Inhibition by steroids of [14C]-guanidinium flux through the voltage-gated sodium channel and the cation channel of the 5-HT3 receptor of N1E-115 neuroblastoma cells
Inhibition by steroids of [14C]-guanidinium flux through the voltage-gated sodium channel and the cation channel of the 5-HT3 receptor of N1E-115 neuroblastoma cells
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DOI：
10.1007/s002109900089
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发表时间：
1999-09-01
影响因子：
3.6
通讯作者：
Bönisch, H
中科院分区：
文献类型：
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作者：
Barann, M;Göthert, M;Bönisch, H
在N1E-115小鼠神经母细胞瘤细胞中，通过测定有机阳离子[C-14]-胍2分钟内流，研究了一些天然类固醇和合成类似物对5-HT3受体阳离子通道和电压门控及河豚毒素敏感的钠通道阳离子通量的影响。正常细胞暴露于5-羟色胺(5-HT，100mM)或藜芦碱(1 MM)2分钟后，细胞内的阳离子通量即可被诱导。所有化合物均呈浓度依赖性地抑制[C-14]-胍通过这两种通道的内流。抑制5-HT3受体诱导的阳离子通量的效力顺序为：氯米芬、环丙孕酮、雌二醇孕酮、异四氢脱氧皮质酮、阿法克松、睾酮、醛固酮、地塞米松。除了地塞米松和睾酮对电压依赖性钠通道的抑制作用更强，孕酮和睾酮对两种阳离子通道的抑制作用几乎相同外，类固醇对5-HT3受体通道的抑制作用是电压门控钠通道的两倍(阿法松、四氢脱氧皮质酮)到107倍(环丙孕酮醋酸酯)。类固醇(和合成的类似物)对5-HT3受体诱导的[C-14]-胍内流的抑制作用与它们的亲脂性(logP值)相关。类固醇通过电压门控醋酸酯抑制藜芦碱诱发的阳离子内流的logP值和Pic(50)值之间没有类似的相关性。结果表明，5-HT3受体通道和电压门控钠通道都是类固醇的靶标。大多数化合物对两个阳离子通道的抑制作用与亲脂性之间的关系符合类固醇抑制两个通道的共同机制原理，即与两个通道附近的某些膜脂发生非特异性疏水相互作用。
Effects of some naturally occurring steroids and synthetic analogues on the cation flux through the cation channel of the 5-HT3 receptor and the voltage-gated and tetrodotoxin-sensitive sodium channel were studied in N1E-115 mouse neuroblastoma cells by measuring the 2-min influx of the organic cation [C-14]-guanidinium. The cation fluxes in intact cells were either induced by 2 min exposure of the cells to 5-hydroxytryptamine (5-HT, 100 mu M) or to veratridine (I mM).Influx of [C-14]-guanidinium through both channels was concentration-dependently inhibited by all compounds studied. The rank order of potency for inhibition of the 5-HT3 receptor-induced cation flux was clomiphene cyproterone acetate > estradiol > progesterone congruent to allotetrahydrodeoxycorticosterone > alfaxalone congruent to testosterone > aldosterone > dexamethasone. With the exception of dexamethasone and testosterone, which were more potent at the voltage-dependent sodium channel, and progesterone and testosterone, which were about nearly equipotent in inhibiting both cation channels, the steroids were twofold (alfaxalone, allotetrahydrodeoxycorticosterone) to 107-fold (cyproterone acetate) more potent at the 5-HT3 receptor channel than at the voltage-gated sodium channel. The potencies of the steroids (and the synthetic analogues) for inhibition of the 5-HT3 receptor-induced [C-14]-guanidinium influx were correlated with their lipophilicity (log P values). A similar correlation between log P values and pIC(50) values for the steroid-induced inhibition of the veratridine-evoked cation influx through the voltage-gated acetate (a compound with extremely low inhibitory potency at this channel) was not included in the regression analysis.The results indicate that both the 5-HT3 receptor channel and the voltage-gated sodium channel are targets for steroids. The relationship between most of the compounds in inhibiting both cation channels and lipophilicity is compatible with a common mechanistic principle in steroid-induced inhibition of the two channels, i.e. a non-specific hydrophobic interaction with cer-tain membrane lipids in the neighbourhood of the two channels.