Identification of an ovarian voltage-activated Na+-channel type: hints to involvement in luteolysis.
Identification of an ovarian voltage-activated Na+-channel type: hints to involvement in luteolysis.
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DOI：
10.1210/mend.14.7.0481
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发表时间：
2000-07
影响因子：
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通讯作者：
Andreas Bulling;Frank Dieter Berg;U. Berg;Diane M. Duffy;R. Stouffer;S. Ojeda;Manfred Gratzl;Artur Mayerhofer
中科院分区：
文献类型：
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作者：
Andreas Bulling;Frank Dieter Berg;U. Berg;Diane M. Duffy;R. Stouffer;S. Ojeda;Manfred Gratzl;Artur Mayerhofer
在人卵巢和人黄素化颗粒细胞（GC）中发现了一种内分泌型电压激活钠通道（eNaCh）。全细胞膜片钳研究表明，GC中的eNaCh是功能性的，并且对河豚毒素（TTX）敏感。发现促黄体激素人CG（hCG）在数秒内降低钠电流的峰值幅度。hCG处理24-48 h不仅抑制eNaCh mRNA水平，而且抑制平均Na+峰电流和静息膜电位。在使用TTX（NaCh阻断剂）和藜芦碱（NaCh激活剂）对GC培养物中假定的eNaCh稳态活性进行药理学调节24-48小时后，表明eNaCh在调节细胞形态和功能中的意想不到的作用。TTX保留了高度分化的细胞表型。藜芦定不仅增加次级溶酶体的数量，而且还导致孕酮的产生显着减少。重要的是，非人灵长类动物黄体（CL）的内分泌细胞（代表体内对应的黄体化GC）也含有eNaCh mRNA。虽然在生理条件下通道活动的机制尚不清楚，但它可能包括持续的Na+电流。如在培养物中的GC中所观察到的，丰富的次级溶酶体在退化CL中特别明显，表明eNaCh活性与体内这种形式的细胞退化之间存在功能联系。我们的研究结果确定了卵巢内分泌细胞中的eNaCh，并证明它们的表达是在hCG的抑制控制下。由于促性腺激素支持的丧失，黄体细胞中eNaChs的激活可能引发一系列事件，导致CL功能降低，这是一个涉及溶酶体激活和自噬的过程。这些结果表明，卵巢eNaChs参与生理消亡的临时内分泌器官CL在灵长类动物卵巢在月经周期。由于常用药物，包括苯妥英钠，目标氯化钠，这些结果可能具有临床意义。
An endocrine type of voltage-activated sodium channel (eNaCh) was identified in the human ovary and human luteinized granulosa cells (GC). Whole-cell patch-clamp studies showed that the eNaCh in GC is functional and tetrodotoxin (TTX) sensitive. The luteotrophic hormone human CG (hCG) was found to decrease the peak amplitude of the sodium current within seconds. Treatment with hCG for 24-48 h suppressed not only eNaCh mRNA levels, but also mean Na+ peak currents and resting membrane potentials. An unexpected role for eNaChs in regulating cell morphology and function was indicated after pharmacological modulation of presumed eNaCh steady-state activity in GC cultures for 24-48 h using TTX (NaCh blocker) and veratridine (NaCh activator). TTX preserved a highly differentiated cellular phenotype. Veratridine not only increased the number of secondary lysosomes but also led to a significantly reduced progesterone production. Importantly, endocrine cells of the nonhuman primate corpus luteum (CL), which represent in vivo counterparts of luteinized GC, also contain eNaCh mRNA. Although the mechanism of channel activity under physiological conditions is not clear, it may include persistent Na+ currents. As observed in GC in culture, abundant secondary lysosomes were particularly evident in the regressing CL, suggesting a functional link between eNaCh activity and this form of cellular regression in vivo. Our results identify eNaCh in ovarian endocrine cells and demonstrate that their expression is under the inhibitory control of hCG. Activation of eNaChs in luteal cells, due to loss of gonadotropin support, may initiate a cascade of events leading to decreased CL function, a process that involves lysosomal activation and autophagy. These results imply that ovarian eNaChs are involved in the physiological demise of the temporary endocrine organ CL in the primate ovary during the menstrual cycle. Because commonly used drugs, including phenytoin, target NaChs, these results may be of clinical relevance.