| Title: | The Fungal Sexual Pheromone Sirenin Activates the Human CatSper Channel Complex |
| Author(s): | Syeda SS; Carlson EJ; Miller MR; Francis R; Clapham DE; Lishko PV; Hawkinson JE; Hook D; Georg GI; |
| Address: | "Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55414, United States. Department of Molecular and Cell Biology, University of California , Berkeley, California 94720, United States. Department of Physiology, University of California , San Francisco, California 94158, United States. Department of Cardiology, Howard Hughes Medical Institute, Boston Children's Hospital , Boston, Massachusetts 02115, United States. Department of Neurobiology, Harvard Medical School , Boston, Massachusetts 02115, United States" |
| DOI: | 10.1021/acschembio.5b00748 |
| ISSN/ISBN: | 1554-8937 (Electronic) 1554-8929 (Print) 1554-8929 (Linking) |
| Abstract: | "The basal fungus Allomyces macrogynus (A. macrogynus) produces motile male gametes displaying well-studied chemotaxis toward their female counterparts. This chemotaxis is driven by sirenin, a sexual pheromone released by the female gametes. The pheromone evokes a large calcium influx in the motile gametes, which could proceed through the cation channel of sperm (CatSper) complex. Herein, we report the total synthesis of sirenin in 10 steps and 8% overall yield and show that the synthetic pheromone activates the CatSper channel complex, indicated by a concentration-dependent increase in intracellular calcium in human sperm. Sirenin activation of the CatSper channel was confirmed using whole-cell patch clamp electrophysiology with human sperm. Based on this proficient synthetic route and confirmed activation of CatSper, analogues of sirenin can be designed as blockers of the CatSper channel that could provide male contraceptive agents" |
| Keywords: | Allomyces/*chemistry Calcium/*metabolism Calcium Channels/*metabolism Humans Male Pheromones/chemical synthesis/*chemistry/*pharmacology Spermatozoa/*drug effects/metabolism; |
| Notes: | "MedlineSyeda, Shameem Sultana Carlson, Erick J Miller, Melissa R Francis, Rawle Clapham, David E Lishko, Polina V Hawkinson, Jon E Hook, Derek Georg, Gunda I eng HHSN275201300017C/HD/NICHD NIH HHS/ HHSN275201300017C/PHS HHS/ R21HD081403/HD/NICHD NIH HHS/ HHSN275201300017I/HD/NICHD NIH HHS/ R01GM111802/GM/NIGMS NIH HHS/ 1U01 HDO45857/PHS HHS/ U01 HD045857/HD/NICHD NIH HHS/ Howard Hughes Medical Institute/ U01 HD076542/HD/NICHD NIH HHS/ R01 GM111802/GM/NIGMS NIH HHS/ R21 HD081403/HD/NICHD NIH HHS/ 1U01HD076542/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2015/12/18 ACS Chem Biol. 2016 Feb 19; 11(2):452-9. doi: 10.1021/acschembio.5b00748. Epub 2015 Dec 16" |
