{"doi":"10.1101/2021.06.18.448929","title":"External fertilization is orchestrated by a pH-regulated soluble adenylyl cyclase controlling sperm motility and chemotaxis","abstract":"ABSTRACT The reaction of CO 2 with H 2 O to form HCO 3 - and H + is one of the most important chemical equilibria in cells. In mammalian sperm, a soluble adenylyl cyclase (sAC) serves as cellular HCO 3 - sensor that conveys the equilibrium state via cAMP synthesis to cAMP-signaling molecules. The function of sAC and cAMP in non-mammalian sperm is largely unknown. Here, we identify sAC orthologs in sea urchin and salmon sperm that, surprisingly, are activated by alkaline pH rather than HCO 3 - . Two amino-acid residues required for HCO 3 - binding of mammalian sAC are lacking in pH-regulated sAC. Orthologs identified in ten other phyla are also lacking either one of these key residues, suggesting that pH control is widespread among non-mammalian metazoan. The pH-sensitive sAC controls several functions of sperm from external fertilizers. Upon spawning, alkalization triggers cAMP synthesis and, thereby, activates motility of quiescent sperm. Egg-derived chemoattractants also alkalize sperm and elevate cAMP, which then-modulates pacemaker HCN channels to trigger a chemotactic Ca 2+ response. Finally, the sAC and the voltage- and cAMP-activated Na + /H + exchanger sNHE mutually control each other. A picture of evolutionary significance is emerging: motility and sensory signaling of sperm from both internal and external fertilizers rely on cAMP, yet, their sAC is regulated by HCO 3 - or pH i , respectively. Acidification of aquatic habitats due to climate change may adversely affect pH-sensing by sAC and thereby sexual reproduction in the sea. Statement of significance Adenylyl cyclases synthesize cAMP, a prominent cellular messenger. A bicarbonate-sensitive AC family member, soluble AC (sAC), is tied to the chemical equilibrium: H 2 O + CO 2 ↔ HCO 3 - (bicarbonate) + H + . The sAC is required for fertilization: Mammals lacking sAC are infertile and sperm immotile. We now identify a new sAC form in sperm of non-mammalian animals that reproduce in the sea. This novel sAC is activated at alkaline pH rather than bicarbonate. It controls sperm motility and chemotaxis. The switch from HCO 3 - to pH rests on substitution of two amino-acids, which represents an adaptation to aquatic environments low in bicarbonate. Acidification of aquatic habitats due to climate change may adversely affect sAC activity and, thereby, fertilization.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":215480,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":481282,"name":"Hussein Hamzeh","orcid":"0000-0002-3056-788X","position":1,"is_corresponding":false},{"id":810797,"name":"R.A. Pascal","orcid":null,"position":2,"is_corresponding":false},{"id":810225,"name":"Luis Álvarez","orcid":"0000-0002-1027-2291","position":3,"is_corresponding":false},{"id":810798,"name":"Wolfgang Bönigk","orcid":null,"position":4,"is_corresponding":false},{"id":810226,"name":"Navpreet Kaur","orcid":"0000-0002-5900-6066","position":5,"is_corresponding":false},{"id":246035,"name":"Lonny R. Levin","orcid":"0000-0002-5204-6356","position":6,"is_corresponding":false},{"id":246034,"name":"Jochen Buck","orcid":"0000-0002-3568-5869","position":7,"is_corresponding":false},{"id":810799,"name":"Christian Kambach","orcid":null,"position":8,"is_corresponding":false},{"id":611060,"name":"Mayako Michino","orcid":"0000-0002-5469-025X","position":9,"is_corresponding":false},{"id":810800,"name":"A.J. Jennings","orcid":null,"position":10,"is_corresponding":false},{"id":810227,"name":"Akira Sato","orcid":"0000-0001-7015-4038","position":11,"is_corresponding":false},{"id":810228,"name":"R. Seifert","orcid":"0009-0006-7421-4222","position":12,"is_corresponding":false},{"id":282593,"name":"Timo Strünker","orcid":"0000-0003-0812-1547","position":13,"is_corresponding":false},{"id":295617,"name":"Clemens Steegborn","orcid":"0000-0002-0913-1467","position":14,"is_corresponding":false},{"id":481289,"name":"U. Benjamin Kaupp","orcid":"0000-0002-0696-6397","position":15,"is_corresponding":false},{"id":810224,"name":"Heinz G. Körschen","orcid":"0000-0003-3927-1433","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-18T23:52:55.971300Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}