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Featured ArticleResearch Articles, Cellular/Molecular

Shisa7-Dependent Regulation of GABAA Receptor Single-Channel Gating Kinetics

David Castellano, Kunwei Wu, Angelo Keramidas and Wei Lu
Journal of Neuroscience 23 November 2022, 42 (47) 8758-8766; DOI: https://doi.org/10.1523/JNEUROSCI.0510-22.2022
David Castellano
1Synapse and Neural Circuit Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892
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Kunwei Wu
1Synapse and Neural Circuit Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892
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Angelo Keramidas
2Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Wei Lu
1Synapse and Neural Circuit Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892
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Abstract

GABAA receptors (GABAARs) mediate the majority of fast inhibitory transmission throughout the brain. Although it is widely known that pore-forming subunits critically determine receptor function, it is unclear whether their single-channel properties are modulated by GABAAR-associated transmembrane proteins. We previously identified Shisa7 as a GABAAR auxiliary subunit that modulates the trafficking, pharmacology, and deactivation properties of these receptors. However, whether Shisa7 also regulates GABAAR single-channel properties has yet to be determined. Here, we performed single-channel recordings of α2β3γ2L GABAARs cotransfected with Shisa7 in HEK293T cells and found that while Shisa7 does not change channel slope conductance, it reduced the frequency of receptor openings. Importantly, Shisa7 modulates GABAAR gating by decreasing the duration and open probability within bursts. Through kinetic analysis of individual dwell time components, activation modeling, and macroscopic simulations, we demonstrate that Shisa7 accelerates GABAAR deactivation by governing the time spent between close and open states during gating. Together, our data provide a mechanistic basis for how Shisa7 controls GABAAR gating and reveal for the first time that GABAAR single-channel properties can be modulated by an auxiliary subunit. These findings shed light on processes that shape the temporal dynamics of GABAergic transmission.

SIGNIFICANCE STATEMENT Although GABAA receptor (GABAAR) single-channel properties are largely determined by pore-forming subunits, it remains unknown whether they are also controlled by GABAAR-associated transmembrane proteins. Here, we show that Shisa7, a recently identified GABAAR auxiliary subunit, modulates GABAAR activation by altering single-channel burst kinetics. These results reveal that Shisa7 primarily decreases the duration and open probability of receptor burst activity during gating, leading to accelerated GABAAR deactivation. These experiments are the first to assess the gating properties of GABAARs in the presence of an auxiliary subunit and provides a kinetic basis for how Shisa7 modifies temporal attributes of GABAergic transmission at the single-channel level.

  • deactivation
  • GABAA receptor
  • GABRA2
  • gating kinetics
  • Shisa7
  • single-channel

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The Journal of Neuroscience: 42 (47)
Journal of Neuroscience
Vol. 42, Issue 47
23 Nov 2022
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Shisa7-Dependent Regulation of GABAA Receptor Single-Channel Gating Kinetics
David Castellano, Kunwei Wu, Angelo Keramidas, Wei Lu
Journal of Neuroscience 23 November 2022, 42 (47) 8758-8766; DOI: 10.1523/JNEUROSCI.0510-22.2022

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Shisa7-Dependent Regulation of GABAA Receptor Single-Channel Gating Kinetics
David Castellano, Kunwei Wu, Angelo Keramidas, Wei Lu
Journal of Neuroscience 23 November 2022, 42 (47) 8758-8766; DOI: 10.1523/JNEUROSCI.0510-22.2022
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Keywords

  • deactivation
  • GABAA receptor
  • GABRA2
  • gating kinetics
  • Shisa7
  • single-channel

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