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Stimulation of Cl^- secretion by chlorzoxazone

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期292卷 778-787页

作者： Singh, AK Devor, DC Gerlach, AC Gondor, M Pilewski, JM Bridges, RJ Univ Pittsburgh Sch Med Dept Cell Biol & Physiol Pittsburgh PA 15261 USA Univ Pittsburgh Dept Med Pittsburgh PA 15261 USA Univ Pittsburgh Dept Pediat Pittsburgh PA 15261 USA

We previously demonstrated that 1-ethyl-2-benzimidazolone (1-EBIO) directly activates basolateral membrane calcium-activated K+ channels (K-Ca), thereby stimulating Cl- secretion across several epithelia. In our pursuit to identify potent modulators of Cl- secretion that may be useful to overcome the Cl- secretory defect in cystic fibrosis (CF), we have identified chlorzoxazone [5-chloro-2(3H)-benzoxazolone], a clinically used centrally acting muscle relaxant, as a stimulator of Cl- secretion in several epithelial cell types, including T84, Calu-3, and human bronchial epithelium. The Cl- secretory response induced by chlorzoxazone was blocked by charybdotoxin (CTX), a known blocker of K-Ca. In nystatin-permeabilized monolayers, chlorzoxazone stimulated a basolateral membrane I-K, which was inhibited by CTX and also stimulated an apical I-Cl that was inhibited by glibenclamide, indicating that the G(Cl) responsible for this I-Cl may be cystic fibrosis transmembrane conductance regulator (CFTR). In membrane vesicles prepared from T84 cells, chlorzoxazone stimulated Rb-86(+) uptake in a CTX-sensitive manner. In excised, inside-out patches, chlorzoxazone activated an inwardly-rectifying K+ channel, which was inhibited by CTX. 6-Hydroxychlorzoxazone, the major metabolite of chlorzoxazone, did not activate K-Ca, whereas zoxazolamine (2-amino-5-chlorzoxazole) showed a similar response profile as chlorzoxazone. In normal human nasal epithelium, chlorzoxazone elicited hyperpolarization of the potential difference that was similar in magnitude to isoproterenol. However, in the nasal epithelium of CF patients with the Delta F508 mutation of CFTR, there was no detectable Cl- secretory response to chlorzoxazone. These studies demonstrate that chlorzoxazone stimulates transepithelial Cl- secretion in normal airway epithelium in vitro and in vivo, and suggest that stimulation requires functional CFTR in the epithelia.

关键词：阿米洛利/药理学阴离子/代谢支气管/代谢布美他尼/药理学细胞膜/药物作用细胞培养的蝎毒素/药理学氯/代谢氯唑沙宗/类似物和衍生物氯唑沙宗/药理学囊性纤维化/代谢囊性纤维化跨膜传导调节因子/遗传学药物相互作用上皮/代谢福司柯林/药理学格列本脲/药理学异丙肾上腺素/药理学鼻黏膜/药物作用制霉菌素/药理学钾通道阻滞剂铷/药代动力学氯苯恶唑胺/药理学人类

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Early copper-induced leakage of K⁺ from Arabidopsis seedlings is mediated by ion channels and coupled to citrate efflux

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PLANT PHYSIOLOGY 1999年第4期121卷 1375-1382页

作者： Murphy, AS Eisinger, WR Shaff, JE Kochian, LV Taiz, L Univ Calif Santa Cruz Dept Biol Santa Cruz CA 95064 USA Santa Clara Univ Dept Biol Santa Clara CA 95053 USA Cornell Univ USDA ARS US Plant Soil & Nutr Lab Ithaca NY 14853 USA

Copper tolerance among Arabidopsis ecotypes is inversely correlated with long-term K+ leakage and positively correlated with short-term K+ leakage (A. Murphy, L. Taiz [1997] New Phytol 136:211-222). To probe the mechanism of the early phase of K+ efflux, we tested various channel blockers on copper and peroxide-induced K+ efflux from seedling roots. The K+ channel blockers tetraethyl ammonium chloride and 4-aminopyridine (4-AP) both inhibited short-term copper-induced K+ efflux. In contrast, peroxide-induced K+ efflux was insensitive to both tetraethyl ammonium chloride and 4-AP. Copper-induced lipid peroxidation exhibited a lag time of 4 h, while peroxide-induced lipid peroxidation began immediately. These results suggest that short-term copper-induced K+ efflux is mediated by channels, while peroxide-induced K+ efflux represents leakage through nonspecific lesions in the lipid bilayer. Tracer studies with Rb-86(+) confirmed that copper promotes K+ efflux rather than inhibiting K+ uptake. Short-term K+ release is electroneutral, since electrophysiological measurements indicated that copper does not cause membrane depolarization. Short-term K+ efflux was accompanied by citrate release, and copper increased total citrate levels. Since citrate efflux was blocked by 4-AP, K+ appears to serve as a counterion during copper-induced citrate efflux. As copper but not aluminum selectively induces citrate production and release, it is proposed that copper may inhibit a cytosolic form of aconitase.

关键词： 4 4'-二异硫氰基苯-2 2'-二磺酸/药理学 4-氨基吡啶/药理学乌头酸水合酶/拮抗剂和抑制剂乌头酸水合酶/代谢拟南芥属/药物作用拟南芥属/生理学生物转运柠檬酸盐类/代谢铜/药理学胞质溶胶/酶学电生理学/方法没食子酸/类似物和衍生物没食子酸/药理学离子通道/拮抗剂和抑制剂离子通道/生理学动力学脂质过氧化作用/药物作用苹果酸盐/代谢膜电位/药物作用膜电位/生理学尼氟灭酸/药理学钾/代谢钾通道阻滞剂钾通道/生理学铷/药代动力学四乙基铵/药理学硫巴比妥酸反应物/分析三氟拉嗪/药理学

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Volume regulatory responses of basolateral membrane vesicles from Necturus enterocytes:: Role of the cytoskeleton

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第16期96卷 9421-9426页

作者： Dubinsky, WP Mayorga-Wark, O Schultz, SG Univ Texas Sch Med Dept Integrat Biol Pharmacol & Physiol Houston TX 77265 USA

Previous studies from this laboratory have demonstrated that basolateral membrane vesicles isolated from Necturus maculosus small intestinal epithelial cells possess a K+ channel that is inhibited by ATP. In the present studies, we demonstrate that these vesicles, which are essentially devoid of soluble cytoplasmic contaminants, exhibit volume regulatory responses that parallel those of intact epithelial cells, Thus, suspension of these vesicles in a solution that is hypotonic to the intravesicular solution increases channel activity whereas suspension in a solution that is hypertonic to the intravesicular solution decreases, and may abolish, channel activity. These volume regulatory responses appear to be mediated by the same K-ATP channel and depend on an intact actin cytoskeletal network. The responses to both hypotonic and hypertonic challenge are abolished by cytochalasin D or by incubating the vesicles under conditions that are known to depolymerize actin, Phalloidin, which is known to stabilize actin filaments, partially prevents the action of cytochalasin D, Thus, the present results indicate that the K-ATP channel activity of basolateral membrane vesicles from Necturus basolateral membranes respond to hypo- and hypertonic challenge monotonically around an isotonic "set point" and that these responses depend on an intact actin cytoskeleton.

关键词：肌动蛋白类/药物作用肌动蛋白类/生理学生物转运/药物作用细胞膜/生理学细胞膜/超微结构细胞大小细胞松弛素D/药理学细胞骨架/生理学格列本脲/药理学内环境稳定肠黏膜/细胞学肠黏膜/生理学肠黏膜/超微结构动力学泥螈属容积渗克分子浓度鬼笔环肽/药理学钾通道/药物作用钾通道/生理学铷/药代动力学铷放射性同位素动物

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Activation of the sodium pump blocks the growth hormone-induced increase in cytosolic free calcium in rat adipocytes

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ENDOCRINOLOGY 2000年第2期141卷 513-519页

作者： Gaur, S Yamaguchi, H Goodman, HM Univ Massachusetts Sch Med Dept Physiol Worcester MA 01655 USA

GH promptly increases cytosolic free calcium ([Ca2+](i)) in freshly isolated rat adipocytes. Adipocytes deprived of GH for 3 h or longer are incapable of increasing [Ca2+](i) in response to GH, but instead respond in an insulin-like manner. Insulin blocks the GH-induced increase in [Ca2+](i) in GH-replete cells and stimulates the sodium pump (i.e. Na+/K+-ATPase), thereby hyperpolarizing the cell membrane. Blockade of the Na+/K+-ATPase with 100 mu M ouabain reversed these effects of insulin and enabled GH to increase [Ca2+](i) in GH-deprived adipocytes. Both insulin and GH activated the sodium pump in GH-deprived adipocytes, as indicated by increased uptake of Rb-86(+). Decreasing availability of intracellular Na+ by blockade of Na+/K+/2Cl(-) symporters or Na+/H+ antiporters abolished the effects of both hormones on Rb-86(+) uptake and enabled both GH and insulin to increase [Ca2+](i) in GH-deprived adipocytes. The data suggest that hormonal stimulation of Na+/K+-ATPase activity interferes with activation of voltage-sensitive calcium channels by either membrane hyperpolarization or some unknown interaction between the sodium pump and calcium channels.

关键词：脂细胞/药物作用脂细胞/代谢生物转运/药物作用布美他尼/药理学钙/代谢细胞培养的胞质溶胶/代谢酶激活生长激素/药理学生长激素/生理学胰岛素/药理学动力学模型生物学尼莫地平/药理学哇巴因/药理学铷/药代动力学动物男(雄)性大鼠

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Combined allosteric and competitive interaction between extracellular Na⁺ and K⁺ during ion transport by the α₁, α₂, and α₃ isoforms of the Na, K-ATPase

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BIOPHYSICAL JOURNAL 2000年第2期79卷 853-862页

作者： Balshaw, DM Millette, LA Tepperman, K Wallick, ET Univ Cincinnati McMicken Coll Arts & Sci Dept Biol Sci Cincinnati OH 45267 USA Univ Cincinnati Coll Med Dept Pharmacol & Cell Biophys Cincinnati OH 45267 USA

A combined allosteric and competitive model describes the interaction between extracellular Na+ and Rb+ during ion transport mediated by the Na, K-ATPase. The model was developed from experiments based on Rb-86 uptake by whole cells transfected with rat isoforms of the enzyme. In the absence of Na+, only a single transport site for extracellular Rb+ exists. After the occupation of the Na+-specific allosteric site, the Rb+ transport pocket opens to allow occupation by an additional Rb+ and the subsequent transport of the two Rb+ ions into the cells. Na+ can also directly compete with Rb+ for binding to at least one of the transport sites. While the model derived here applies to each of the three rat isoforms of the Na, K-ATPase expressed in HeLa cells, subtle differences exist among the isoforms. The alpha(3)* isoform has an increased intrinsic affinity for Rb+ and a lower affinity for the allosteric Na+ site than alpha(1) or alpha(2)*. The stimulation of uptake observed according to the best-fit model is due to the displacement by Rb+ of inhibitory Na+ bound to the transport site.

关键词：别构调节别构部位结合竞争性 HeLa细胞同工酶类/化学同工酶类/代谢动力学模型化学钾/代谢重组蛋白质类/化学重组蛋白质类/代谢铷/药代动力学钠/代谢钠钾交换ATP酶/化学钠钾交换ATP酶/代谢转染动物人类大鼠

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