Research Article

Unconventional endocannabinoid signaling governs sperm activation via sex hormone progesterone

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Science  17 Mar 2016:
DOI: 10.1126/science.aad6887

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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, of which the key components remain unknown. Here, we present characterization of the human sperm progesterone receptor that is conveyed by orphan enzyme ABHD2. We show that ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as progesterone-dependent lipid hydrolase by depleting endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane. 2AG inhibits sperm calcium channel CatSper, and 2AG 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.

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