{"doi":"10.3389/fphys.2024.1434359","title":"Effects of extracellular metabolic acidosis and out-of-equilibrium CO2/HCO3− solutions on intracellular pH in cultured rat hippocampal neurons","abstract":"Metabolic acidosis (MAc)—an extracellular pH (pH o ) decrease caused by a [HCO 3 − ] o decrease at constant [CO 2 ] o —usually causes intracellular pH (pH i ) to fall. Here we determine the extent to which the pH i decrease depends on the pH o decrease vs the concomitant [HCO 3 − ] o decrease. We use rapid-mixing to generate out-of-equilibrium CO 2 /HCO 3 − solutions in which we stabilize [CO 2 ] o and [HCO 3 − ] o while decreasing pH o (pure acidosis, pAc), or stabilize [CO 2 ] o and pH o while decreasing [HCO 3 − ] o (pure metabolic/down, pMet↓). Using the fluorescent dye 2′,7′-bis-2-carboxyethyl)-5(and-6)carboxyfluorescein (BCECF) to monitor pH i in rat hippocampal neurons in primary culture, we find that—in naïve neurons—the pH i decrease caused by MAc is virtually the sum of those caused by pAc (∼70%) + pMet↓ (∼30%). However, if we impose a first challenge (MAc 1 , pAc 1 , or pMet↓ 1 ), allow the neurons to recover, and then impose a second challenge (MAc 2 , pAc 2 , or pMet↓ 2 ), we find that pAc/pMet↓ additivity breaks down. In a twin-challenge protocol in which challenge #2 is MAc, the pH o and [HCO 3 − ] o decreases during challenge #1 must be coincident in order to mimic the effects of MAc 1 on MAc 2 . Conversely, if challenge #1 is MAc, then the pH o and [HCO 3 − ] o decreases during challenge #2 must be coincident in order for MAc 1 to produce its physiological effects during the challenge #2 period. We conclude that the history of challenge #1 (MAc 1 , pAc 1 , or pMet↓ 1 )—presumably as detected by one or more acid-base sensors—has a major impact on the pH i response during challenge #2 (MAc 2 , pAc 2 , or pMet↓ 2 ).","journal":"Frontiers in Physiology","year":2024,"id":469455,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9614,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":560530,"name":"Ahlam Salameh","orcid":"0000-0003-1687-6093","position":1,"is_corresponding":false},{"id":444456,"name":"Yuehan Zhou","orcid":null,"position":2,"is_corresponding":false},{"id":1303141,"name":"Tiffany N. Kolba","orcid":"0000-0003-0828-3968","position":3,"is_corresponding":false},{"id":426412,"name":"Walter F. Boron","orcid":"0000-0003-4741-7287","position":4,"is_corresponding":false},{"id":1303550,"name":"Patrice G. Bouyer","orcid":null,"position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T02:05:32.241298Z","pmid":"39444753","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":[]}