Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone

Melissa R. Miller, Nadja Mannowetz, Anthony T. Iavarone, Rojin Safavi, Elena O. Gracheva, James F. Smith, Rose Z. Hill, Diana M. Bautista, Yuriy Kirichok, Polina V. Lishko

Research output: Contribution to journalArticlepeer-review

155 Scopus citations


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.

Original languageEnglish
Pages (from-to)555-559
Number of pages5
Issue number6285
StatePublished - Apr 29 2016


Dive into the research topics of 'Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone'. Together they form a unique fingerprint.

Cite this