Fluoxetine inhibits K+ transport pathways (K+ efflux, Na+-K+-2Cl- cotransport, and Na+ pump) underlying volume regulation in corneal endothelial cells

被引:21
作者
Hara, E
Reinach, PS
Wen, Q
Iserovich, P
Fischbarg, J [1 ]
机构
[1] Columbia Univ Coll Phys & Surg, Dept Ophthalmol, New York, NY 10032 USA
[2] Columbia Univ Coll Phys & Surg, Dept Physiol & Cellular Biophys, New York, NY 10032 USA
[3] SUNY Coll Optometry, Dept Biol Sci, New York, NY 10010 USA
关键词
Na+-K+-2Cl(-) cotransporter; Na+/K+ ATPase; Prozac (fluoxetine); regulatory volume decrease (RVD); regulatory volume increase (RVI); corneal endothelium;
D O I
10.1007/s002329900560
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have studied regulatory volume responses of cultured bovine corneal endothelial cells (CBCEC) using light scattering. We assessed the contributions of fluoxetine (Prozac) and bumetanide-sensitive membrane ion transport pathways to such responses by determining KC efflux and influx. Cells swollen by a 20% hypoosmotic solution underwent a regulatory volume de crease (RVD) response, which after 6 min restored relative cell volume by 98%. Fluoxetine inhibited RVD recovery; 20 mu M by 26%, and 50 mu M totally. Fluoxetine had a triphasic effect on KC efflux; from 20 to 100 mu M it inhibited efflux 2-fold, whereas at higher concentrations the efflux first increased to 1.5-fold above the control value, and then decreased again. Cells shrunk by a 20% hyperosmotic solution underwent a regulatory volume increase (RVI) which also after 6 min restored the cell volume by 99%. Fluoxetine inhibited RVI; 20 mu M by 25%, and 50 mu M completely. Bumetanide(1 mu M) inhibited RVI by 43%. In a Cl--free medium, fluoxetine (50-500 mu M) progressively inhibited bumetanide-insensitive K+ influx. The inhibitions of RVI and K+ influx induced by fluoxetine 20 to 50 mu M Were similar to those induced by 1 mu M bumetanide and by CT-free medium. A computer simulation suggests that fluoxetine can interact with the selectivity filter of K+ channels. The data suggest that CBCEC can mediate RVD and RVI in part through increases in Kf efflux and Na-K-2Cl cotransport (NKCC) activity. Interestingly, the data also suggest that fluoxetine at 20 to 50 IJ mu M inhibits NKCC, and at 100-1000 mu M inhibits the Na+ pump. One possible explanation for these findings is that fluoxetine could interact with K+-selective sites in K+ channels, the NKC cotransporter and the Na+ pump.
引用
收藏
页码:75 / 85
页数:11
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