Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone
Progesterone signaling in sperm Cumulus cells surrounding the ovulated egg release the female hormone progesterone, which is necessary for sperm activation in mammals. Miller et al. identified the human sperm progesterone receptor as the orphan enzyme ABHD2. When bound by progesterone, the ABHD2 receptor acts as a lipid hydrolase to deplete an endocannabinoid inhibitor of the plasma membrane's calcium channel. This allows the entry of calcium ions through the calcium channel to activate sperm that are then primed for fertilization. Science, this issue p. 555 The ABHD2 progesterone receptor cleaves a membrane endocannabinoid to activate the CatSper calcium channel in sperm. 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 a/b 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.
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