Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone | Zendy

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

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Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone

Author(s) -

Melissa 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

Publication year - 2016

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aad6887

Subject(s) - endocannabinoid system , microbiology and biotechnology , sperm , signal transduction , cannabinoid receptor , receptor , lipid signaling , chemistry , medicine , biology , endocrinology , biochemistry , genetics , agonist

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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