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/me.14.7.1064
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发表时间：
2000-07-01
影响因子：
--
通讯作者：
Mayerhofer, A
中科院分区：
文献类型：
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作者：
Bulling, A;Berg, FD;Mayerhofer, A
在人卵巢和人黄体化颗粒细胞（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具有功能性，并且对河豚毒素（TTX）敏感。发现促黄体促性腺激素（hCG）能在几秒钟内降低钠电流的峰值幅度。hCG处理24-48 h不仅能抑制eNaCh mRNA水平，还能抑制Na+峰值电流和静息膜电位。在使用mt （NaCh阻滞剂）和veratridine （NaCh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，发现eNaCh在调节细胞形态末端功能方面具有意想不到的作用。Mt保留了高度分化的细胞表型。Veratridine不仅增加了次级溶酶体的数量，而且显著降低了孕酮的产生。重要的是，非人灵长类动物黄体（CL）的内分泌细胞，代表黄体化GC的体内对应物，也含有eNaCh mRNA。虽然生理条件下通道活性的机制尚不清楚，但可能包括持续的Na+电流。在培养的GC中观察到，大量的次级溶酶体在退化的CL中尤其明显，这表明eNaCh活性与体内这种形式的细胞退化之间存在功能联系。本研究在卵巢内分泌细胞中鉴定出eNaCh，并证实其表达受hCG的抑制。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功能下降，这一过程涉及溶酶体激活和自噬。这些结果表明，卵巢eNaChs参与了灵长类动物卵巢临时内分泌器官CL在月经周期中的生理消亡。因为常用的药物，包括苯妥英，靶向NaChs，这些结果可能具有临床相关性。
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 end function was indicated after pharmacological modulation of presumed eNaCh steady-state activity in GC cultures for 24-48 h using mt (NaCh blocker) and veratridine (NaCh activator). mt 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.