Impaired K+ binding to glial glutamate transporter EAAT1 in migraine
Abstract SLC1A3 encodes the glial glutamate transporter hEAAT1, which removes glutamate from the synaptic cleft via stoichiometrically coupled Na+-K+-H+-glutamate transport. In a young man with migraine with aura including hemiplegia, we identified a novel SLC1A3 mutation that predicts the substitut...
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| Format: | Article |
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Nature Portfolio
2017-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-14176-4 |
| _version_ | 1818841834787438592 |
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| author | Peter Kovermann Margarita Hessel Daniel Kortzak Joanna C. Jen Johannes Koch Christoph Fahlke Tobias Freilinger |
| author_facet | Peter Kovermann Margarita Hessel Daniel Kortzak Joanna C. Jen Johannes Koch Christoph Fahlke Tobias Freilinger |
| author_sort | Peter Kovermann |
| collection | DOAJ |
| description | Abstract SLC1A3 encodes the glial glutamate transporter hEAAT1, which removes glutamate from the synaptic cleft via stoichiometrically coupled Na+-K+-H+-glutamate transport. In a young man with migraine with aura including hemiplegia, we identified a novel SLC1A3 mutation that predicts the substitution of a conserved threonine by proline at position 387 (T387P) in hEAAT1. To evaluate the functional effects of the novel variant, we expressed the wildtype or mutant hEAAT1 in mammalian cells and performed whole-cell patch clamp, fast substrate application, and biochemical analyses. T387P diminishes hEAAT1 glutamate uptake rates and reduces the number of hEAAT1 in the surface membrane. Whereas hEAAT1 anion currents display normal ligand and voltage dependence in cells internally dialyzed with Na+-based solution, no anion currents were observed with internal K+. Fast substrate application demonstrated that T387P abolishes K+-bound retranslocation. Our finding expands the phenotypic spectrum of genetic variation in SLC1A3 and highlights impaired K+ binding to hEAAT1 as a novel mechanism of glutamate transport dysfunction in human disease. |
| first_indexed | 2024-12-19T04:32:23Z |
| format | Article |
| id | doaj.art-29823721443a4019960ff51246f63d0e |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T04:32:23Z |
| publishDate | 2017-10-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj.art-29823721443a4019960ff51246f63d0e2022-12-21T20:35:51ZengNature PortfolioScientific Reports2045-23222017-10-017111010.1038/s41598-017-14176-4Impaired K+ binding to glial glutamate transporter EAAT1 in migrainePeter Kovermann0Margarita Hessel1Daniel Kortzak2Joanna C. Jen3Johannes Koch4Christoph Fahlke5Tobias Freilinger6Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum JülichInstitute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum JülichInstitute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum JülichDepartments of Neurology and Neurobiology, UCLA School of MedicineDepartment of Paediatrics, Salzburger UniversitätsklinikumInstitute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum JülichDepartment of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research (HIH)Abstract SLC1A3 encodes the glial glutamate transporter hEAAT1, which removes glutamate from the synaptic cleft via stoichiometrically coupled Na+-K+-H+-glutamate transport. In a young man with migraine with aura including hemiplegia, we identified a novel SLC1A3 mutation that predicts the substitution of a conserved threonine by proline at position 387 (T387P) in hEAAT1. To evaluate the functional effects of the novel variant, we expressed the wildtype or mutant hEAAT1 in mammalian cells and performed whole-cell patch clamp, fast substrate application, and biochemical analyses. T387P diminishes hEAAT1 glutamate uptake rates and reduces the number of hEAAT1 in the surface membrane. Whereas hEAAT1 anion currents display normal ligand and voltage dependence in cells internally dialyzed with Na+-based solution, no anion currents were observed with internal K+. Fast substrate application demonstrated that T387P abolishes K+-bound retranslocation. Our finding expands the phenotypic spectrum of genetic variation in SLC1A3 and highlights impaired K+ binding to hEAAT1 as a novel mechanism of glutamate transport dysfunction in human disease.https://doi.org/10.1038/s41598-017-14176-4 |
| spellingShingle | Peter Kovermann Margarita Hessel Daniel Kortzak Joanna C. Jen Johannes Koch Christoph Fahlke Tobias Freilinger Impaired K+ binding to glial glutamate transporter EAAT1 in migraine Scientific Reports |
| title | Impaired K+ binding to glial glutamate transporter EAAT1 in migraine |
| title_full | Impaired K+ binding to glial glutamate transporter EAAT1 in migraine |
| title_fullStr | Impaired K+ binding to glial glutamate transporter EAAT1 in migraine |
| title_full_unstemmed | Impaired K+ binding to glial glutamate transporter EAAT1 in migraine |
| title_short | Impaired K+ binding to glial glutamate transporter EAAT1 in migraine |
| title_sort | impaired k binding to glial glutamate transporter eaat1 in migraine |
| url | https://doi.org/10.1038/s41598-017-14176-4 |
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