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  • 1
    Publication Date: 2011-03-18
    Description: Steroid hormone progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg's protective vestments. Progesterone induces Ca(2+) influx into spermatozoa and triggers multiple Ca(2+)-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg. As an ovarian hormone, progesterone acts by regulating gene expression through a well-characterized progesterone nuclear receptor. However, the effect of progesterone upon transcriptionally silent spermatozoa remains unexplained and is believed to be mediated by a specialized, non-genomic membrane progesterone receptor. The identity of this non-genomic progesterone receptor and the mechanism by which it causes Ca(2+) entry remain fundamental unresolved questions in human reproduction. Here we elucidate the mechanism of the non-genomic action of progesterone on human spermatozoa by identifying the Ca(2+) channel activated by progesterone. By applying the patch-clamp technique to mature human spermatozoa, we found that nanomolar concentrations of progesterone dramatically potentiate CatSper, a pH-dependent Ca(2+) channel of the sperm flagellum. We demonstrate that human CatSper is synergistically activated by elevation of intracellular pH and extracellular progesterone. Interestingly, human CatSper can be further potentiated by prostaglandins, but apparently through a binding site other than that of progesterone. Because our experimental conditions did not support second messenger signalling, CatSper or a directly associated protein serves as the elusive non-genomic progesterone receptor of sperm. Given that the CatSper-associated progesterone receptor is sperm specific and structurally different from the genomic progesterone receptor, it represents a promising target for the development of a new class of non-hormonal contraceptives.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lishko, Polina V -- Botchkina, Inna L -- Kirichok, Yuriy -- England -- Nature. 2011 Mar 17;471(7338):387-91. doi: 10.1038/nature09767.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, University of California San Francisco, UCSF Mail Code 2140, Genentech Hall Room N272F, 600 16th Street, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21412339" target="_blank"〉PubMed〈/a〉
    Keywords: Alprostadil/pharmacology ; Animals ; Binding Sites ; Calcium/*metabolism ; Calcium Channels/chemistry/*metabolism ; Calcium Signaling/drug effects ; Cell Membrane/drug effects/metabolism ; Electric Conductivity ; Female ; Humans ; Hydrogen-Ion Concentration ; Male ; Mice ; Patch-Clamp Techniques ; Progesterone/metabolism/*pharmacology ; Receptors, Progesterone/agonists/chemistry/metabolism ; Species Specificity ; Sperm Tail/*drug effects/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-03-19
    Description: 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 alpha/beta 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, Melissa R -- Mannowetz, Nadja -- Iavarone, Anthony T -- Safavi, Rojin -- Gracheva, Elena O -- Smith, James F -- Hill, Rose Z -- Bautista, Diana M -- Kirichok, Yuriy -- Lishko, Polina V -- 1S10OD020062-01/OD/NIH HHS/ -- R01 AR059385/AR/NIAMS NIH HHS/ -- R01AR059385/AR/NIAMS NIH HHS/ -- R01GM111802/GM/NIGMS NIH HHS/ -- R01HD068914/HD/NICHD NIH HHS/ -- R21HD081403/HD/NICHD NIH HHS/ -- S10RR025622/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 29;352(6285):555-9. doi: 10.1126/science.aad6887. Epub 2016 Mar 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. ; QB3/Chemistry Mass Spectrometry Facility, University of California, Berkeley, CA 94720, USA. ; 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. ; Department of Urology, University of California, San Francisco, CA 94143, USA. ; Department of Physiology, University of California, San Francisco, CA 94158, USA. ; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. lishko@berkeley.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26989199" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Animals ; Arachidonic Acids/*deficiency ; Calcium/metabolism ; Calcium Channels/metabolism ; Calcium Signaling ; Cell Membrane/metabolism ; Endocannabinoids/*deficiency ; Fertilization ; Glycerides/*deficiency ; Humans ; Hydrolases/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Progesterone/*metabolism/pharmacology ; Rats ; Rats, Wistar ; Receptors, Progesterone/genetics/*metabolism ; Sperm Motility/drug effects/*physiology ; Spermatozoa/drug effects/metabolism/*physiology ; Young Adult
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2008-12-19
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 4
  • 5
    Publication Date: 2013-04-24
    Description: The female steroid hormone progesterone regulates ovulation and supports pregnancy, but also controls human sperm function within the female reproductive tract. Progesterone causes elevation of sperm intracellular Ca2+ leading to sperm hyperactivation, acrosome reaction, and perhaps chemotaxis toward the egg. Although it has been suggested that progesterone-dependent Ca2+ influx into...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 6
    ISSN: 1573-899X
    Keywords: NMDA ; lipophilicity ; antagonist ; agonist
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Studies of imidazole-4,5- and pyrazole-3,4-dicarboxylic acid derivatives revealed a number of new agonists and antagonists of N-methyl-D-aspartic acid (NMDA) receptors. Studies were based on whole-cell patch-clamp methods applied to rat hippocampus pyramidal cells. Increases in the lipophilicity of the environment of the nitrogen atom, keeping the distance between the terminal acid functions constant, led to a weakening of NMDA antagonism and increases in NMDA antagonism. Increases in the lipophilicity around the nitrogen atom could also lead to less of selectivity in the interaction with NMDA receptors and the appearance of non-NMDA antagonist properties.
    Type of Medium: Electronic Resource
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