TY - JOUR
T1 - Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone
AU - Miller, Melissa R.
AU - Mannowetz, Nadja
AU - Iavarone, Anthony T.
AU - Safavi, Rojin
AU - Gracheva, Elena O.
AU - Smith, James F.
AU - Hill, Rose Z.
AU - Bautista, Diana M.
AU - Kirichok, Yuriy
AU - Lishko, Polina V.
N1 - Publisher Copyright:
© 2016 by the American Association for the Advancement of Science; all rights reserved.
PY - 2016/4/29
Y1 - 2016/4/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84961393718&partnerID=8YFLogxK
U2 - 10.1126/science.aad6887
DO - 10.1126/science.aad6887
M3 - Article
C2 - 26989199
AN - SCOPUS:84961393718
SN - 0036-8075
VL - 352
SP - 555
EP - 559
JO - Science
JF - Science
IS - 6285
ER -