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Title: | Hetero-pentamerization determines mobility and conductance of Glycine receptor alpha 3 splice variants | Authors: | LEMMENS, Veerle Thevelein, Bart VELLA, Yana Kankowski, Svenja Leonhard, Julia Mizuno, Hideaki Rocha, Susana BRONE, Bert Meier, Jochen C. HENDRIX, Jelle |
Issue Date: | 2022 | Publisher: | SPRINGER BASEL AG | Source: | CELLULAR AND MOLECULAR LIFE SCIENCES, 79 (11) (Art N° 540) | Abstract: | Glycine receptors (GlyRs) are ligand-gated pentameric chloride channels in the central nervous system. GlyR-alpha 3 is a possible target for chronic pain treatment and temporal lobe epilepsy. Alternative splicing into K or L variants determines the subcellular fate and function of GlyR-alpha 3, yet it remains to be shown whether its different splice variants can functionally co-assemble, and what the properties of such heteropentamers would be. Here, we subjected GlyR-alpha 3 to a combined fluorescence microscopy and electrophysiology analysis. We employ masked Pearson's and dual-color spatiotemporal correlation analysis to prove that GlyR-alpha 3 splice variants heteropentamerize, adopting the mobility of the K variant. Fluorescence-based single-subunit counting experiments revealed a variable and concentration ratio dependent hetero-stoichiometry. Via cell-attached single-channel electrophysiology we show that heteropentamers exhibit currents in between those of K and L variants. Our data are compatible with a model where alpha 3 heteropentamerization fine-tunes mobility and activity of GlyR-alpha 3 channels, which is important to understand and tackle alpha 3 related diseases. | Notes: | Meier, JC (corresponding author), Tech Univ Carolo Wilhelmina Braunschweig, Zool Inst, Div Cell Physiol, D-38106 Braunschweig, Germany. jochen.meier@tu-braunschweig.de; Jelle.hendrix@uhasselt.be |
Keywords: | Glycine receptors;Ligand gated ion channels;Image correlation spectroscopy;Single-molecule fluorescence;Pearson's correlation coefficient;Subunit counting;Protein co-assembly;Diffusion;Stoichiometry;Electrophysiology;Patch clamp | Document URI: | http://hdl.handle.net/1942/38809 | ISSN: | 1420-682X | e-ISSN: | 1420-9071 | DOI: | 10.1007/s00018-022-04506-9 | ISI #: | 000864124100002 | Rights: | The Author(s) 2022. Open access | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2023 |
Appears in Collections: | Research publications |
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Hetero-pentamerization determines mobility and conductance of Glycine receptor α3 splice variants.pdf | Published version | 3.22 MB | Adobe PDF | View/Open |
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