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Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone

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

in Adult / Anesthesia / Animals / Arachidonic Acids - deficiency / Calcium - metabolism / Calcium channels / Calcium Channels - metabolism / Calcium Signaling / Cell Membrane - metabolism / Cellular biology / Endocannabinoids - deficiency / Fertilization / Glycerides - deficiency / Hormones / Humans / Hydrolases - genetics / Hydrolases - metabolism / Male / Membranes / Mice / Mice, Inbred C57BL / Progesterone / Progesterone - metabolism / Progesterone - pharmacology / Rats / Rats, Wistar / Receptors, Progesterone - genetics / Receptors, Progesterone - metabolism / Sperm / Sperm Motility - drug effects / Sperm Motility - physiology / Spermatozoa - drug effects / Spermatozoa - metabolism / Spermatozoa - physiology / Steroids / Young Adult

2016

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Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone

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

2016

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Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone

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

2016

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Journal Article

Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone

Hill, Rose Z.,

Gracheva, Elena O.,

Mannowetz, Nadja,

Smith, James F.,

Safavi, Rojin,

Kirichok, Yuriy,

Bautista, Diana M.,

Iavarone, Anthony T.,

Lishko, Polina V.,

Miller, Melissa R.

2016

Overview

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–containng 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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Publisher

American Association for the Advancement of Science,The American Association for the Advancement of Science

Subject

Adult

/ Anesthesia

/ Animals

/ Arachidonic Acids - deficiency

/ Calcium - metabolism

/ Calcium channels

/ Calcium Channels - metabolism