Antisense to MDR1 mRNA reduces P‐glycoprotein expression, swelling‐activated Cl− current and volume regulation in bovine ciliary epithelial cells

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Abstract
Native ciliary epithelial cells from the ciliary epithelium of the eye exhibit anti‐P‐glycoprotein (P‐gp) immunofluorescence. We have used an antisense ‘knock‐down’ approach to investigate the relationship between P‐gp and the volume‐activated chloride current (ICl,swell) and its role in volume regulation. An antisense oligonucleotide to the human multidrug resistance (MDR1) gene, taken up by the cells in a dose‐dependent manner, reduced P‐gp immunofluorescence, inhibited ICl,swell and significantly increased the latency of activation of ICl,swell. Increasing the hypotonic stress did not result in an increased activation of ICl,swell. MDR1 antisense ‘knock‐down’ also reduced the ability of the cells to volume regulate following a hypotonic challenge. These cells are known to express at least two volume‐activated chloride channels, and the data suggest that P‐gp is involved in the activation pathway of a subset of channels that contribute to whole‐cell ICl,swell and participate in volume regulation.