A channel in a transporter.

1. 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.