Glutamate is the major excitatory neurotransmitter of the central nervous system. High concentrations of glutamate in the synapse leads to an overstimulation of the glutamatergic receptors, which has been associated with several neurological disorders, such as Alzheimer’s disease, ischemic brain damage following a stroke, amongst others. Thus, Excitatory Amino Acid Transporters (EAATs) play a crucial role in the regulation of synaptic glutamate concentrations (Vandenberg et a., 2013).
In addition to their primary role of clearing extracellular glutamate, binding of substrate to the EAATs activates a thermodynamically uncoupled Cl- conductance, mediated by molecular determinants distinct from those involved in substrate transport. Although the function of this Cl- permeation remains unclear, it has been shown, in bipolar cells of retina, to generate hyperpolarization in cell’s membrane, which in turn prevents further glutamate release (Veruki et al., 2006). Moreover, altered EAAT1 Cl- conductance has been associated with episodic ataxia and epilepsy (Winter et al., 2012).
In this work, we investigate the function and the molecular mechanisms involved in the activation of the Cl- channel of the glutamate transporters using electrophysiological and structural techniques.