Excitatory amino acid transporters (EAATs) do not only mediate secondary-active glutamate transport, but also anion-selective currents. EAAT anion currents are small in the absence and increase upon application of L-glutamate due to substrate-dependent gating of EAAT anion channels. At present, neither the molecular basis nor the physiological importance of the EAAT anion conductance is sufficiently understood. Anion channel gating can be described by a kinetic scheme that is based on the glutamate transport cycle and in which anion channel opening is associated with certain states. All voltage- and substrate-dependent conformational changes of EAAT anion channels are linked to transitions within the transport cycle, and there are no indications for additional substrate–dependent anion channel opening and closing transitions. To account for the substrate dependence of macroscopic currents different transporter states might either exhibit distinct unitary conductances or distinct anion channel open probabilities. Macroscopic current recordings and noise analysis revealed a single channel conductance of 1 pS at symmetrical NO3- for EAAT4 anion channels in the absence as well as in the presence of glutamate (Kovermann et al., 2010). All our experimental data are consistent with opening of a defined anion conduction pathway that opens with different open probability for separate substrate conditions. Although there are marked differences in macroscopic EAAT anion currents, the underlying single channel amplitudes are very similar among different isoforms (Torres-Salazar & Fahlke, 2007; Winter et al., 2012), indicating that the anion conduction pathway is well conserved. All EAAT anion channels exhibit a lyotropic selectivity sequence (Wadiche & Kavanaugh, 1998; Melzer et al., 2003), indicating that selectivity between anion is determined by anion dehydration rather than by association to defined binding sites. These functional data suggest a rather hydrophobic pore with low electrostatic potential. The physiological importance of EAAT anion channels is illustrated by episodic ataxia (EA), a human genetic disease characterized by paroxysmal cerebellar incoordination. There are several genetically and clinically distinct forms of this disease, and one of them, episodic ataxia type 6, is caused by mutations in the gene encoding a glial glutamate transporter, the excitatory amino acid transporter (EAAT) 1. We examined the effects of a disease-associated point mutation, P290R, on glutamate transport, anion current as well as on the subcellular distribution of EAAT1 using heterologous expression in mammalian cells (Winter et al., 2012). P290R reduces the number of EAAT1 in the surface membrane and impairs EAAT1-mediated glutamate uptake. Cells expressing P290R EAAT1 exhibit larger anion currents than WT cells in the absence as well as in the presence of external L-glutamate, despite a lower number of mutant transporters in the surface membrane. Noise analysis revealed unaltered unitary current amplitudes, indicating that P290R modifies opening and closing, and not anion permeation through mutant EAAT1 anion channels. These findings identify gain-of-function of EAAT anion conduction as pathological process in episodic ataxia. Increased EAAT1 anion currents might modify intracellular anion concentrations and thus affect GABAergic transmission. These data illustrate possible functional roles of EAAT anion channels also under physiological conditions.