Readthrough acetylcholinesterase (AChE-R) and regulated necrosis: pharmacological targets for the regulation of ovarian functions?
Readthrough acetylcholinesterase (AChE-R) and regulated necrosis: pharmacological targets for the regulation of ovarian functions?
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DOI：
10.1038/cddis.2015.51
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发表时间：
2015-03-12
影响因子：
9
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中科院分区：
文献类型：
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卵巢细胞的增殖、分化和死亡确保了女性性腺在生殖阶段的有序功能，最终以女性更年期结束。这些过程由几种机制调节，包括通过神经递质的局部信号传导。以往的研究表明，卵巢非神经内分泌细胞产生乙酰胆碱（ACh），这可能是作为一个营养因子在卵泡和黄体通过毒蕈碱ACh受体。它的行动如何受到限制不得而知。我们确定酶活性乙酰胆碱酯酶（AChE）在人类卵巢卵泡液作为人类颗粒细胞的产品。乙酰胆碱酯酶分解乙酰胆碱，从而削弱其营养功能。石杉碱甲阻断乙酰胆碱酯酶可增加颗粒细胞的营养作用。在卵巢AChE变体中，鉴定了通读亚型AChE-R，其具有进一步的非酶促作用。AChE-R在卵泡液、颗粒细胞、卵泡膜细胞和黄体细胞中均有表达，提示AChE-R在体内也有表达。合成AChE-R肽（阿普）被用来探索这种行动，并诱导在原代培养的人颗粒细胞的一个独特的气球样形态和释放乳酸脱氢酶的细胞死亡的半胱天冬酶独立的形式。RIPK 1抑制剂necrostatin-1和MLKL阻断剂necrosulfonamide显著减少了这种形式的细胞死亡。因此，AChE-R的一种新的非酶功能是刺激RIPK 1/MLKL依赖性调节性坏死（坏死性凋亡）。后者补充了卵巢中的胆碱能系统，该系统决定卵巢细胞的生死。坏死性凋亡可能发生在灵长类动物卵巢中，因为颗粒细胞和黄体细胞对磷酸化MLKL呈免疫阳性，因此坏死性凋亡可能导致卵泡闭锁和黄体溶解。结果表明，干扰AChE的酶活性和/或干扰坏死性凋亡可能是影响卵巢功能的新途径。
Proliferation, differentiation and death of ovarian cells ensure orderly functioning of the female gonad during the reproductive phase, which ultimately ends with menopause in women. These processes are regulated by several mechanisms, including local signaling via neurotransmitters. Previous studies showed that ovarian non-neuronal endocrine cells produce acetylcholine (ACh), which likely acts as a trophic factor within the ovarian follicle and the corpus luteum via muscarinic ACh receptors. How its actions are restricted was unknown. We identified enzymatically active acetylcholinesterase (AChE) in human ovarian follicular fluid as a product of human granulosa cells. AChE breaks down ACh and thereby attenuates its trophic functions. Blockage of AChE by huperzine A increased the trophic actions as seen in granulosa cells studies. Among ovarian AChE variants, the readthrough isoform AChE-R was identified, which has further, non-enzymatic roles. AChE-R was found in follicular fluid, granulosa and theca cells, as well as luteal cells, implying that such functions occur in vivo. A synthetic AChE-R peptide (ARP) was used to explore such actions and induced in primary, cultured human granulosa cells a caspase-independent form of cell death with a distinct balloon-like morphology and the release of lactate dehydrogenase. The RIPK1 inhibitor necrostatin-1 and the MLKL-blocker necrosulfonamide significantly reduced this form of cell death. Thus a novel non-enzymatic function of AChE-R is to stimulate RIPK1/MLKL-dependent regulated necrosis (necroptosis). The latter complements a cholinergic system in the ovary, which determines life and death of ovarian cells. Necroptosis likely occurs in the primate ovary, as granulosa and luteal cells were immunopositive for phospho-MLKL, and hence necroptosis may contribute to follicular atresia and luteolysis. The results suggest that interference with the enzymatic activities of AChE and/or interference with necroptosis may be novel approaches to influence ovarian functions.
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影响因子：
5.8
作者：
ELLMAN, GL;COURTNEY, KD;FEATHERSTONE, RM
通讯作者：
FEATHERSTONE, RM
影响因子：
5.7
作者：
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通讯作者：
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影响因子：
4
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
Bulling, A;Berg, FD;Mayerhofer, A
通讯作者：
Mayerhofer, A