Glutamate transporters have a chloride channel with two hydrophobic gates

Ichia Chen, Shashank Pant, Qianyi Wu, Rosemary J. Cater, Meghna Sobti, Robert J. Vandenberg, Alastair G. Stewart, Emad Tajkhorshid (), Josep Font () and Renae M. Ryan ()
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Ichia Chen: University of Sydney
Shashank Pant: University of Illinois at Urbana-Champaign
Qianyi Wu: University of Sydney
Rosemary J. Cater: University of Sydney
Meghna Sobti: The Victor Chang Cardiac Research Institute
Robert J. Vandenberg: University of Sydney
Alastair G. Stewart: The Victor Chang Cardiac Research Institute
Emad Tajkhorshid: University of Illinois at Urbana-Champaign
Josep Font: University of Sydney
Renae M. Ryan: University of Sydney

Nature, 2021, vol. 591, issue 7849, 327-331

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03240-9

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