Understanding Cannabinoid Receptor Signaling Complexity: Keys for Improved Therapeutic Drug Development

A special issue of Receptors (ISSN 2813-2564).

Deadline for manuscript submissions: 31 August 2024 | Viewed by 2575

Special Issue Editor


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Guest Editor
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA
Interests: G-protein coupled receptors (GPCRs); cannabinoid receptors; cannabinoid receptor signaling; bias signaling; synthetic cannabinoid receptor agonists (SCRAs); synthetic cannabinoid receptor agonist toxicity; drug abuse; drug development; drug metabolism

Special Issue Information

Dear Colleagues,

The endocannabinoid system is widely expressed throughout the body and regulates many important physiological and pathophysiological processes. Cannabinoid receptors (CBRs) are G-protein coupled receptors (GPCRs) and, ligands modulating activity of these receptors are structurally diverse. CBR activation results in both therapeutic, and unfortunately adverse, effects, which currently limits the clinical use of drugs in this class. However, mechanisms controlling cannabinoid receptor activation and subsequent intracellular signaling processes are highly complex and thus might be exploited to overcome these limitations to preferentially activate pathways responsible for therapeutic rather than adverse effects. For example, ligand-specific modulation of CBRs can result in distinct intracellular signaling patterns via a number of mechanisms including functional selectivity, biased signaling and allosteric modulation. CBR signaling specificity can also be achieved by tissue-selective receptor expression and activity of ligands at non-canonical CBRs. Therefore, articles for this Special Issue are sought to provide improved knowledge to help harness these and other mechanisms of producing CBR signaling diversity and to lead to the development of cannabinoid-based drugs with enhanced therapeutic activity and reduced toxicity.

Topics of interest include but are not limited to:

  1. Orthosteric and allosteric CBR signaling;
  2. CBR functional selectivity and bias signaling;
  3. CBR-interacting proteins;
  4. Signaling of non-canonical CBRs;
  5. CBR-signaling networks;
  6. Tissue-specific CBR signaling;
  7. CBR signaling in cancer cells;
  8. Molecular modeling of CBR ligands;
  9. CBR structure and function.

Prof. Dr. Paul L. Prather
Guest Editor

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Keywords

  • G-protein coupled receptors (GPCRs)
  • endocannabinoids
  • functional selectivity
  • bias signaling
  • molecular modeling
  • synthetic cannabinoid receptor agonists
  • CB1 receptors
  • CB2 receptors

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Published Papers (2 papers)

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Research

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17 pages, 3422 KiB  
Article
Comparison of Agonist Activity between CB1 and CB2 Receptors with Orthosteric Site Mutations
by Christina A. Brust, Matthew A. Swanson, Christos Iliopoulos Tsoutsouvas, Snezana T. Dimova, Vuong Q. Dang, Edward L. Stahl, Jo-Hao Ho, Spyros P. Nikas, Alexandros Makriyannis and Laura M. Bohn
Receptors 2024, 3(3), 380-396; https://doi.org/10.3390/receptors3030018 - 6 Aug 2024
Viewed by 706
Abstract
Human endocannabinoid signaling is primarily mediated by the cannabinoid receptors, CB1 and CB2, which are G protein-coupled receptors (GPCRs). These receptors have been linked to a variety of physiological processes and are being pursued as prospective drug targets due to their potential in [...] Read more.
Human endocannabinoid signaling is primarily mediated by the cannabinoid receptors, CB1 and CB2, which are G protein-coupled receptors (GPCRs). These receptors have been linked to a variety of physiological processes and are being pursued as prospective drug targets due to their potential in treating pain and inflammation. However, because of their homology and shared signaling mechanisms, investigating the individual physiological roles of these receptors and designing subtype-selective ligands has been challenging. Using active-state CB1 and CB2 structures as guides, homologous residues within the orthosteric pocket of each receptor were mutated to alanine to test whether they equally impair CB1 and CB2 activity in response to two high-affinity, nonselective agonists (CP55,940 and AM12033). Interestingly, mutating the Y5.39 position impairs CB1 but not CB2 function. Conversely, mutating residue C6.47 improves CB1 but impairs CB2 signaling. The F7.35A mutation leads to a decrease in CP55,940 potency at CB1 and impairs internalization; however, AM12033 gains potency and promotes CB1 internalization. In CB2, mutation of F7.35A decreases the potency of CP55,940 and neither agonist induces internalization. These observations provide some insight into functional sensitivity of CB1 and CB2 to different agonists when conserved residues are mutated in the orthosteric pocket. Full article
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23 pages, 4948 KiB  
Review
Molecular Targets for Cannabinoids in Natural Killer Cells: Do They Modulate the Antitumor Activity?
by Miguel Olivas-Aguirre, Cecilia Gutiérrez-Iñiguez, Igor Pottosin and Oxana Dobrovinskaya
Receptors 2024, 3(2), 122-144; https://doi.org/10.3390/receptors3020007 - 25 Mar 2024
Cited by 2 | Viewed by 1267
Abstract
Recent research has emphasized the potential of natural and synthetic cannabinoids as anticancer agents. Yet it remains unclear whether and in which sense cannabinoids affect the anticancer activity of NK cells, an important branch of anticancer immunity. Similar uncertainty exists regarding NK cells-based [...] Read more.
Recent research has emphasized the potential of natural and synthetic cannabinoids as anticancer agents. Yet it remains unclear whether and in which sense cannabinoids affect the anticancer activity of NK cells, an important branch of anticancer immunity. Similar uncertainty exists regarding NK cells-based immunotherapy. Here we presented an overview of multiple cannabinoid targets as canonical (mainly CB2) and non-canonical receptors, ion channels, transporters, and enzymes, expressed in NK cells, along with underlying molecular mechanisms. Through them, cannabinoids can affect viability, proliferation, migration, cytokine production, and the overall anticancer activity of NK cells. Respective holistic studies are limited, and, mostly, are phenomenological, not linking observed effects with certain molecular targets. Another problem of existing studies is the lack of standardisation, so that diverse cannabinoids at variable concentrations and ways of administration are applied, and often, instead of purified NK cells, the whole lymphocyte population is used. Therefore, there is an urgent need for more focused, systemic, and in-depth studies of the impact of the cannabinoid toolkit on NK cell function, to critically address the compatibility and potential synergies between NK activity and cannabinoid utilization in the realm of anticancer interventions. Full article
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