eprintid: 10112803 rev_number: 16 eprint_status: archive userid: 608 dir: disk0/10/11/28/03 datestamp: 2020-10-20 11:12:56 lastmod: 2021-09-20 22:27:16 status_changed: 2020-10-20 11:12:56 type: article metadata_visibility: show creators_name: Theparambil, SM creators_name: Hosford, PS creators_name: Ruminot, I creators_name: Kopach, O creators_name: Reynolds, JR creators_name: Sandoval, PY creators_name: Rusakov, DA creators_name: Barros, LF creators_name: Gourine, AV title: Astrocytes regulate brain extracellular pH via a neuronal activity-dependent bicarbonate shuttle ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F81 divisions: C08 divisions: D09 divisions: G02 keywords: Astrocyte, Neurochemistry, Neuronal physiology note: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. abstract: Brain cells continuously produce and release protons into the extracellular space, with the rate of acid production corresponding to the levels of neuronal activity and metabolism. Efficient buffering and removal of excess H+ is essential for brain function, not least because all the electrogenic and biochemical machinery of synaptic transmission is highly sensitive to changes in pH. Here, we describe an astroglial mechanism that contributes to the protection of the brain milieu from acidification. In vivo and in vitro experiments conducted in rodent models show that at least one third of all astrocytes release bicarbonate to buffer extracellular H+ loads associated with increases in neuronal activity. The underlying signalling mechanism involves activity-dependent release of ATP triggering bicarbonate secretion by astrocytes via activation of metabotropic P2Y1 receptors, recruitment of phospholipase C, release of Ca2+ from the internal stores, and facilitated outward HCO3− transport by the electrogenic sodium bicarbonate cotransporter 1, NBCe1. These results show that astrocytes maintain local brain extracellular pH homeostasis via a neuronal activity-dependent release of bicarbonate. The data provide evidence of another important metabolic housekeeping function of these glial cells. date: 2020-10-08 date_type: published official_url: https://doi.org/10.1038/s41467-020-18756-3 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1822098 doi: 10.1038/s41467-020-18756-3 pii: 10.1038/s41467-020-18756-3 lyricists_name: Gourine, Aliaksandr lyricists_name: Kopach, Olga lyricists_name: Reynolds, James lyricists_name: Rusakov, Dmitri lyricists_name: Theparambil, Mohammed lyricists_id: AGOUR78 lyricists_id: OKOPA85 lyricists_id: JPREY62 lyricists_id: DRUSA01 lyricists_id: MSMAT23 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Nature Communications volume: 11 article_number: 5073 event_location: England citation: Theparambil, SM; Hosford, PS; Ruminot, I; Kopach, O; Reynolds, JR; Sandoval, PY; Rusakov, DA; ... Gourine, AV; + view all <#> Theparambil, SM; Hosford, PS; Ruminot, I; Kopach, O; Reynolds, JR; Sandoval, PY; Rusakov, DA; Barros, LF; Gourine, AV; - view fewer <#> (2020) Astrocytes regulate brain extracellular pH via a neuronal activity-dependent bicarbonate shuttle. Nature Communications , 11 , Article 5073. 10.1038/s41467-020-18756-3 <https://doi.org/10.1038/s41467-020-18756-3>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10112803/1/s41467-020-18756-3.pdf