Presence of ethanol‐sensitive and ethanol‐insensitive glycine receptors in the ventral tegmental area and prefrontal cortex in mice

Araya, Anibal; Gallegos, Scarlet; Viveros, Rodrigo; Martín, Loreto San; Muñoz, Braulio; Harvey, Robert J.; Zeilhofer, Hanns Ulrich; Aguayo, Luis G.

doi:10.1111/bph.15649

Cited by 5 publications

(2 citation statements)

References 77 publications

(183 reference statements)

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“…Consistent with this, non-synaptic taurine or glycine release onto GlyRs was found to be vital for neocortical and spinal cord development (Flint et al, 1998;Scain et al, 2010). Studies using Glra2 knockout mice have since revealed pivotal roles for GlyR α2 in retinal photoreceptor development (Young and Cepko, 2004) and the control of receptive field surrounds in retinal ganglion cells (Nobles et al, 2012;Zhang et al, 2015a), as well as modulation of ethanol intake, aversion and preference (Blednov et al, 2015;San Martin et al, 2020;Araya et al, 2021). However, a major role for GlyR α2 has been identified in dorsal cortical progenitor homeostasis and cortical interneuron migration (Avila et al, 2013(Avila et al, , 2014.…”

Section: Introductionmentioning

confidence: 68%

Loss, Gain and Altered Function of GlyR α2 Subunit Mutations in Neurodevelopmental Disorders

Chen

Wilson

Schaefer³

et al. 2022

Front. Mol. Neurosci.

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Glycine receptors (GlyRs) containing the α2 subunit govern cell fate, neuronal migration and synaptogenesis in the developing cortex and spinal cord. Rare missense variants and microdeletions in the X-linked GlyR α2 subunit gene (GLRA2) have been associated with human autism spectrum disorder (ASD), where they typically cause a loss-of-function via protein truncation, reduced cell-surface trafficking and/or reduced glycine sensitivity (e.g., GLRA2Δex8-9 and extracellular domain variants p.N109S and p.R126Q). However, the GlyR α2 missense variant p.R323L in the intracellular M3-M4 domain results in a gain-of-function characterized by slower synaptic decay times, longer duration active periods and increases in channel conductance. This study reports the functional characterization of four missense variants in GLRA2 associated with ASD or developmental disorders (p.V-22L, p.N38K, p.K213E, p.T269M) using a combination of bioinformatics, molecular dynamics simulations, cellular models of GlyR trafficking and electrophysiology in artificial synapses. The GlyR α2V–22L variant resulted in altered predicted signal peptide cleavage and a reduction in cell-surface expression, suggestive of a partial loss-of-function. Similarly, GlyR α2N38K homomers showed reduced cell-surface expression, a reduced affinity for glycine and a reduced magnitude of IPSCs in artificial synapses. By contrast, GlyR α2K213E homomers showed a slight reduction in cell-surface expression, but IPSCs were larger, with faster rise/decay times, suggesting a gain-of-function. Lastly, GlyR α2T269M homomers exhibited a high glycine sensitivity accompanied by a substantial leak current, suggestive of an altered function that could dramatically enhance glycinergic signaling. These results may explain the heterogeneity of clinical phenotypes associated with GLRA2 mutations and reveal that missense variants can result in a loss, gain or alteration of GlyR α2 function. In turn, these GlyR α2 missense variants are likely to either negatively or positively deregulate cortical progenitor homeostasis and neuronal migration in the developing brain, leading to changes in cognition, learning, and memory.

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Section: Introductionmentioning

confidence: 68%

Loss, Gain and Altered Function of GlyR α2 Subunit Mutations in Neurodevelopmental Disorders

Chen

Wilson

Schaefer³

et al. 2022

Front. Mol. Neurosci.

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“…However, it is worth noting that the effects on membrane lipids are relatively small at clinically relevant concentrations ( Peoples et al, 1996 ). Nevertheless, ethanol at such concentrations can modulate the functions of ligand-gated ion channels, including nicotinic acetylcholine (nACh) ( Coverton and Connolly, 1997 ), GABA A ( Wick et al, 1998 ), glycine ( Araya et al, 2021 ), N-methyl-D-aspartate (NMDA) ( Peoples and Weight, 1995 ), 5-hydroxytryptamine 3 (5-HT3) ( Lovinger and White, 1991 ), ATP receptor channels ( Li et al, 1994 ), as well as voltage-gated Ca 2+ and K + channels ( Treistman et al, 1991 ). The modulation of these responses by ethanol is contingent upon activating the channels by agonists or membrane depolarization ( Treistman et al, 1991 ; Li et al, 1994 ).…”

Section: Protein Modulation Of Girk Channelsmentioning

confidence: 99%

Direct modulation of G protein-gated inwardly rectifying potassium (GIRK) channels

Nguyen,

Glaaser,

Slesinger

2024

Front. Physiol.

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Ion channels play a pivotal role in regulating cellular excitability and signal transduction processes. Among the various ion channels, G-protein-coupled inwardly rectifying potassium (GIRK) channels serve as key mediators of neurotransmission and cellular responses to extracellular signals. GIRK channels are members of the larger family of inwardly-rectifying potassium (Kir) channels. Typically, GIRK channels are activated via the direct binding of G-protein βγ subunits upon the activation of G-protein-coupled receptors (GPCRs). GIRK channel activation requires the presence of the lipid signaling molecule, phosphatidylinositol 4,5-bisphosphate (PIP2). GIRK channels are also modulated by endogenous proteins and other molecules, including RGS proteins, cholesterol, and SNX27 as well as exogenous compounds, such as alcohol. In the last decade or so, several groups have developed novel drugs and small molecules, such as ML297, GAT1508 and GiGA1, that activate GIRK channels in a G-protein independent manner. Here, we aim to provide a comprehensive overview focusing on the direct modulation of GIRK channels by G-proteins, PIP2, cholesterol, and novel modulatory compounds. These studies offer valuable insights into the underlying molecular mechanisms of channel function, and have potential implications for both basic research and therapeutic development.

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Reducing the harms of alcohol: nutritional interventions and functional alcohol alternatives

Belelli,

Riva,

Nutt

2024

International Review of Neurobiology

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Presence of ethanol‐sensitive and ethanol‐insensitive glycine receptors in the ventral tegmental area and prefrontal cortex in mice

Abstract: Availability data statementThe data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions.

Cited by 5 publications

References 77 publications

Loss, Gain and Altered Function of GlyR α2 Subunit Mutations in Neurodevelopmental Disorders

Loss, Gain and Altered Function of GlyR α2 Subunit Mutations in Neurodevelopmental Disorders

Direct modulation of G protein-gated inwardly rectifying potassium (GIRK) channels

Reducing the harms of alcohol: nutritional interventions and functional alcohol alternatives

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