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In recent years, multidrug resistance-associated protein 4 (MRP4) has emerged as a novel regulator of cAMP homeostasis by facilitating its efflux. Previous studies from our laboratory have identified MRP4 in mammalian sperm and demonstrated its role in capacitation-associated events in murine and bovine species. However, its relevance in human sperm remains unknown. Our study demonstrates a functional MRP4 in human sperm, as its pharmacological inhibition led to a rapid (5\u2009min) intracellular cAMP accumulation and a subsequent decrease in extracellular levels (30\u2009min) under capacitating conditions, as assessed by radio binding protein assay. At the biological level, MRP4 inhibition resulted in a decrease in tyrosine phosphorylation at 360\u2009min of capacitation. Membrane hyperpolarization was also affected, diminishing the induced acrosome reaction. Moreover, a significant reduction in intracellular Ca2+ levels was observed, leading to a significant decrease in progressive and total motility, as well as an inhibition of hyperactivation. In addition, our results indicated that the decrease in Ca2+ levels was due to impaired CatSper channel activity upon MRP4 inhibition. These findings suggest that MRP4-mediated cAMP efflux is essential for proper sperm function, playing a critical role in maintaining nucleotide homeostasis, which is a key determinant in the regulation of human sperm capacitation.<\/jats:p>","DOI":"10.1093\/molehr\/gaaf060","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T12:54:07Z","timestamp":1766062447000},"source":"Crossref","is-referenced-by-count":1,"title":["MRP4 transporter is involved in the acquisition of human sperm\u2019s fertilizing ability"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7790-7607","authenticated-orcid":false,"given":"Sofia","family":"R\u00edo","sequence":"first","affiliation":[{"name":"Centro de Estudios Farmacol\u00f3gicos y Bot\u00e1nicos (CEFYBO); Facultad de Medicina-Universidad de Buenos Aires, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (UBA-CONICET) , Buenos Aires,","place":["Argentina"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1s J","family":"Steeman","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario (CONICET-Universidad Nacional de Rosario (UNR)), and Laboratorio de Medicina Reproductiva, Facultad de Ciencias Bioqu\u00edmicas y Farmac\u00e9uticas, UNR , Rosario,","place":["Argentina"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristian","family":"Dotto","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones en Microbiolog\u00eda y Parasitolog\u00eda M\u00e9dica (IMPaM)-Facultad de Medicina (UBA-CONICET) , Buenos Aires,","place":["Argentina"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camila","family":"Arroyo-Salvo","sequence":"additional","affiliation":[{"name":"Centro de Estudios Farmacol\u00f3gicos y Bot\u00e1nicos (CEFYBO); Facultad de Medicina-Universidad de Buenos Aires, Consejo 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Magal\u00ed","family":"Silberman","sequence":"additional","affiliation":[{"name":"Centro de Estudios Farmacol\u00f3gicos y Bot\u00e1nicos (CEFYBO); Facultad de Medicina-Universidad de Buenos Aires, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (UBA-CONICET) , Buenos Aires,","place":["Argentina"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos A","family":"Davio","sequence":"additional","affiliation":[{"name":"Facultad de Farmacia y Bioqu\u00edmica, Instituto de Investigaciones Farmacol\u00f3gicas (ININFA)\u2014(UBA-CONICET) , Buenos Aires,","place":["Argentina"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dar\u00edo","family":"Krapf","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario (CONICET-Universidad Nacional de Rosario (UNR)), and Laboratorio de Medicina Reproductiva, Facultad de Ciencias Bioqu\u00edmicas y Farmac\u00e9uticas, UNR , 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