to the phosphorylation of proteins that conduct oxidative phosphorylation—in particular NDUFS2, a respiratory complex I subunit—and blocking this signaling pathway curbs the amnesic effects of cannabinoids. In sum, the findings suggest that one route to memory gated by cannabinoids goes through mitochondria via the modulation of energy metabolism. The connection, however, is undoubtedly complex, as it has been reported that CB1 agonists increase mitochondrial respiration at low doses and decrease it at high ones (Koch et al., 2015Koch M. Varela L. Kim J.G. Kim J.D. Hernández-Nuño F. Simonds S.E. Castorena C.M. Vianna C.R. Elmquist J.K. Morozov Y.M. et al.Nature. 2015; 519: 45-50Crossref PubMed Scopus (276) Google Scholar). Teasing apart these phenomena in individual biological contexts might be aided by discoveries from Younts et al., 2016Younts T.J. Monday H.R. Dudok B. Klein M.E. Jordan B.A. Katona I. Castillo P.E. Neuron. 2016; 92: 479-492Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, who show that a functionally important consequence of CB1 activation by endocannabinoids is pre-synaptic protein synthesis. The findings add support to the notion that axons in the mammalian central nervous system are a site of translation, a subject of long scientific disagreement, unlike post-synaptic compartments, where translation regulation is long appreciated to have a critical role in synaptic plasticity. Endocannabinoids are generated post-synaptically and travel across the synapse to modulate the pre-synaptic neurons. Here, the authors show that presynaptic protein synthesis stimulated by endocannabinoids is essential to the long-term depression of GABA release from hippocampal interneurons. They further establish that this effect is mediated by the mTOR pathway, which has previously been implicated in the amnesic effects of cannabinoids. In light of the report by Herbert-Chatelain et al. discussed above, a mTOR-mitochondria axis of regulation could be central to what is happening in axon terminals in response to endocannabinoids in memory processes. A composite view from these studies promises increased opportunities for developing therapies with greater molecular and cellular specificity and reveals a nexus between cannabinoids and cellular metabolism that might be critical to understanding the context dependence and diversity of cannabinoid functions.
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