Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone.Librarian's Comment : Progesterone released by cumulus cells surrounding the egg is known as potent stimulator of physiological responses of human spermatozoa essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis. The study by Miller et al. delineates that nongenomic signaling does not only involve the sperm calcium channel CatSper, but also a progesteronedependent lipid hydrolase (a/ß hydrolase domain-containing protein 2; ABHD2) depleting the endocannabinoid 2-arachidonoylglycerol (2AG). The removal of 2AG, an inhibitor of CatSper, from the plasma membrane results in sperm activation. Unravelling these molecular mechanisms of sperm function has a major impact on understanding disorders male fertility. Moreover, the progesterone signaling system represents a target for xenobiotic factors such as exogenous cannabinoids or compounds serving as non-hormonal contraceptives.
Published in : Science (New York, N.Y.)
Authors : Miller MR, Mannowetz N, Iavarone AT, Safavi R, Gracheva EO, Smith JF, Hill RZ, Bautista DM, Kirichok Y, Lishko PV
Abstract : 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/ß 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.