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In <jats:italic>Toxoplasma gondii<\/jats:italic>, the controlled influx of extracellular and intracellular Ca<jats:sup>2+<\/jats:sup> into the cytosol initiates a signaling cascade that promotes pathogenic processes like tissue destruction and dissemination. In this work, we studied the role of proton transport in cytosolic Ca<jats:sup>2+<\/jats:sup> homeostasis and the initiation of Ca<jats:sup>2+<\/jats:sup> signaling. We used a <jats:italic>T. gondii<\/jats:italic> mutant of the V\u2010H<jats:sup>+<\/jats:sup>\u2010ATPase, a pump previously shown to transport protons to the extracellular medium, and to control intracellular pH and membrane potential and we show that proton gradients are important for maintaining resting cytosolic Ca<jats:sup>2+<\/jats:sup> at physiological levels and for Ca<jats:sup>2+<\/jats:sup> influx. Proton transport was also important for Ca<jats:sup>2+<\/jats:sup> storage by acidic stores and, unexpectedly, the endoplasmic reticulum. Proton transport impacted the amount of polyphosphate (polyP), a phosphate polymer that binds Ca<jats:sup>2+<\/jats:sup> and concentrates in acidocalcisomes. This was supported by the co\u2010localization of the vacuolar transporter chaperone 4 (VTC4), the catalytic subunit of the VTC complex that synthesizes polyP, with the V\u2010ATPase in acidocalcisomes. Our work shows that proton transport regulates plasma membrane Ca<jats:sup>2+<\/jats:sup> transport and control acidocalcisome polyP and Ca<jats:sup>2+<\/jats:sup> content, impacting Ca<jats:sup>2+<\/jats:sup> signaling and downstream stimulation of motility and egress in <jats:italic>T. gondii<\/jats:italic>.<\/jats:p>","DOI":"10.1111\/mmi.14722","type":"journal-article","created":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T10:31:39Z","timestamp":1617273099000},"page":"1054-1068","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Ca<sup>2+<\/sup> entry at the plasma membrane and uptake by acidic stores is regulated by the activity of the V\u2010H<sup>+<\/sup>\u2010ATPase in <i>Toxoplasma gondii<\/i>"],"prefix":"10.1111","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3209-6302","authenticated-orcid":false,"given":"Andrew J.","family":"Stasic","sequence":"first","affiliation":[{"name":"Center for Tropical and Emerging Global Diseases University of Georgia Georgia GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric J.","family":"Dykes","sequence":"additional","affiliation":[{"name":"Center for Tropical and Emerging Global Diseases University of Georgia Georgia GA USA"},{"name":"Department of Cellular Biology University of Georgia Athens GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ciro D.","family":"Cordeiro","sequence":"additional","affiliation":[{"name":"Center for Tropical and Emerging Global Diseases University of Georgia Georgia GA USA"},{"name":"Department of Cellular Biology University of Georgia Athens GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen A.","family":"Vella","sequence":"additional","affiliation":[{"name":"Center for Tropical and Emerging Global Diseases University of Georgia Georgia GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mojtaba S.","family":"Fazli","sequence":"additional","affiliation":[{"name":"Department of Computer Sciences University of Georgia Athens GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shannon","family":"Quinn","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology University of Georgia Athens GA USA"},{"name":"Department of Computer Sciences University of Georgia Athens GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4229-8784","authenticated-orcid":false,"given":"Roberto","family":"Docampo","sequence":"additional","affiliation":[{"name":"Center for Tropical and Emerging Global Diseases University of Georgia Georgia GA USA"},{"name":"Department of Cellular Biology University of Georgia Athens GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2041-6295","authenticated-orcid":false,"given":"Silvia N. 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