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CCeMMP Seminar Series Prof Renae Ryan – June 2023

The split personality of glutamate transporters: a chloride channel and a transporter

Excitatory amino acid transporters (EAATs) regulate excitatory neurotransmission by transporting glutamate into cells, mostly glia, to terminate neurotransmission and to avoid neurotoxicity. EAATs also conduct chloride ions via a channel-like process that is thermodynamically uncoupled from transport. The molecular mechanisms that allow these dual-function transporters to carry out two seemingly contradictory roles, and the physiological role of chloride ion conductance of the EAATs, are not clear. Renae will describe the cryo-electron microscopy structure of a glutamate transporter homologue in an open-channel state, revealing an aqueous-accessible chloride ion permeation pathway that is formed during the transport cycle and discuss the impact of a series of mutations in EAAT1 that have been identified in patients with the neurological disease episodic ataxia type 6 (EA6). By studying EAAT1 function and using a Drosophila melanogaster model of locomotor behaviour, their results indicate that mutations that lead to functional glutamate transport but either increased OR decreased chloride ion channel activity contribute to the pathology of EA6, highlighting the importance of chloride ion homeostasis in glial cells for proper central nervous system function. Her findings provide insight into the mechanism by which glutamate transporters support their dual functions and provides a framework for the rational development of therapeutics that can differentially modulate substrate transport or channel properties for the treatment of neurological disorders caused by EAAT dysfunction, such as episodic ataxia.

Prof Renae Ryan

Transporter Biology Group

Faculty of Medicine and Health

The University of Sydney, Australia