A channel in a transporter

Abstract

SUMMARY1. Glutamate transporters (or excitatory amino acid transporters (EAAT)) are responsible for removing synaptically released glutamate from the extracellular space. The failure of EAAT to carry out this role will lead to excessive stimulation of glutamatergic receptors, causing excitotoxicity and cell death.2. Glutamate is cotransported into the cell with three Na + and one H + , followed by the counter-transport of one K + . In addition, glutamate and Na + binding activates an uncoupled chloride conductance. Thus, glutamate transporters can function as both a transporter and an ion channel. At present, there is no clear understanding of the structural basis for the dual functions of glutamate transporters and, in the present review, we shall discuss some recent studies that have started to address this question.3. It is possible to modulate one function of glutamate transporters without affecting the other, which suggests that the two functions have separate molecular determinants, and a number of models have been suggested to account for the dual functions of the EAAT that predict both single and dual pores for transporter function.4. It appears that the two functions of glutamate transporters arise from separate transmembrane domains. The C-terminal region of the transporters forms the glutamate translocation domain, whereas the second transmembrane domain in the N-terminal half of the protein plays a crucial role in chloride channel function. Although the two functions arise from separate molecular determinants, the two functional domains are likely to be in close proximity. The significance of these observations will be discussed in terms of likely functional models for the transport and channel processes.

A novel splice variant of the Excitatory Amino Acid Transporter 5: Cloning, immunolocalization and functional characterization of hEAAT5v in human retina

“…Furthermore, the calculated K m value for hEAAT5v is similar to that of hEAAT5, suggesting that this loop structure does not alter substrate affinity. This accords with prior data (Ryan and Vandenberg 2005) showing that the critical molecular determinants for glutamate binding and translocation are associated with residues coded by exon 9 (encompassing the second re-entrant loop) and similarly the key molecular determinants for chloride permeation are associated with transmembrane region 2. These data support the observation in this study that hEAAT5v is a functional variant of EAAT5 with functional glutamate transporting properties, and that it should, in the absence of secondary impact, also exhibit chloride-conducting properties.…”

Solute-Inhibitor Interactions in the Plasmodial Surface Anion Channel Reveal Complexities in the Transport Process

“…One explanation for our findings is that PSAC may have two parallel routes for solute transport. Because similar behavior has been reported in other channels that transport divergent solutes (Wadiche and Kavanaugh, 1998;Ryan and Vandenberg, 2005), we propose that PSAC may also use two distinct routes for permeating solutes to achieve its unusual selectivity properties. The presence of more than one route for uptake of nutrient precursors also has important implications for the discovery and development of antimalarial drugs that target PSAC.…”

Heterologous Expression of the Glutamine Transporter SNAT3 in Xenopus Oocytes Is Associated with Four Modes of Uncoupled Transport

“…The currents associated with glutamate transporters of the SLC1 family have two components, a current elicited by the thermodynamically coupled cotransport of 3Na ϩ and 1H ϩ into the cell during glutamate uptake and an uncoupled conductance, which is carried by anions (7). The ratio between uncoupled and coupled current varies between the different glutamate transporter isoforms (8). Substrate-induced anion currents are also observed for the ASC-type neutral amino acid transporters, which are sequence related to the glutamate transporters (9,10).…”