Influence of extracellular ATP on mammalian sperm physiology
I. López-González
A * , I. Oseguera-López A , R. Castillo A and A. Darszon A *
A
Abstract
In addition to its central role in cellular metabolism, adenosine 5′-triphosphate (ATP) is an important extracellular signalling molecule involved in various physiological processes. In reproduction, extracellular ATP participates in both autocrine and paracrine paths regulating gametogenesis, gamete maturation and fertilisation. This review focusses on how extracellular ATP modulates sperm physiology with emphasis on the mammalian acrosome reaction. The presence of extracellular ATP in the reproductive tract is primarily determined by the ion channels and transporters that influence its movement within the cells comprising the tract. The main targets of extracellular ATP in spermatozoa are its own transporters, particularly species-specific sperm purinergic receptors. We also discuss notable phenotypes from knock-out mouse models and human Mendelian inheritance related to ATP release mechanisms, along with immunological, proteomic, and functional observations regarding sperm purinergic receptors and their involvement in sperm signalling.
Keywords: acrosome reaction, ATP permeant channels, ATP regulation, reproductive system, sperm head volume change, sperm motility, sperm purinergic receptors, spermatogenic cells.
References
Abou-Haila A, Tulsiani DRP (2000) Mammalian sperm acrosome: formation, contents, and function. Archives of Biochemistry and Biophysics 379(2), 173-182.
| Crossref | Google Scholar | PubMed |
Albuisson J, Murthy SE, Bandell M, et al. (2013) Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels. Nature Communications 4, 1884.
| Crossref | Google Scholar | PubMed |
Allison AC, Hartree EF (1970) Lysosomal enzymes in the acrosome and their possible role in fertilization. Journal of Reproduction and Fertility 21(3), 501-515.
| Crossref | Google Scholar | PubMed |
Andolfo I, Alper SL, De Franceschi L, et al. (2013) Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1. Blood 121(19), 3925-3935.
| Crossref | Google Scholar |
Avella MA, Dean J (2011) Fertilization with acrosome-reacted mouse sperm: implications for the site of exocytosis. Proceedings of the National Academy of Sciences of the United States of America 108(50), 19843-19844.
| Crossref | Google Scholar |
Balestrini PA, Jabloñski M, Schiavi-Ehrenhaus LJ, et al. (2020) Seeing is believing: current methods to observe sperm acrosomal exocytosis in real time. Molecular Reproduction and Development 87, 1188-1198.
| Crossref | Google Scholar | PubMed |
Banks FCL, Calvert RC, Burnstock G (2010) Changing P2X receptor localization on maturing sperm in the epididymides of mice, hamsters, rats, and humans: a preliminary study. Fertility and Sterility 93(5), 1415-1420.
| Crossref | Google Scholar | PubMed |
Bardini M, Lee HY, Burnstock G (2000) Distribution of P2X receptor subtypes in the rat female reproductive tract at late pro-oestrus/early oestrus. Cell and Tissue Research 299(1), 105-113.
| Crossref | Google Scholar |
Battistone MA, Merkulova M, Park Y-J, et al. (2019) Unravelling purinergic regulation in the epididymis: activation of V-ATPase-dependent acidification by luminal ATP and adenosine. The Journal of Physiology 597(7), 1957-1973.
| Crossref | Google Scholar | PubMed |
Bedford JM (2011) Site of the mammalian sperm physiological acrosome reaction. Proceedings of the National Academy of Sciences of the United States of America 108(12), 4703-4704.
| Crossref | Google Scholar |
Bellezza I, Minelli A (2017) Adenosine in sperm physiology. Molecular Aspects of Medicine 55, 102-109.
| Crossref | Google Scholar |
Brenker C, Goodwin N, Weyand I, et al. (2012) The CatSper channel: a polymodal chemosensor in human sperm. The EMBO Journal 31(7), 1654-1665.
| Crossref | Google Scholar | PubMed |
Burnstock G (1972) Purinergic nerves. Pharmacological Reviews 24(3), 509-581.
| Google Scholar | PubMed |
Burnstock G (2014) Purinergic signalling in the reproductive system in health and disease. Purinergic Signalling 10, 157-187.
| Crossref | Google Scholar | PubMed |
Cao H, Li L, Liu S, et al. (2024) The multifaceted role of extracellular ATP in sperm function: from spermatogenesis to fertilization. Theriogenology 214, 98-106.
| Crossref | Google Scholar | PubMed |
Chen X, Zheng Y, Zheng J, et al. (2019) The progesterone-induced sperm acrosome reaction is a good option for the prediction of fertilization in vitro compared with other sperm parameters. Andrologia 51, e13278.
| Crossref | Google Scholar | PubMed |
Chi S, Cui Y, Wang H, et al. (2022) Astrocytic Piezo1-mediated mechanotransduction determines adult neurogenesis and cognitive functions. Neuron 110(18), 2984-2999.e8.
| Crossref | Google Scholar |
Coddou C, Stojilkovic SS, Huidobro-Toro JP (2011) Allosteric modulation of ATP-gated P2X receptor channels. Reviews in the Neurosciences 22(3), 335-354.
| Crossref | Google Scholar | PubMed |
Cyr DG (2011) Connexins and pannexins: Coordinating cellular communication in the testis and epididymis. Spermatogenesis 1(4), 325-338.
| Google Scholar |
Dalghi MG, Clayton DR, Ruiz WG, et al. (2019) Expression and distribution of PIEZO1 in the mouse urinary tract. American Journal of Physiology - Renal Physiology 317(2), F303-F321.
| Crossref | Google Scholar |
Darszon A, Nishigaki T, López-González I, et al. (2020) Differences and similarities: the richness of comparative sperm physiology. Physiology 35(3), 196-208.
| Crossref | Google Scholar | PubMed |
de la Sancha CU, Martínez-Cadena G, López-Godínez J, et al. (2007) Rho-kinase (ROCK) in sea urchin sperm: its role in regulating the intracellular pH during the acrosome reaction. Biochemical and Biophysical Research Communications 364, 470-475.
| Crossref | Google Scholar |
Demott RP, Suarez SS (1992) Hyperactivated sperm progress in the mouse oviduct. Biology of Reproduction 46(5), 779-785.
| Crossref | Google Scholar | PubMed |
Di Virgilio F, Schmalzing G, Markwardt F (2018) The Elusive P2X7 Macropore. Trends in Cell Biology 28(5), 392-404.
| Crossref | Google Scholar |
Dickinson ME, Flenniken AM, Ji X, et al. (2016) High-throughput discovery of novel developmental phenotypes. Nature 537, 508-514.
| Crossref | Google Scholar | PubMed |
Dubyak GR (2007) Go it alone no more—P2X7 joins the society of heteromeric ATP-gated receptor channels. Molecular Pharmacology 72, 1402-1405.
| Crossref | Google Scholar | PubMed |
Ducummon CC, Berger T (2006) Localization of the Rho GTPases and some Rho effector proteins in the sperm of several mammalian species. Zygote 14, 249-257.
| Crossref | Google Scholar | PubMed |
D’Ambrosi N, Volonte C (2013) Metabotropic purinergic receptors in lipid membrane microdomains. Current Medicinal Chemistry 20(1), 56-63.
| Google Scholar | PubMed |
Edwards SE, Buffone MG, Knee GR, et al. (2007) Effects of extracellular adenosine 5′-triphosphate on human sperm motility. Reproductive Sciences 14(7), 655-666.
| Crossref | Google Scholar | PubMed |
Fang X-Z, Zhou T, Xu J-Q, et al. (2021) Structure, kinetic properties and biological function of mechanosensitive Piezo channels. Cell & Bioscience 11(1), 13.
| Crossref | Google Scholar |
Fleck D, Mundt N, Bruentgens F, et al. (2016) Distinct purinergic signaling pathways in prepubescent mouse spermatogonia. Journal of General Physiology 148(3), 253-271.
| Crossref | Google Scholar | PubMed |
Fleck D, Kenzler L, Mundt N, et al. (2021) ATP activation of peritubular cells drives testicular sperm transport. eLife 10, e62885.
| Crossref | Google Scholar |
Foresta C, Rossato M, Di Virgilio F (1992) Extracellular ATP is a trigger for the acrosome reaction in human spermatozoa. Journal of Biological Chemistry 267(27), 19443-19447.
| Crossref | Google Scholar | PubMed |
Foresta C, Rossato M, Chiozzi P, et al. (1996) Mechanism of human sperm activation by extracellular ATP. American Journal of Physiology-Cell Physiology 270(6), C1709-C1714.
| Crossref | Google Scholar |
Forst A-L, Olteanu VS, Mollet G, et al. (2016) Podocyte purinergic P2X4 channels are mechanotransducers that mediate cytoskeletal disorganization. Journal of the American Society of Nephrology 27, 848-862.
| Crossref | Google Scholar | PubMed |
Freitas MJ, Vijayaraghavan S, Fardilha M (2017) Signaling mechanisms in mammalian sperm motility. Biology of Reproduction 96(1), 2-12.
| Crossref | Google Scholar | PubMed |
Garcia-Elias A, Lorenzo IM, Vicente R, et al. (2008) IP3 receptor binds to and sensitizes TRPV4 channel to osmotic stimuli via a calmodulin-binding site. Journal of Biological Chemistry 283(46), 31284-31288.
| Crossref | Google Scholar | PubMed |
Gorodeski GI (2015) Purinergic signalling in the reproductive system. Autonomic Neuroscience: Basic and Clinical 191, 82-101.
| Crossref | Google Scholar | PubMed |
Grahn E, Kaufmann SV, Askarova M, et al. (2023) Control of intracellular pH and bicarbonate by CO2 diffusion into human sperm. Nature Communications 14, 5395.
| Crossref | Google Scholar |
Gu B, Zhang J, Wu Y, et al. (2011) Proteomic analyses reveal common promiscuous patterns of cell surface proteins on human embryonic stem cells and sperms. PLoS ONE 6(5), e19386.
| Crossref | Google Scholar | PubMed |
Hautke A, Ebbinghaus S (2023) The emerging role of ATP as a cosolute for biomolecular processes. Biological Chemistry 404(10), 897-908.
| Crossref | Google Scholar | PubMed |
Holton FA, Holton P (1954) The capillary dilator substances in dry powders of spinal roots; a possible role of adenosine triphosphate in chemical transmission from nerve endings. The Journal of Physiology 126, 124-140.
| Crossref | Google Scholar | PubMed |
Human Protein Atlas (2015) Protein Atlas Organization. Available at www.proteinatlas.org
Ibrahim E, Aballa TC, Lynne CM, et al. (2018) Oral probenecid improves sperm motility in men with spinal cord injury. The Journal of Spinal Cord Medicine 41(5), 567-570.
| Crossref | Google Scholar | PubMed |
International Mouse Phenotyping Consortium (2016). Available at www.mousephenotype.org
Kim S, Hooper S, Agca C, et al. (2016) Post-thaw ATP supplementation enhances cryoprotective effect of iodixanol in rat spermatozoa. Reproductive Biology and Endocrinology. Reproductive Biology and Endocrinology 14(1), 5.
| Crossref | Google Scholar |
Köttgen M, Buchholz B, Garcia-Gonzalez MA, et al. (2008) TRPP2 and TRPV4 form a polymodal sensory channel complex. Journal of Cell Biology 182(3), 437-447.
| Crossref | Google Scholar | PubMed |
Lahey LJ, Mardjuki RE, Wen X, et al. (2020) LRRC8A:C/E heteromeric channels are ubiquitous transporters of cGAMP. Molecular Cell 80(4), 578-591.e5.
| Crossref | Google Scholar |
Lee HY, Bardini M, Burnstock G (2000) P2X receptor immunoreactivity in the male genital organs of the rat. Cell and Tissue Research 300(2), 321-330.
| Crossref | Google Scholar |
Lindemann CB, Lesich KA (2016) Functional anatomy of the mammalian sperm flagellum. Cytoskeleton 73, 652-669.
| Crossref | Google Scholar | PubMed |
Luria A, Rubinstein S, Lax Y, et al. (2002) Extracellular adenosine triphosphate stimulates acrosomal exocytosis in bovine spermatozoa via P2 purinoceptor. Biology of Reproduction 66(2), 429-437.
| Crossref | Google Scholar | PubMed |
Lutter D, Ullrich F, Lueck JC, et al. (2017) Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels. Journal of Cell Science 130(6), 1122-1133.
| Crossref | Google Scholar | PubMed |
López-González I, Sánchez-Cárdenas C, De la Vega-Beltrán JL, et al. (2023) ATP increases head volume in capacitated human sperm via a purinergic channel. Biochemical and Biophysical Research Communications 671, 318-326.
| Crossref | Google Scholar | PubMed |
Lück JC, Puchkov D, Ullrich F, et al. (2018) LRRC8/VRAC anion channels are required for late stages of spermatid development in mice. Journal of Biological Chemistry 293(30), 11796-11808.
| Crossref | Google Scholar | PubMed |
Ma Z, Siebert AP, Cheung K-H, et al. (2012) Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability. Proceedings of the National Academy of Sciences of the United States of America 109(28), E1963-E1971.
| Crossref | Google Scholar |
Ma Z, Taruno A, Ohmoto M, et al. (2018) CALHM3 is essential for rapid ion channel-mediated purinergic neurotransmission of GPCR-mediated tastes. Neuron 98(3), 547-561.e10.
| Crossref | Google Scholar | PubMed |
Meyers SA (2008) Sperm physiology. In ‘Equine breeding management and artificial insemination’. 2nd edn. (Ed. JC Samper) pp. 47–55. (W B Saunders: PA, USA) 10.1016/B978-1-4160-5234-0.00005-2
Mihara H, Boudaka A, Tominaga M, Sugiyama T (2020) Transient receptor potential vanilloid 4 regulation of adenosine triphosphate release by the adenosine triphosphate transporter vesicular nucleotide transporter, a novel therapeutic target for gastrointestinal baroreception and chronic inflammation. Digestion 101(1), 6-11.
| Crossref | Google Scholar |
Mohanty G, Sanchez-Cardenas C, Paudel B, et al. (2024) Differential role of bovine serum albumin and HCO3- in the regulation of GSK3 alpha during mouse sperm capacitation. Molecular Human Reproduction 30(3), gaae007.
| Crossref | Google Scholar |
Mundt N, Spehr M, Lishko PV (2018) TRPV4 is the temperature-sensitive ion channel of human sperm. eLife 7, e35853.
| Crossref | Google Scholar |
Nakatsukasa E, Inomata T, Ikeda T, et al. (2001) Generation of live rat offspring by intrauterine insemination with epididymal spermatozoa cryopreserved at -196 degrees C. Reproduction 122, 463-467.
| Crossref | Google Scholar |
Navarro B, Miki K, Clapham DE (2011) ATP-activated P2X2 current in mouse spermatozoa. Proceedings of the National Academy of Sciences of the United States of America 108(34), 14342-14347.
| Crossref | Google Scholar | PubMed |
Noblanc A, Klaassen A, Robaire B (2020) The exacerbation of aging and oxidative stress in the epididymis of sod1 null mice. Antioxidants 9(2), 151.
| Crossref | Google Scholar | PubMed |
North RA (2002) Molecular physiology of P2X receptors. Physiological Reviews 82(4), 1013-1067.
| Crossref | Google Scholar | PubMed |
OMIM (1995) OMIM online Mendelian inheritance in man. Available at www.omim.org
Pang J, Feng X, Liang Q, et al. (2022) Ferritin-nanocaged ATP traverses the blood-testis barrier and enhances sperm motility in an asthenozoospermia model. ACS Nano 16(3), 4175-4185.
| Crossref | Google Scholar | PubMed |
Pegoraro A, Bortolotti D, Marci R, et al. (2020) The P2X7 receptor 489C>T gain of function polymorphism favors HHV-6A infection and associates with female idiopathic infertility. Frontiers in Pharmacology 11, 96.
| Crossref | Google Scholar |
Pellegatti P, Falzoni S, Pinton P, et al. (2005) A novel recombinant plasma membrane-targeted luciferase reveals a new pathway for ATP secretion. Molecular Biology of the Cell 16(8), 3659-3665.
| Crossref | Google Scholar | PubMed |
Persoons E, Hennes A, De Clercq K, et al. (2018) Functional expression of TRP ion channels in endometrial stromal cells of endometriosis patients. International Journal of Molecular Sciences 19(9), 2467.
| Crossref | Google Scholar |
Pfeiffer ZA, Aga M, Prabhu U, et al. (2004) The nucleotide receptor P2X7 mediates actin reorganization and membrane blebbing in RAW 264.7 macrophages via p38 MAP kinase and Rho. Journal of Leukocyte Biology 75, 1173-1182.
| Crossref | Google Scholar | PubMed |
Pubill D, Dayanithi G, Siatka C, et al. (2001) ATP induces intracellular calcium increases and actin cytoskeleton disaggregation via P2x receptors. Cell Calcium 29(5), 299-309.
| Crossref | Google Scholar | PubMed |
Qudrat A, Kim JI, Truong K (2016) The spatiotemporal relationship between local Ca2+ signaling and P2X2R-activated membrane blebbing. Cell Calcium 59(4), 164-171.
| Crossref | Google Scholar | PubMed |
Rodríguez-Miranda E, Buffone MG, Edwards SE, et al. (2008) Extracellular adenosine 5′-triphosphate alters motility and improves the fertilizing capability of mouse sperm. Biology of Reproduction 79(1), 164-171.
| Crossref | Google Scholar | PubMed |
Roger S, Pelegrin P, Surprenant A (2008) Facilitation of P2X7 receptor currents and membrane blebbing via constitutive and dynamic calmodulin binding. The Journal of Neuroscience 28(25), 6393-6401.
| Crossref | Google Scholar | PubMed |
Romarowski A, Battistone MA, La Spina FA, et al. (2015) PKA-dependent phosphorylation of LIMK1 and Cofilin is essential for mouse sperm acrosomal exocytosis. Developmental Biology 405(2), 237-249.
| Crossref | Google Scholar |
Romarowski A, Luque GM, La Spina FA, et al. (2016) Role of actin cytoskeleton during mammalian sperm acrosomal exocytosis. In ‘Sperm acrosome biogenesis and function during fertilization. Advances in Anatomy, Embryology and Cell Biology’. (Ed. MG Buffone) pp. 129–144. (Springer International Publishing: Switzerland)
Rossato M, La Sala GB, Balasini M, et al. (1999) Sperm treatment with extracellular ATP increases fertilization rates in in-vitro fertilization for male factor infertility. Human Reproduction 14(3), 694-697.
| Crossref | Google Scholar | PubMed |
Ruan YC, Shum WWC, Belleannée C, et al. (2012) ATP secretion in the male reproductive tract: essential role of CFTR. The Journal of Physiology 590(17), 4209-4222.
| Crossref | Google Scholar | PubMed |
Sabeur K, Edwards DP, Meizel S (1996) Human sperm plasma membrane progesterone receptor(s) and the acrosome reaction. Biology of Reproduction 54(5), 993-1001.
| Crossref | Google Scholar | PubMed |
Sang Q, Zhang Z, Shi J, et al. (2019) A pannexin 1 channelopathy causes human oocyte death. Science Translational Medicine 11(485), eaav8731.
| Crossref | Google Scholar |
Semenova S, Shatrova A, Vassilieva I, et al. (2020) Adenosine-5′-triphosphate suppresses proliferation and migration capacity of endometrial stem cells. Journal of Cellular and Molecular Medicine 24(8), 4580-4588.
| Crossref | Google Scholar |
Siebert AP, Ma Z, Grevet JD, et al. (2013) Structural and functional similarities of calcium homeostasis modulator 1 (CALHM1) ion channel with connexins, pannexins, and innexins. Journal of Biological Chemistry 288(9), 6140-6153.
| Crossref | Google Scholar | PubMed |
Singh V, Ram M, Kandasamy K, et al. (2015) Molecular and functional characterization of TRPV4 channels in pregnant and nonpregnant mouse uterus. Life Sciences 122, 51-58.
| Crossref | Google Scholar |
Strotmann R, Schultz G, Plant TD (2003) Ca2+-dependent potentiation of the nonselective cation channel TRPV4 is mediated by a C-terminal calmodulin binding site. Journal of Biological Chemistry 278(29), 26541-26549.
| Crossref | Google Scholar | PubMed |
Suarez SS, Dai X (1992) Hyperactivation enhances mouse sperm capacity for penetrating viscoelastic media. Biology of Reproduction 46(4), 686-691.
| Crossref | Google Scholar | PubMed |
Sun X-F, Qiao W-W, Meng L-Y, et al. (2022) PIEZO1 ion channels mediate mechanotransduction in odontoblasts. Journal of Endodontics 48(6), 749-758.
| Crossref | Google Scholar |
Syeda R, Qiu Z, Dubin AE, et al. (2016) LRRC8 proteins form volume-regulated anion channels that sense ionic strength. Cell 164(3), 499-511.
| Crossref | Google Scholar |
Sánchez-Cárdenas C, Servín-Vences MR, José O, et al. (2014) Acrosome reaction and Ca2+ imaging in single human spermatozoa: new regulatory roles of [Ca2+]i. Biology of Reproduction 91(3), 1-13.
| Crossref | Google Scholar |
Takahashi N, Hamada-Nakahara S, Itoh Y, et al. (2014) TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2. Nature Communications 5, 4994.
| Crossref | Google Scholar |
Taruno A (2018) ATP release channels. International Journal of Molecular Sciences 19(3), 808.
| Crossref | Google Scholar | PubMed |
Taruno A, Vingtdeux V, Ohmoto M, et al. (2013) CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature 495(7440), 223-226.
| Crossref | Google Scholar | PubMed |
Thuwanut P, Arya N, Comizzoli P, et al. (2015) Effect of extracellular adenosine 5′-triphosphate on cryopreserved epididymal cat sperm intracellular ATP concentration, sperm quality, and in vitro fertilizing ability. Theriogenology 84(5), 702-709.
| Crossref | Google Scholar |
Torres-Fuentes JL, Rios M, Moreno RD (2015) Involvement of a P2X7 receptor in the acrosome reaction induced by ATP in rat spermatozoa. Journal of Cellular Physiology 230, 3068-3075.
| Crossref | Google Scholar | PubMed |
Turmel P, Dufresne J, Hermo L, et al. (2011) Characterization of pannexin1 and pannexin3 and their regulation by androgens in the male reproductive tract of the adult rat. Molecular Reproduction and Development 78(2), 124-138.
| Crossref | Google Scholar | PubMed |
Uhlén M, Fagerberg L, Hallström BM, et al. (2015) Tissue-based map of the human proteome. Science 347(6220), 1260419.
| Crossref | Google Scholar | PubMed |
Vadnais ML, Aghajanian HK, Lin A, et al. (2013) Signaling in sperm: toward a molecular understanding of the acquisition of sperm motility in the mouse epididymis. Biology of Reproduction 89(5), 1-10.
| Crossref | Google Scholar |
Voss FK, Ullrich F, Münch J, et al. (2014) Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science 344(6184), 634-638.
| Crossref | Google Scholar | PubMed |
Wang Q, Li X, Wang L, et al. (2004) Antiapoptotic effects of estrogen in normal and cancer human cervical epithelial cells. Endocrinology 145(12), 5568-5579.
| Crossref | Google Scholar |
Wang G, Guo Y, Zhou T, et al. (2013) In-depth proteomic analysis of the human sperm reveals complex protein compositions. Journal of Proteomics 79, 114-122.
| Crossref | Google Scholar | PubMed |
Yamamoto Y, Hishikawa D, Ono F (2024) Trpv4-mediated apoptosis of Leydig cells induced by high temperature regulates sperm development and motility in zebrafish. Communications Biology 7(1), 1-11.
| Crossref | Google Scholar |
Yanagimachi R (2022) Mysteries and unsolved problems of mammalian fertilization and related topics. Biology of Reproduction 106(4), 644-675.
| Crossref | Google Scholar | PubMed |
