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Glutamate transporters have a chloride channel with two hydrophobic gates.

<div class='caption-title'>GltPh utilizes an elevator mechanism that can be probed by cross-links between the transport and scaffold domains.</div>
<div class='caption-title'>GltPh can be trapped in an open-channel conformation.</div>
<div class='caption-title'>Energetic landscape for the movement of Cl− through GltPh-ClCS.</div>
Chen I, Pant S, Wu Q, Cater RJ, Sobti M, Vandenberg RJ, Stewart AG, Tajkhorshid E, Font J, Ryan RM
OpenAccess logo Nature 591 327-331 (2021)
Related entries: 6wyj, 6wyk, 6wzb, 6x01

Cited: 29 times
EuropePMC logo PMID: 33597752

Abstract

Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, and its precise control is vital to maintain normal brain function and to prevent excitotoxicity1. The removal of extracellular glutamate is achieved by plasma-membrane-bound transporters, which couple glutamate transport to sodium, potassium and pH gradients using an elevator mechanism2-5. Glutamate transporters also conduct chloride ions by means of a channel-like process that is thermodynamically uncoupled from transport6-8. However, the molecular mechanisms that enable these dual-function transporters to carry out two seemingly contradictory roles are unknown. Here we report the cryo-electron microscopy structure of a glutamate transporter homologue in an open-channel state, which reveals an aqueous cavity that is formed during the glutamate transport cycle. The functional properties of this cavity, combined with molecular dynamics simulations, reveal it to be an aqueous-accessible chloride permeation pathway that is gated by two hydrophobic regions and is conserved across mammalian and archaeal glutamate transporters. Our findings provide insight into the mechanism by which glutamate transporters support their dual function, and add information that will assist in mapping the complete transport cycle shared by the solute carrier 1A transporter family.

Articles - 6wyl mentioned but not cited (3)

  1. Viral macrodomains: a structural and evolutionary assessment of the pharmacological potential. Rack JGM, Zorzini V, Zhu Z, Schuller M, Ahel D, Ahel I. Open Biol 10 200237 (2020)
  2. Glutamate transporters have a chloride channel with two hydrophobic gates. Chen I, Pant S, Wu Q, Cater RJ, Sobti M, Vandenberg RJ, Stewart AG, Tajkhorshid E, Font J, Ryan RM. Nature 591 327-331 (2021)
  3. research-article Structure Reveals Homology in Elevator Transporters. Trebesch N, Tajkhorshid E. bioRxiv 2023.06.14.544989 (2023)


Reviews citing this publication (8)

  1. Regulation of Glutamate, GABA and Dopamine Transporter Uptake, Surface Mobility and Expression. Ryan RM, Ingram SL, Scimemi A. Front Cell Neurosci 15 670346 (2021)
  2. Cellular Physiology and Pathophysiology of EAAT Anion Channels. Kovermann P, Engels M, Müller F, Fahlke C. Front Cell Neurosci 15 815279 (2021)
  3. General principles of secondary active transporter function. Beckstein O, Naughton F. Biophys Rev (Melville) 3 011307 (2022)
  4. New Horizons in Structural Biology of Membrane Proteins: Experimental Evaluation of the Role of Conformational Dynamics and Intrinsic Flexibility. Puthenveetil R, Christenson ET, Vinogradova O. Membranes (Basel) 12 227 (2022)
  5. Conquer by cryo-EM without physically dividing. Lander GC, Glaeser RM. Biochem Soc Trans 49 2287-2298 (2021)
  6. A mini-review of the role of vesicular glutamate transporters in Parkinson's disease. Zhao C, Wang C, Zhang H, Yan W. Front Mol Neurosci 16 1118078 (2023)
  7. Elucidating the Mechanism Behind Sodium-Coupled Neurotransmitter Transporters by Reconstitution. Schmidt SG, Gether U, Loland CJ. Neurochem Res 47 127-137 (2022)
  8. SLC26 Anion Transporters. Geertsma ER, Oliver D. Handb Exp Pharmacol 283 319-360 (2024)

Articles citing this publication (18)

  1. Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function. Wu Q, Akhter A, Pant S, Cho E, Zhu JX, Garner A, Ohyama T, Tajkhorshid E, van Meyel DJ, Ryan RM. J Clin Invest 132 e154891 (2022)
  2. Proton-driven alternating access in a spinster lipid transporter. Dastvan R, Rasouli A, Dehghani-Ghahnaviyeh S, Gies S, Tajkhorshid E. Nat Commun 13 5161 (2022)
  3. Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2. Kato T, Kusakizako T, Jin C, Zhou X, Ohgaki R, Quan L, Xu M, Okuda S, Kobayashi K, Yamashita K, Nishizawa T, Kanai Y, Nureki O. Nat Commun 13 4714 (2022)
  4. Structural basis of ligand binding modes of human EAAT2. Zhang Z, Chen H, Geng Z, Yu Z, Li H, Dong Y, Zhang H, Huang Z, Jiang J, Zhao Y. Nat Commun 13 3329 (2022)
  5. Cryo-EM structures of pentameric autoinducer-2 exporter from Escherichia coli reveal its transport mechanism. Khera R, Mehdipour AR, Bolla JR, Kahnt J, Welsch S, Ermler U, Muenke C, Robinson CV, Hummer G, Xie H, Michel H. EMBO J 41 e109990 (2022)
  6. Linking function to global and local dynamics in an elevator-type transporter. Ciftci D, Martens C, Ghani VG, Blanchard SC, Politis A, Huysmans GHM, Boudker O. Proc Natl Acad Sci U S A 118 e2025520118 (2021)
  7. Microscopic Characterization of the Chloride Permeation Pathway in the Human Excitatory Amino Acid Transporter 1 (EAAT1). Pant S, Wu Q, Ryan R, Tajkhorshid E. ACS Chem Neurosci 13 776-785 (2022)
  8. Extended-ensemble docking to probe dynamic variation of ligand binding sites during large-scale structural changes of proteins. Kapoor K, Thangapandian S, Tajkhorshid E. Chem Sci 13 4150-4169 (2022)
  9. Functional and Kinetic Comparison of Alanine Cysteine Serine Transporters ASCT1 and ASCT2. Wang J, Dong Y, Grewer C. Biomolecules 12 113 (2022)
  10. Mutation in glutamate transporter homologue GltTk provides insights into pathologic mechanism of episodic ataxia 6. Colucci E, Anshari ZR, Patiño-Ruiz MF, Nemchinova M, Whittaker J, Slotboom DJ, Guskov A. Nat Commun 14 1799 (2023)
  11. Characterizing unexpected interactions of a glutamine transporter inhibitor with members of the SLC1A transporter family. Freidman NJ, Briot C, Ryan RM. J Biol Chem 298 102178 (2022)
  12. Exploiting Molecular Dynamics in Composite Coatings to Design Robust Super-Repellent Surfaces. Guo R, Goudeli E, Xu W, Richardson JJ, Xu W, Pan S. Adv Sci (Weinh) 9 e2104331 (2022)
  13. Symport and antiport mechanisms of human glutamate transporters. Qiu B, Boudker O. Nat Commun 14 2579 (2023)
  14. Apo state pore opening as functional basis of increased EAAT anion channel activity in episodic ataxia 6. Suslova M, Kortzak D, Machtens JP, Kovermann P, Fahlke C. Front Physiol 14 1147216 (2023)
  15. IUPAB 2021 Symposium 13: ion channels and membrane transporters. Baenziger JE, Ananchenko A, Hussein TOK, Mody D. Biophys Rev 13 871-873 (2021)
  16. Molecular insights into disease-associated glutamate transporter (EAAT1 / SLC1A3) variants using in silico and in vitro approaches. Gorostiola González M, Sijben HJ, Dall' Acqua L, Liu R, IJzerman AP, Heitman LH, van Westen GJP. Front Mol Biosci 10 1286673 (2023)
  17. Structures and mechanisms of the Arabidopsis cytokinin transporter AZG1. Xu L, Jia W, Tao X, Ye F, Zhang Y, Ding ZJ, Zheng SJ, Qiao S, Su N, Zhang Y, Wu S, Guo J. Nat Plants 10 180-191 (2024)
  18. When is a hydrophobic gate not a hydrophobic gate? Seiferth D, Biggin PC, Tucker SJ. J Gen Physiol 154 e202213210 (2022)


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