Bulling A, Berg F D, Berg U, Duffy D M, Stouffer R L, Ojeda S R, Gratzl M, Mayerhofer A
Anatomisches Institut der Technischen Universität München Germany.
Mol Endocrinol. 2000 Jul;14(7):1064-74. doi: 10.1210/mend.14.7.0481.
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.
在人类卵巢和人黄体化颗粒细胞（GC）中鉴定出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具有功能且对河豚毒素（TTX）敏感。发现促黄体生成素人绒毛膜促性腺激素（hCG）在数秒内可降低钠电流的峰值幅度。用hCG处理24 - 48小时不仅抑制了eNaCh mRNA水平，还抑制了平均Na⁺峰值电流和静息膜电位。在用TTX（钠通道阻滞剂）和藜芦碱（钠通道激活剂）对GC培养物中假定的eNaCh稳态活性进行24 - 48小时的药理学调节后，表明eNaCh在调节细胞形态和功能方面具有意想不到的作用。TTX保留了高度分化的细胞表型。藜芦碱不仅增加了次级溶酶体的数量，还导致孕酮产量显著降低。重要的是，非人类灵长类动物黄体（CL）的内分泌细胞，其代表黄体化GC的体内对应物，也含有eNaCh mRNA。尽管生理条件下通道活性的机制尚不清楚，但可能包括持续性Na⁺电流。如在培养的GC中观察到的那样，丰富的次级溶酶体在退化的CL中尤为明显，这表明eNaCh活性与体内这种细胞退化形式之间存在功能联系。我们的数据鉴定了卵巢内分泌细胞中的eNaCh，并证明其表达受hCG的抑制性控制。由于促性腺激素支持的丧失，黄体细胞中eNaCh的激活可能引发一系列事件，导致CL功能下降，这一过程涉及溶酶体激活和自噬。这些结果表明，卵巢eNaCh参与了灵长类动物卵巢月经周期中临时内分泌器官CL的生理性衰退。由于包括苯妥英在内的常用药物靶向钠通道，这些结果可能具有临床相关性。
