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      The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets

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          Abstract

          Cannabidiol (CBD), the major nonpsychoactive Cannabis constituent, has been proposed for the treatment of a wide panel of neurological and neuropsychiatric disorders, including anxiety, schizophrenia, epilepsy and drug addiction due to the ability of its versatile scaffold to interact with diverse molecular targets that are not restricted to the endocannabinoid system. Albeit the molecular mechanisms responsible for the therapeutic effects of CBD have yet to be fully elucidated, many efforts have been devoted in the last decades to shed light on its complex pharmacological profile. In particular, an ever-increasing number of molecular targets linked to those disorders have been identified for this phytocannabinoid, along with the modulatory effects of CBD on their cascade signaling. In this view, here we will try to provide a comprehensive and up-to-date overview of the molecular basis underlying the therapeutic effects of CBD involved in the treatment of neurological and neuropsychiatric disorders.

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          The capsaicin receptor: a heat-activated ion channel in the pain pathway.

          Michael Caterina, Mark Schumacher, Makoto Tominaga … (1997)
          Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
          Article 0 comments Cited 788 times – based on 0 reviews     Review now
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            Structure of the TRPV1 ion channel determined by electron cryo-microscopy

            Maofu Liao, Erhu Cao, David Julius … (2013)
            Transient receptor potential (TRP) channels are sensors for a wide range of cellular and environmental signals, but elucidating how these channels respond to physical and chemical stimuli has been hampered by a lack of detailed structural information. Here, we exploit advances in electron cryo-microscopy to determine the structure of a mammalian TRP channel, TRPV1, at 3.4Å resolution, breaking the side-chain resolution barrier for membrane proteins without crystallization. Like voltage-gated channels, TRPV1 exhibits four-fold symmetry around a central ion pathway formed by transmembrane helices S5–S6 and the intervening pore loop, which is flanked by S1–S4 voltage sensor-like domains. TRPV1 has a wide extracellular ‘mouth’ with short selectivity filter. The conserved ‘TRP domain’ interacts with the S4–S5 linker, consistent with its contribution to allosteric modulation. Subunit organization is facilitated by interactions among cytoplasmic domains, including N-terminal ankyrin repeats. These observations provide a structural blueprint for understanding unique aspects of TRP channel function.
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              The orphan receptor GPR55 is a novel cannabinoid receptor.

              E Ryberg, N. Larsson, S Sjögren … (2007)
              The endocannabinoid system functions through two well characterized receptor systems, the CB1 and CB2 receptors. Work by a number of groups in recent years has provided evidence that the system is more complicated and additional receptor types should exist to explain ligand activity in a number of physiological processes. Cells transfected with the human cDNA for GPR55 were tested for their ability to bind and to mediate GTPgammaS binding by cannabinoid ligands. Using an antibody and peptide blocking approach, the nature of the G-protein coupling was determined and further demonstrated by measuring activity of downstream signalling pathways. We demonstrate that GPR55 binds to and is activated by the cannabinoid ligand CP55940. In addition endocannabinoids including anandamide and virodhamine activate GTPgammaS binding via GPR55 with nM potencies. Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB1 or CB2 activity and are believed to function at a novel cannabinoid receptor, also showed activity at GPR55. GPR55 couples to Galpha13 and can mediate activation of rhoA, cdc42 and rac1. These data suggest that GPR55 is a novel cannabinoid receptor, and its ligand profile with respect to CB1 and CB2 described here will permit delineation of its physiological function(s).
              Article 0 comments Cited 459 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Aron Weller: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 05 May 2021
                Publication date Collection: May 2021
                Volume: 22
                Issue: 9
                Electronic Location Identifier: 4876
                Affiliations
                [1 ]Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy; fabio.iannotti@ 123456icb.cnr.it (F.A.I.); pamodeo@ 123456icb.cnr.it (P.A.)
                [2 ]Endocannabinoid Research Group (ERG), Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy
                Author notes
                [* ]Correspondence: rmvitale@ 123456icb.cnr.it ; Tel.: +39-0818-675-316
                Author information
                https://orcid.org/0000-0001-9243-1307
                https://orcid.org/0000-0003-4480-8370
                https://orcid.org/0000-0002-6439-7575
                Article
                Publisher ID: ijms-22-04876
                DOI: 10.3390/ijms22094876
                PMC ID: 8124847
                PubMed ID: 34062987
                SO-VID: 85e86ad4-20fd-4ad3-a094-19a7954c800d
                Copyright © © 2021 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 15 April 2021
                Date accepted : 03 May 2021
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: cannabidiol,pharmacology,neuropsychiatric disorders,receptors,pharmacological targets
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: cannabidiol, pharmacology, neuropsychiatric disorders, receptors, pharmacological targets

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