Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone.
Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone.
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DOI：
10.1126/science.aad6887
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发表时间：
2016-04-29
期刊：
影响因子：
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通讯作者：
Lishko PV
中科院分区：
文献类型：
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作者：
Miller MR;Mannowetz N;Iavarone AT;Safavi R;Gracheva EO;Smith JF;Hill RZ;Bautista DM;Kirichok Y;Lishko PV
类固醇通过两种途径调节细胞增殖、组织发育和细胞信号传导：核受体机制和基因组非依赖性信号传导。精子激活、卵子成熟和类固醇诱导的麻醉都是通过后一种途径进行的，其关键成分仍然未知。在这里，我们提出了人精子孕酮受体的孤儿酶α/β水解酶结构域蛋白2（ABHD 2）的特点。我们发现ABHD 2在精子中高度表达，结合孕酮，并通过从质膜中消耗内源性大麻素2-花生四烯酸甘油（2AG）作为胆固醇依赖性脂质水解酶。2AG抑制精子钙通道（CatSper），其去除导致钙通过CatSper流入并确保精子活化。这项研究表明，ABHD 2对孕酮激活的内源性大麻素的消耗是孕酮发挥其基因组独立作用并使精子受精的一般机制。
Steroids regulate cell proliferation, tissue development, and cell signaling via two pathways: a nuclear receptor mechanism and genome-independent signaling. Sperm activation, egg maturation, and steroid-induced anesthesia are executed via the latter pathway, the key components of which remain unknown. Here, we present characterization of the human sperm progesterone receptor that is conveyed by the orphan enzyme α/β hydrolase domain–containing protein 2 (ABHD2). We show that ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane. The 2AG inhibits the sperm calcium channel (CatSper), and its removal leads to calcium influx via CatSper and ensures sperm activation. This study reveals that progesterone-activated endocannabinoid depletion by ABHD2 is a general mechanism by which progesterone exerts its genome-independent action and primes sperm for fertilization.