Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function
Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). Excitatory amino acid transporters (EAATs) regulate extracellular glutamate by transporting it into cells, mostly glia, to terminate neurotransmission and to avoid neurotoxicity. EAATs are also ch...
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-04-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI154891 |
| _version_ | 1818549482457923584 |
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| author | Qianyi Wu Azman Akhter Shashank Pant Eunjoo Cho Jin Xin Zhu Alastair Garner Tomoko Ohyama Emad Tajkhorshid Donald J. van Meyel Renae M. Ryan |
| author_facet | Qianyi Wu Azman Akhter Shashank Pant Eunjoo Cho Jin Xin Zhu Alastair Garner Tomoko Ohyama Emad Tajkhorshid Donald J. van Meyel Renae M. Ryan |
| author_sort | Qianyi Wu |
| collection | DOAJ |
| description | Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). Excitatory amino acid transporters (EAATs) regulate extracellular glutamate by transporting it into cells, mostly glia, to terminate neurotransmission and to avoid neurotoxicity. EAATs are also chloride (Cl–) channels, but the physiological role of Cl– conductance through EAATs is poorly understood. Mutations of human EAAT1 (hEAAT1) have been identified in patients with episodic ataxia type 6 (EA6). One mutation showed increased Cl– channel activity and decreased glutamate transport, but the relative contributions of each function of hEAAT1 to mechanisms underlying the pathology of EA6 remain unclear. Here we investigated the effects of 5 additional EA6-related mutations on hEAAT1 function in Xenopus laevis oocytes, and on CNS function in a Drosophila melanogaster model of locomotor behavior. Our results indicate that mutations resulting in decreased hEAAT1 Cl– channel activity but with functional glutamate transport can also contribute to the pathology of EA6, highlighting the importance of Cl– homeostasis in glial cells for proper CNS function. We also identified what we believe is a novel mechanism involving an ectopic sodium (Na+) leak conductance in glial cells. Together, these results strongly support the idea that EA6 is primarily an ion channelopathy of CNS glia. |
| first_indexed | 2024-12-12T08:33:55Z |
| format | Article |
| id | doaj.art-49af9ee812bc490baa7336527ea0c147 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-12-12T08:33:55Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-49af9ee812bc490baa7336527ea0c1472022-12-22T00:30:59ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-04-011327Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS functionQianyi WuAzman AkhterShashank PantEunjoo ChoJin Xin ZhuAlastair GarnerTomoko OhyamaEmad TajkhorshidDonald J. van MeyelRenae M. RyanGlutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). Excitatory amino acid transporters (EAATs) regulate extracellular glutamate by transporting it into cells, mostly glia, to terminate neurotransmission and to avoid neurotoxicity. EAATs are also chloride (Cl–) channels, but the physiological role of Cl– conductance through EAATs is poorly understood. Mutations of human EAAT1 (hEAAT1) have been identified in patients with episodic ataxia type 6 (EA6). One mutation showed increased Cl– channel activity and decreased glutamate transport, but the relative contributions of each function of hEAAT1 to mechanisms underlying the pathology of EA6 remain unclear. Here we investigated the effects of 5 additional EA6-related mutations on hEAAT1 function in Xenopus laevis oocytes, and on CNS function in a Drosophila melanogaster model of locomotor behavior. Our results indicate that mutations resulting in decreased hEAAT1 Cl– channel activity but with functional glutamate transport can also contribute to the pathology of EA6, highlighting the importance of Cl– homeostasis in glial cells for proper CNS function. We also identified what we believe is a novel mechanism involving an ectopic sodium (Na+) leak conductance in glial cells. Together, these results strongly support the idea that EA6 is primarily an ion channelopathy of CNS glia.https://doi.org/10.1172/JCI154891Neuroscience |
| spellingShingle | Qianyi Wu Azman Akhter Shashank Pant Eunjoo Cho Jin Xin Zhu Alastair Garner Tomoko Ohyama Emad Tajkhorshid Donald J. van Meyel Renae M. Ryan Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function The Journal of Clinical Investigation Neuroscience |
| title | Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function |
| title_full | Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function |
| title_fullStr | Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function |
| title_full_unstemmed | Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function |
| title_short | Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function |
| title_sort | ataxia linked slc1a3 mutations alter eaat1 chloride channel activity and glial regulation of cns function |
| topic | Neuroscience |
| url | https://doi.org/10.1172/JCI154891 |
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