Glutamate transporters: a broad review of the most recent archaeal and human structures

Abstract

Glutamate transporters play important roles in bacteria, archaea and eukaryotes. Their function in the mammalian central nervous system is essential for preventing excitotoxicity, and their dysregulation is implicated in many diseases, such as epilepsy and Alzheimer's. Elucidating their transport mechanism would further the understanding of these transporters and promote drug design as they provide compelling targets for understanding the pathophysiology of diseases and may have a direct role in the treatment of conditions involving glutamate excitotoxicity. This review outlines the insights into the transport cycle, uncoupled chloride conductance and modulation, as well as identifying areas that require further investigation.*These authors contributed equally to this work.

ASCT1 and ASCT2: Brother and Sister?

“…Then, over almost two decades, other 3D structures of GLT Ph in different conformations have been solved, together with those of other bacterial transporters for glutamate/aspartate, such as GLT tk . 2,7,30 These studies confirmed the homotrimeric architecture and gave further insights into the molecular determinants of the transport mechanism and allowed studying the human members of the SLC1 family by homology modeling coupled to biochemical approaches. 31–33 Later, in 2017, the 3D structure of the human isoform of EAAT1 was solved, demonstrating that the eukaryotic proteins show the same homotrimer organization as the bacterial counterparts; since then, more refined homology models have been built for the other members of the SLC1 family, including ASCT2.…”

“…36 This observation, supported by structural analyses, still requires experimental pieces of evidence to be definitively confirmed. 6,39 The one-gate elevator mechanism is shared by all the SLC1 family members; 2,7 during the cycle, the substrate is occluded in the transport domain that performs a large movement from the extracellular to the intracellular milieu and vice versa ( Fig. 3 ).…”

“…Another residue that was found to be crucial in substrate binding site layout is located in TM7: in EAATs this helix harbors the motif NMDGT responsible for allosteric coupling of the substrate and sodium binding. Interestingly, the last amino acid of the motif, that is, Thr, is not conserved in ASCTs that harbor an Ala residue 7,31 ( Fig. 5A,B ).…”

“…2 In line with this, several eminent reviews are available on the mentioned aspects of the SLC1 family with a special focus on the EAAT group. 1–3,6,7 A systematic and up-to-date report of the ASCT group is, to our knowledge, lacking or incomplete; therefore, the scope of the present review is to compare the two members, namely, ASCT1 (SLC1A4) and ASCT2 (SLC1A5), to furnish a more refined picture of their structural, physiological, and possibly regulatory features. It has to be stressed that ASCT1 and ASCT2 deserved a different degree of attention from the scientific community.…”

Kir4.1 may represent a novel therapeutic target for diabetic retinopathy (Review)

“…In order to prevent excessive glutamate levels outside of nerve cells, the body maintains normal glutamate levels through the glutamate receptor. Glutamate transporters may be divided into a variety of types, such as excitatory amino acid transporters (EAAT) and vesicle glutamate transporters, according to their structural and functional characteristics ( 27 , 28 ). Glutamate/L-aspartate transporter (GLAST) is a subtype of EAAT, also known as EAAT1, mainly distributed on Müller cells in the retina ( 29 ).…”