{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:13:31Z","timestamp":1786119211461,"version":"build-2736575974"},"reference-count":105,"publisher":"American Physiological Society","issue":"5","funder":[{"DOI":"10.13039\/100009633","name":"HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["P50 HD113015"],"award-info":[{"award-number":["P50 HD113015"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01 HD111549"],"award-info":[{"award-number":["R01 HD111549"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100032455","name":"Male Contraceptive Initiative","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100032455","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["Physiology"],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:p>Soluble adenylyl cyclase (sAC; ADCY10) is an evolutionarily ancient, intracellular source of cAMP that is molecularly and mechanistically distinct from the more widely studied, hormone-responsive, G protein-regulated transmembrane adenylyl cyclases. Unlike other mammalian cyclases, sAC is most abundantly expressed in male germ cells and is directly regulated by bicarbonate and calcium. Genetic and pharmacological evidence in rodents and humans establishes sAC as essential for male fertility: loss of sAC activity yields immotile sperm incapable of fertilizing the egg, resulting in male-specific infertility. These features position sAC as a promising target for developing nonhormonal, on-demand contraceptives suitable for men and women. A proof-of-concept inhibitor has demonstrated a rapid, reversible contraceptive effect in vivo in mice, but translation to a clinical product must address challenges inherent to on-demand sperm-targeted pharmacology. In addition to ensuring a high safety margin and navigating an emerging regulatory and commercial landscape, common to any male contraceptive, on-demand male contraception must define the onset\/duration of efficacy while ensuring persistent inactivation of sperm function after ejaculation.<\/jats:p>","DOI":"10.1152\/physiol.00009.2026","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T17:21:01Z","timestamp":1773768061000},"page":"534-544","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting Soluble Adenylyl Cyclase for On-Demand Contraception"],"prefix":"10.1152","volume":"41","author":[{"given":"Erin R.","family":"Gardner","sequence":"first","affiliation":[{"name":"Gardner Pharmacology, LLC, Vienna, Virginia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory S.","family":"Kopf","sequence":"additional","affiliation":[{"name":"Sacyl Pharmaceuticals, Inc.","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3568-5869","authenticated-orcid":false,"given":"Jochen","family":"Buck","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medicine, New York, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5204-6356","authenticated-orcid":false,"given":"Lonny R.","family":"Levin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medicine, New York, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","first-page":"69","volume":"9","author":"Neer EJ","year":"1978","journal-title":"Adv Cyclic Nucleotide Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.72.3.1097"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2744(77)90155-3"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3109\/01485018208987040"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.1981.tb00701.x"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/0303-7207(82)90155-1"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(91)95160-l"},{"key":"B8","first-page":"271","volume":"1","author":"Braun T","year":"1975","journal-title":"J Cyclic Nucleotide Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)34229-7"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(87)81036-0"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)39295-5"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4889(90)90246-a"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.1.79"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.07.045"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2011.95"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2018.05.008"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3109\/01485018208987017"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/0303-7207(81)90064-2"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-2795(200005)56:1\u2009<\u20096::AID-MRD2\u2009>\u20093.0.CO;2-M"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5479.625"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00584.2004"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2025.110889"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M011698200"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.08.012"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1322778111"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb880"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/mrd.20409"},{"key":"B28","first-page":"251","volume":"13","author":"Garbers DL","year":"1980","journal-title":"Adv Cyclic Nucleotide Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/j.1939-4640.1998.tb01994.x"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod61.1.76"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212475200"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.708255"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M507144200"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2005.06.007"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.08.032"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.284679"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200709784"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00761.2009"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911790107"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.510073"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2151"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.113.208496"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.2337\/db10-1087"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.1c00273"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioaa052"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01133"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.1013845"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2017.11.008"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.07.013"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/mrd.23773"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/168558c0"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/168697b0"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1530\/jrf.0.0520333"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00353"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501430200"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121.4.1139"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/s0165-0378(01)00103-6"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1831008100"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.humrep.a137807"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400050101"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26041489"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1134051"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dez048"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gaab054"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.05.038"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2024.104481"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0041030"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.733653"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36119-6"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deaf225"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.953903"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(81)90105-8"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmi047"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1530\/jrf.0.0780093"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1530\/REP-15-0582"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod44.2.375"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2008.05.007"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2016.08.036"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(18)30029-9"},{"key":"B80","unstructured":"Centers for Disease Control and Prevention. Birth Control Methods 2021. https:\/\/www.cdc.gov\/contraception\/about\/index.html [2021 Oct 5]."},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(20)30315-6"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1111\/j.1728-4465.2014.00393.x"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1080\/13625187.2023.2289831"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1136\/bmjsrh-2024-202573"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2003.07.002"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1210\/er.2007-0041"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1017\/S0021932016000560"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deh574"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1111\/andr.13726"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/15.3.637"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1080\/00224499.2021.1905764"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/15.3.646"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.06.023"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0542OC"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M309543200"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.01.012"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.05.003"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201303159"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1089\/jop.2017.0027"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20150354"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201611606"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2024.101281"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2013.04.027"},{"key":"B104","volume-title":"Laboratory Manual for the Examination and Processing of Human Semen","author":"World Health Organization","year":"2016","edition":"6"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1111\/andr.13525"}],"container-title":["Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/physiol.00009.2026","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T17:45:06Z","timestamp":1786038306000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/physiol.00009.2026"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":105,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,9,1]]}},"alternative-id":["10.1152\/physiol.00009.2026"],"URL":"https:\/\/doi.org\/10.1152\/physiol.00009.2026","relation":{},"ISSN":["1548-9213","1548-9221"],"issn-type":[{"value":"1548-9213","type":"print"},{"value":"1548-9221","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"assertion":[{"value":"2026-02-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-28","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}