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Bestrophin-2 (Best2) is a member of the bestrophin family of calcium-activated anion channels with critical involvement in ocular physiology(1–4). Here, we uncover a directional permeability of Best2 to glutamate heavily favoring glutamate exit, identify glutamine synthetase (GS) as a binding partner of Best2 in the ciliary body of the eye, and solve the structure of the Best2-GS complex. Best2 reduces cytosolic GS activity by tethering GS to the cell membrane. GS extends the ion conducting pathway of Best2 through its central cavity and inhibits Best2 channel function in the absence of intracellular glutamate, but sensitizes Best2 to intracellular glutamate, which promotes opening of Best2 and thus relieves the inhibitory effect of GS. The physiological role of Best2 in conducting chloride and glutamate and the influence of GS are demonstrated in non-pigmented ciliary epithelial cells. Together, our results reveal a novel mechanism of glutamate release through Best2-GS. |
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