Overview
BICARBONATE-ACTIVATED SOLUBLE ADENYLYL CYCLASE
The second messenger molecule cAMP, which modulates cell growth and differentiation in organisms from bacteria to higher eukaryotes, is produced by adenylyl cyclases. Mammals possess two distinct classes of adenylyl cyclase, the hormone-responsive, transmembrane adenylyl cyclases (tmAC) and the bicarbonate-regulated Soluble Adenylyl Cyclase (sAC). sAC, which we purified and cloned in collaboration with Dr. Lonny Levin's Laboratory, and tmACs define distinct cAMP signaling pathways within eukaryotic cells. tmACs are modulated by heterotrimeric G proteins in response to extracellular signals acting through seven-transmembrane spanning, G protein-coupled receptors. In contrast, sAC is directly regulated by bicarbonate ions suggesting it functions as the physiological carbon dioxide chemosensor. sAC most closely resembles cyanobacterial adenylyl cyclases, and regulation by bicarbonate ions is also conserved in these cyclases from blue-green algae. Therefore, sAC may represent the primordial cyclase in mammals. sAC is most abundantly expressed in male germ cells, and it appears to mediate the bicarbonate-induced, cAMP-dependent processes required for sperm to fertilize an egg, including capacitation, hyperactivated motility, and the acrosome reaction. Additionally, as the only identified bicarbonate/carbon dioxide chemosensor in mammals, sAC may also be involved in fluid reabsorption in the kidney, fluid secretion in the ciliary bodies and choroid plexus, and metabolic regulation in response to nutritional signals. We are currently testing these hypothesized physiological functions by making inducible, tissue-specific knockouts of the sAC gene in mice. The evolutionary conservation from unicellular bacteria to man and its involvement in developmental changes spermatozoa undergo post-ejaculation suggest that sAC may be involved in sensing signals important to the cell as an individual entity instead of carrying out instructions originating in other parts of the organism. Additionally, the laboratory is studying enzymes involved in retinol (vitamin A) metabolism. Retinol is enzymatically processed to derivatives with distinct biological functions. For example, the vitamin A derivative anhydroretinol is found in high amounts in insect pupae, mammalian liver and lung and may be involved in the regulation of cell death. We purified and cloned retinol dehydratase, the enzyme producing anhydroretinol, and are studying its enzymatic mechanism. For further information see: Dr. Buck's Lab
Highlights
- 1Biology of reproduction · 2020
- 2Frontiers in cell and developmental biology · 2023
- 3Frontiers in pharmacology · 2022
Publications
Funding
Active
5 grants- MPIP50HD123367-01Advancing an ADCY10 inhibitor on-demand male contraceptive into humansEunice Kennedy Shriver National Institute of Child Health and Human Development · 2026–2030
- MPIR01AI175437-03A Novel, Multi-compartment Intravaginal Ring for Prevention of Genital Herpes and Unintended Pregnancy.National Institute of Allergy and Infectious Diseases · 2024–2029 · via Oak Crest Institute of Science
- MPIR01HD111549-04Optimization of lead candidates for an on-demand male contraceptiveEunice Kennedy Shriver National Institute of Child Health and Human Development · 2023–2028
- MPIR01HD088571-10Comparative studies on the regulation of metabolism during sperm capacitationEunice Kennedy Shriver National Institute of Child Health and Human Development · 2017–2027· 3 renewals
- MPIP50HD113015-01On-demand nonhormonal male contraception via ADCY10 inhibitionEunice Kennedy Shriver National Institute of Child Health and Human Development · 2023–2026
Completed grants (13)
- Sub-PI7200AA22CA00002Microbicide R&D to Advance HIV Prevention Technologies through Responsive Innovation and eXcellence, MATRIXUnited States Agency for International Development · 2021–2025 · via Oak Crest Institute of Science
- Co-IMCI 231731-01ADCY10 inhibitors as pre-coital, 'on-demand', non-hormonal male contraceptivesMale Contraceptive Initiative · 2022–2024
- KPT32GM007739-41Weill Cornell/Rockefeller/Sloan Kettering MST ProgramNational Institute of General Medical Sciences · 2019–2024Training
- MPIR01AG061290-01High Throughput screen to identify "first of their kind" activators of ADCY10National Institute on Aging · 2019–2023
- Co-IMCI-223430-01ADCY10 inhibitors as pre-coital, 'on-demand', non-hormonal male contraceptivesMale Contraceptive Initiative · 2022–2023
- MPIP50HD100549-03On-Demand Pharmacological Contraception by Blocking ADCY 10Eunice Kennedy Shriver National Institute of Child Health and Human Development · 2019–2022
- PIDFI 180012-02"First of their Kind" Activators of Soluble Adenylyl Cyclase for the Treatment of GlaucomaDaedalus Fund for Innovation (Weill Cornell) · 2017–2020
- PITDI 190493-01Small molecule inhibitor of ADCY10 to treat ocular hypotonyTri-Institutional Therapeutics Discovery Institute, Inc. · 2018–2019BioPharma Alliance
- Co-IR01GM107442-04Metabolic Regulation via Intramitochondrial sACNational Institute of General Medical Sciences · 2014–2018
- PIR21EY025810-02Modulating Intraocular Pressure to Treat Ocular Hypotony and GlaucomaNational Eye Institute · 2015–2017
- KPR01HD059913-05Soluble Adenylyl Cyclase Isoforms Essential for Male FertilityEunice Kennedy Shriver National Institute of Child Health and Human Development · 2009–2014
- PIR01GM062328-12Bicarbonate Regulated Adenylyl CyclaseNational Institute of General Medical Sciences · 2010–2014
- PIR01HD040260-05Physiological isoforms of sAC in male germ cellsNICHD · 2001–2006 · via NIH RePORTER
Honors & distinctions
- Pew Scholar in the Biomedical Sciences · Pew Charitable Trusts · 1993
Clinical research
Active
1 study- PIUse of human sperm samples from healthy donors to study the effect of compounds modifying soluble adenylyl cyclase activity.Weill Medical College of Cornell University · OPEN TO ACCRUAL (as of 2021)
Available technologies
Show 5 more technologies
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News mentions
- Weill Cornell Medicine Receives NIH Grant to Test Novel Male ContraceptiveOctober 23, 2026
Weill Cornell Medicine has received a four-year, $8.2 million grant from the National Institute of Child Health and Human Development (NICHD) to develop and test an experimental on-demand male contraceptive pill that temporarily stops sperm in their tracks.
- NIH Center Grant Bolsters Male Contraceptive ResearchSeptember 21, 2023
Weill Cornell Medicine has received a three-year, nearly $6 million grant to lead one of three national contraceptive research centers.
- On-Demand Male Contraceptive Shows Promise in Preclinical StudyFebruary 14, 2023
An experimental contraceptive drug candidate developed by Weill Cornell Medicine investigators temporarily stops sperm in their tracks and prevents pregnancies in preclinical models.
Media highlights
- Experimental Male Contraceptive Pill May Immobilise Sperm, Work Within 30 Minutes & Give Protection For 8 HoursHealth And Me · October 27, 2026
- Scientists Developing Male Birth Control Pill To Take 30 Minutes Before SexNewsweek · October 26, 2026
- AT A GLANCE: Male Birth ControlCrain's New York Health Pulse · October 23, 2026
Mentoring
- JFJacob FerreiraPharmacology · 2024–2026
- MBMelanie BalbachPostdoc mentee · 2021–2023
- TRThomas RossettiPharmacology · Class of 2023
- NRNawreen RahmanNeuroscience (PhD) · Class of 2016
- AVAnna VarunokPharmacology (PhD)
External relationships
Ownership
FemFort Contraception LLC · Sacyl Pharmaceuticals, Inc.
Proprietary Interest
MilliporeSigma