2. Academic Validation
  3. Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone

Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone

  • Science. 2016 Apr 29;352(6285):555-9. doi: 10.1126/science.aad6887.
Melissa R Miller 1,  Nadja Mannowetz 1,  Anthony T Iavarone 2,  Rojin Safavi 1,  Elena O Gracheva 3,  James F Smith 4,  Rose Z Hill 1,  Diana M Bautista 1,  Yuriy Kirichok 5,  Polina V Lishko 6
Affiliations

Affiliations

  • 1 Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
  • 2 QB3/Chemistry Mass Spectrometry Facility, University of California, Berkeley, CA 94720, USA.
  • 3 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.
  • 4 Department of Urology, University of California, San Francisco, CA 94143, USA.
  • 5 Department of Physiology, University of California, San Francisco, CA 94158, USA.
  • 6 Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. lishko@berkeley.edu.
PMID: 26989199 DOI: 10.1126/science.aad6887
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.

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