title: Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone.
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 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.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Miller
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Nadja
authors.initials: N
authors.lastname: Mannowetz
authors.affiliation: QB3/Chemistry Mass Spectrometry Facility, University of California, Berkeley, CA 94720, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Iavarone
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Rojin
authors.initials: R
authors.lastname: Safavi
authors.affiliation: Department of Cellular and Molecular Physiology; Department of Neuroscience, Program in Cellular Neuroscience, Neurodegeneration, and Repair (CNNR), Yale School of Medicine, Yale University, New Haven, CT 06536, USA.
authors.forename: Elena O
authors.initials: EO
authors.lastname: Gracheva
authors.affiliation: Department of Urology, University of California, San Francisco, CA 94143, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Smith
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Rose Z
authors.initials: RZ
authors.lastname: Hill
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Bautista
authors.affiliation: Department of Physiology, University of California, San Francisco, CA 94158, USA.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Kirichok
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. lishko@berkeley.edu.
authors.forename: Polina V
authors.initials: PV
authors.lastname: Lishko
mesh_terms: D000328:Adult; D000818:Animals; D001095:Arachidonic Acids / Q000172:deficiency*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002462:Cell Membrane / Q000378:metabolism; D063388:Endocannabinoids / Q000172:deficiency*; D005306:Fertilization; D005989:Glycerides / Q000172:deficiency*; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D013081:Sperm Motility / Q000187:drug effects / Q000502:physiology*; D013094:Spermatozoa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D055815:Young Adult
chemical_list: D001095:Arachidonic Acids; C438823:CATSPER1 protein, human; D015220:Calcium Channels; D063388:Endocannabinoids; D005989:Glycerides; D011980:Receptors, Progesterone; D011374:Progesterone; C094503:glyceryl 2-arachidonate; D006867:Hydrolases; C525115:ABHD2 protein, human; D002118:Calcium