{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:59:06Z","timestamp":1775696346612,"version":"3.50.1"},"reference-count":82,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T00:00:00Z","timestamp":1728432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Metabolic acidosis (MAc)\u2014an extracellular pH (pH<jats:sub>o<\/jats:sub>) decrease caused by a [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>]<jats:sub>o<\/jats:sub> decrease at constant [CO<jats:sub>2<\/jats:sub>]<jats:sub>o<\/jats:sub>\u2014usually causes intracellular pH (pH<jats:sub>i<\/jats:sub>) to fall. Here we determine the extent to which the pH<jats:sub>i<\/jats:sub> decrease depends on the pH<jats:sub>o<\/jats:sub> decrease vs the concomitant [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>]<jats:sub>o<\/jats:sub> decrease. We use rapid-mixing to generate out-of-equilibrium CO<jats:sub>2<\/jats:sub>\/HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> solutions in which we stabilize [CO<jats:sub>2<\/jats:sub>]<jats:sub>o<\/jats:sub> and [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>]<jats:sub>o<\/jats:sub> while decreasing pH<jats:sub>o<\/jats:sub> (pure acidosis, pAc), or stabilize [CO<jats:sub>2<\/jats:sub>]<jats:sub>o<\/jats:sub> and pH<jats:sub>o<\/jats:sub> while decreasing [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>]<jats:sub>o<\/jats:sub> (pure metabolic\/down, pMet\u2193). Using the fluorescent dye 2\u2032,7\u2032-bis-2-carboxyethyl)-5(and-6)carboxyfluorescein (BCECF) to monitor pH<jats:sub>i<\/jats:sub> in rat hippocampal neurons in primary culture, we find that\u2014in na\u00efve neurons\u2014the pH<jats:sub>i<\/jats:sub> decrease caused by MAc is virtually the sum of those caused by pAc (\u223c70%) + pMet\u2193 (\u223c30%). However, if we impose a first challenge (MAc<jats:sub>1<\/jats:sub>, pAc<jats:sub>1<\/jats:sub>, or pMet\u2193<jats:sub>1<\/jats:sub>), allow the neurons to recover, and then impose a second challenge (MAc<jats:sub>2<\/jats:sub>, pAc<jats:sub>2<\/jats:sub>, or pMet\u2193<jats:sub>2<\/jats:sub>), we find that pAc\/pMet\u2193 additivity breaks down. In a twin-challenge protocol in which challenge #2 is MAc, the pH<jats:sub>o<\/jats:sub> and [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>]<jats:sub>o<\/jats:sub> decreases during challenge #1 must be coincident in order to mimic the effects of MAc<jats:sub>1<\/jats:sub> on MAc<jats:sub>2<\/jats:sub>. Conversely, if challenge #1 is MAc, then the pH<jats:sub>o<\/jats:sub> and [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>]<jats:sub>o<\/jats:sub> decreases during challenge #2 must be coincident in order for MAc<jats:sub>1<\/jats:sub> to produce its physiological effects during the challenge #2 period. We conclude that the history of challenge #1 (MAc<jats:sub>1<\/jats:sub>, pAc<jats:sub>1<\/jats:sub>, or pMet\u2193<jats:sub>1<\/jats:sub>)\u2014presumably as detected by one or more acid-base sensors\u2014has a major impact on the pH<jats:sub>i<\/jats:sub> response during challenge #2 (MAc<jats:sub>2<\/jats:sub>, pAc<jats:sub>2<\/jats:sub>, or pMet\u2193<jats:sub>2<\/jats:sub>).<\/jats:p>","DOI":"10.3389\/fphys.2024.1434359","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T04:56:05Z","timestamp":1728449765000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Effects of extracellular metabolic acidosis and out-of-equilibrium CO2\/HCO3\u2212 solutions on intracellular pH in cultured rat hippocampal neurons"],"prefix":"10.3389","volume":"15","author":[{"given":"Patrice G.","family":"Bouyer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahlam I.","family":"Salameh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuehan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiffany N.","family":"Kolba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter F.","family":"Boron","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/299161a0","article-title":"Modifier role of internal H+ in activating the Na+-H+ exchanger in renal microvillus membrane vesicles","volume":"299","author":"Aronson","year":"1982","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1113\/jphysiol.1996.sp021396","article-title":"Characterization of acid extrusion mechanisms in cultured fetal rat hippocampal neurones","volume":"493","author":"Baxter","year":"1996","journal-title":"J. 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