ArticlePloS one2011
Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 1 of them a synthesis that pooled it.
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Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 69 citations in OpenAlex.
- Cys-loop receptors on cannabinoids: All high?Frontiers in physiology · 2022Pooled it
- Human GlyRα2 pore dynamics in gating and inhibition.Structure (London, England : 1993) · 2026Article
- Allosteric modulation and direct activation of glycine receptors by a tricyclic sulfonamide.Scientific reports · 2025Article
- A millisecond coarse-grained simulation approach to decipher allosteric cannabinoid binding at the glycine receptor α1.Nature communications · 2024Article
- Unraveling the Mechanisms of Cannabidiol's Pharmacological Actions: A Comprehensive Research Overview.Topics in current chemistry (Cham) · 2024Review
- Molecular Pharmacology ofInternational journal of molecular sciences · 2024Article
- Schisandrin B, a dual positive allosteric modulator of GABAActa pharmacologica Sinica · 2024Article
- Cannabidiol as a modulator of α7 nicotinic receptors.Cellular and molecular life sciences : CMLS · 2022Article
- Positive Allosteric Modulators of Glycine Receptors and Their Potential Use in Pain Therapies.Pharmacological reviews · 2022Review
- Effects of cannabinoids on ligand-gated ion channels.Frontiers in physiology · 2022Review
- Presence of ethanol-sensitive and ethanol-insensitive glycine receptors in the ventral tegmental area and prefrontal cortex in mice.British journal of pharmacology · 2021Article
- Glycine Receptors in Spinal Nociceptive Control-An Update.Biomolecules · 2021Review
- Analgesia for Sheep in Commercial Production: Where to Next?Animals : an open access journal from MDPI · 2021Review
- Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors.Frontiers in molecular neuroscience · 2021Article
- Modulation of glycine receptor single-channel conductance by intracellular phosphorylation.Scientific reports · 2020Article
- Review
- Activity of novel lipid glycine transporter inhibitors on synaptic signalling in the dorsal horn of the spinal cord.British journal of pharmacology · 2018Article
- Structure-Function Analysis of the GlyR α2 Subunit Autism Mutation p.R323L Reveals a Gain-of-Function.Frontiers in molecular neuroscience · 2017Article
- Electrophysiological Signature of Homomeric and Heteromeric Glycine Receptor Channels.The Journal of biological chemistry · 2016Article
- Functional modulation of glycine receptors by the alkaloid gelsemine.British journal of pharmacology · 2016Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Glycine receptors (GlyRs) are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs) have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA) are positive modulators of α(1), α(2) and α(3) GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly) potentiate α(1) GlyRs but inhibit α(2) and α(3). This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM) region 2 and intracellular lysine 385 determine the positive modulation of α(1) GlyRs by NA-Gly. Successive substitution of non-conserved extracellular and TM residues in α(2) converted NA-Gly-mediated inhibition into potentiation. Conversely, mutation of the conserved lysine within the intracellular loop between TM3 and TM4 attenuated NA-Gly-mediated potentiation of α(1) GlyRs, without affecting inhibition of α(2) and α(3). Notably, this mutation reduced modulation by AEA of all three GlyRs. These results define molecular sites for allosteric control of GlyRs by ECs and reveal an unrecognized function for the TM3-4 intracellular loop in the allosteric modulation of Cys-loop ion channels. The identification of these sites may help to understand the physiological role of this modulation and facilitate the development of novel therapeutic approaches to diseases such as spasticity, startle disease and possibly chronic pain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.