Episodic ataxia is 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-1. So far, reduced glutamate uptake by mutant excitatory 
amino acid transporter-1 has been thought to be the main pathophysiological 
process in episodic ataxia type 6. However, excitatory amino acid transporter-1 
does not only mediate secondary-active glutamate transport, but also functions 
as an ion channel. Here, we examined the effects of a disease-associated point 
mutation, P290R, on glutamate transport, anion current as well as on the 
subcellular distribution of excitatory amino acid transporter-1 using 
heterologous expression in mammalian cells. P290R reduces the number of 
excitatory amino acid transporter-1 in the surface membrane and impairs 
excitatory amino acid transporter-1-mediated glutamate uptake. Cells expressing 
P290R excitatory amino acid transporter-1 exhibit larger anion currents than 
wild-type 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 excitatory amino acid transporter-1 anion channels. These 
findings identify gain-of-function of excitatory amino acid transporter anion 
conduction as a pathological process in episodic ataxia. Episodic ataxia type 6 
represents the first human disease found to be associated with altered function 
of excitatory amino acid transporter anion channels and illustrates possible 
physiological and pathophysiological impacts of this functional mode of this 
class of glutamate transporters.