Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels

Koniuszewski, Filip; Vogel, Florian; Bampali, Konstantina; Fabjan, Jure; Seidel, Thomas; Scholze, Petra; Schmiedhofer, Philip B.; Langer, Thomas; Ernst, Margot

doi:10.3389/fmolb.2022.860246

Cited by 10 publications

(17 citation statements)

References 124 publications

(191 reference statements)

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“…In humans the term “Cys-loop receptors” refers to all pentameric ligand gated ion channels that are formed by subunits encoded by GABR, GLYR, CHRN, 5HT3 and ZAC genes ( Koniuszewski et al, 2022 ). They form pentameric ligand gated ion channels known as cation selective nicotinic ACh receptors (nAChRs) and 5HT type 3 receptors (5-HT3Rs), the zinc activated cation channel (ZAC), and the anion selective GABA type A (GABAARs) and glycine receptors (GlyRs).…”

Section: Cys-loop Receptors Have Cannabinoid Interaction Sitesmentioning

confidence: 99%

“…They form pentameric ligand gated ion channels known as cation selective nicotinic ACh receptors (nAChRs) and 5HT type 3 receptors (5-HT3Rs), the zinc activated cation channel (ZAC), and the anion selective GABA type A (GABAARs) and glycine receptors (GlyRs). Due to the highly conserved sequence and structure properties in this family, they share not only structural features but also ligands ( Koniuszewski et al, 2022 ). While the agonist sites in the extracellular domain are less promiscuous, certain allosteric binding sites and specifically those in the transmembrane domain are quite similar across most Cys-loop receptors.…”

Section: Cys-loop Receptors Have Cannabinoid Interaction Sitesmentioning

confidence: 99%

“…Silent and negative allosteric modulation can occur as well (SAM, NAM). We have recently analyzed the structural evidence for binding sites in human Cys-loop receptors ( Koniuszewski et al, 2022 Figure 2 ) and provide here an update, with special focus on the known and candidate sites for cannabinoid interactions.…”

Section: Cys-loop Receptors Have Cannabinoid Interaction Sitesmentioning

confidence: 99%

“…Many subunit assemblies are thought to consist of two α, two β and one γ subunits ( Olsen and Sieghart, 2008 ), with recent evidence pointing to a wide diversity of alternative combinations ( Sente et al, 2022 ). GABAAR targeting compounds interact either with orthosteric (GABA) sites or with allosteric sites, which are present in the extracellular and membrane spanning domains ( Koniuszewski et al, 2022 ).…”

Section: Cys-loop Receptors Have Cannabinoid Interaction Sitesmentioning

confidence: 99%

“…Due to the high homology between GABAA- and Gly-receptors, the allosteric binding sites appear to be largely overlapping ( Koniuszewski et al, 2022 , and Figure 2 ). Prior to the recent structural findings, mutational studies have examined possible localizations of cannabinoid sites in Cys-loop receptors, see Table 1 .…”

Section: Cys-loop Receptors Have Cannabinoid Interaction Sitesmentioning

confidence: 99%

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Cys-loop receptors on cannabinoids: All high?

et al. 2022

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Endocannabinoids (eCBS) are endogenously derived lipid signaling molecules that serve as tissue hormones and interact with multiple targets, mostly within the endocannabinoid system (ECS). The ECS is a highly conserved regulatory system involved in homeostatic regulation, organ formation, and immunomodulation of chordates. The term “cannabinoid” evolved from the distinctive class of plant compounds found in Cannabis sativa, an ancient herb, due to their action on CB1 and CB2 receptors. CB1/2 receptors are the primary targets for eCBs, but their effects are not limited to the ECS. Due to the high interest and extensive research on the ECS, knowledge on its constituents and physiological role is substantial and still growing. Crosstalk and multiple targeting of molecules are common features of endogenous and plant compounds. Cannabimimetic molecules can be divided according to their origin, natural or synthetic, including phytocannabinoids (pCB’s) or synthetic cannabinoids (sCB’s). The endocannabinoid system (ECS) consists of receptors, transporters, enzymes, and signaling molecules. In this review, we focus on the effects of cannabinoids on Cys-loop receptors. Cys-loop receptors belong to the class of membrane-bound pentameric ligand gated ion channels, each family comprising multiple subunits. Mammalians possess GABA type A receptors (GABAAR), glycine receptors (GlyR), serotonin receptors type 3 (5-HT3R), and nicotinic acetylcholine receptors (nAChR). Several studies have shown different modulatory effects of CBs on multiple members of the Cys-loop receptor family. We highlight the existing knowledge, especially on subunits and protein domains with conserved binding sites for CBs and their possible pharmacological and physiological role in epilepsy and in chronic pain. We further discuss the potential for cannabinoids as first line treatments in epilepsy, chronic pain and other neuropsychiatric conditions, indicated by their polypharmacology and therapeutic profile.

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Section: Cys-loop Receptors Have Cannabinoid Interaction Sitesmentioning

confidence: 99%

Section: Cys-loop Receptors Have Cannabinoid Interaction Sitesmentioning

confidence: 99%

Section: Cys-loop Receptors Have Cannabinoid Interaction Sitesmentioning

confidence: 99%

Section: Cys-loop Receptors Have Cannabinoid Interaction Sitesmentioning

confidence: 99%

Section: Cys-loop Receptors Have Cannabinoid Interaction Sitesmentioning

confidence: 99%

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Cys-loop receptors on cannabinoids: All high?

et al. 2022

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GABAA receptor-mediated seizure liabilities: a mixed-methods screening approach

et al. 2023

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GABAA receptors, members of the pentameric ligand-gated ion channel superfamily, are widely expressed in the central nervous system and mediate a broad range of pharmaco-toxicological effects including bidirectional changes to seizure threshold. Thus, detection of GABAA receptor-mediated seizure liabilities is a big, partly unmet need in early preclinical drug development. This is in part due to the plethora of allosteric binding sites that are present on different subtypes of GABAA receptors and the critical lack of screening methods that detect interactions with any of these sites. To improve in silico screening methods, we assembled an inventory of allosteric binding sites based on structural data. Pharmacophore models representing several of the binding sites were constructed. These models from the NeuroDeRisk IL Profiler were used for in silico screening of a compiled collection of drugs with known GABAA receptor interactions to generate testable hypotheses. Amoxapine was one of the hits identified and subjected to an array of in vitro assays to examine molecular and cellular effects on neuronal excitability and in vivo locomotor pattern changes in zebrafish larvae. An additional level of analysis for our compound collection is provided by pharmacovigilance alerts using FAERS data. Inspired by the Adverse Outcome Pathway framework, we postulate several candidate pathways leading from specific binding sites to acute seizure induction. The whole workflow can be utilized for any compound collection and should inform about GABAA receptor-mediated seizure risks more comprehensively compared to standard displacement screens, as it rests chiefly on functional data.

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