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SC Mangel, KE Gavrikov, AV Dmitriev, KT Keyser; Direction Selectivity in the Retina is Mediated by the Na-K-Cl and K-Cl Cotransporters . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2980.
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Purpose: The neurotransmitter GABA mediates null direction inhibition of On-Off rabbit directionally selective (DS) ganglion cells (Caldwell et al., 1978) via activation of chloride channels. Because cation chloride cotransporters regulate the intracellular chloride concentration and determine whether GABA hyperpolarizes or depolarizes neurons (Russell, 2000), we studied whether blockade of the Na-K-Cl and K-Cl cotransporters affects direction selectivity. Methods: Extracellular recordings of On-Off rabbit DS ganglion cells were obtained and the effects of various blockers of chloride cotransporters assessed. Results: Superfusion of bumetanide (10 µM), a selective blocker of the Na-K-Cl cotransporter, which pumps chloride into cells, eliminated the directional responses of DS ganglion cells by increasing the response to movement in the null direction. In contrast, furosemide (25 µM), a selective blocker of the K-Cl cotransporter, which pumps chloride out of cells, or replacement of 15 mM Cl with pentanesulfonate, an anion that does not traverse chloride channels, also eliminated direction selectivity, but did so by decreasing the response to movement in the preferred direction. Application of nitrate (1 mM), an anion that flows through chloride channels, but inhibits chloride cotransporter activity, eliminated direction selectivity, but did not affect the response to flashing spots of light. Conclusion: These results indicate that the Na-K-Cl and K-Cl cotransporters mediate GABA-dependent direction selectivity. The results also show that direction selectivity is highly sensitive to the chloride gradient and that the mechanisms that underlie it are distinct from those that underlie the response to flashing stimuli. In addition, because elimination of the starburst amacrine cell eliminates direction selectivity (Yoshida et al., 2001), the results are consistent with the idea that an asymmetric or differential distribution of these chloride cotransporters on the dendrites of the starburst amacrine cell mediates direction selectivity.
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