{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:23:16Z","timestamp":1787016196397,"version":"build-2736575974"},"reference-count":53,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T00:00:00Z","timestamp":1687996800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL108609"],"award-info":[{"award-number":["HL108609"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL074011"],"award-info":[{"award-number":["HL074011"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL148004"],"award-info":[{"award-number":["HL148004"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL154660"],"award-info":[{"award-number":["HL154660"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL061974"],"award-info":[{"award-number":["HL061974"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM007055"],"award-info":[{"award-number":["GM007055"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      The interoceptive homeostatic mechanism that controls breathing, blood gases and acid\u2010base balance in response to changes in CO\n                      <jats:sub>2<\/jats:sub>\n                      \/H\n                      <jats:sup>+<\/jats:sup>\n                      is exquisitely sensitive, with convergent roles proposed for chemosensory brainstem neurons in the retrotrapezoid nucleus (RTN) and their supporting glial cells. For astrocytes, a central role for NBCe1, a Na\n                      <jats:sup>+<\/jats:sup>\n                      \u2010HCO\n                      <jats:sub>3<\/jats:sub>\n                      <jats:sup>\u2212<\/jats:sup>\n                      cotransporter encoded by\n                      <jats:italic>Slc4a4<\/jats:italic>\n                      , has been envisaged in multiple mechanistic models (i.e. underlying enhanced CO\n                      <jats:sub>2<\/jats:sub>\n                      \u2010induced local extracellular acidification or purinergic signalling). We tested these NBCe1\u2010centric models by using conditional knockout mice in which\n                      <jats:italic>Slc4a4<\/jats:italic>\n                      was deleted from astrocytes. In GFAP\u2010Cre;\n                      <jats:italic>Slc4a4<\/jats:italic>\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      mice we found diminished expression of\n                      <jats:italic>Slc4a4<\/jats:italic>\n                      in RTN astrocytes by comparison to control littermates, and a concomitant reduction in NBCe1\u2010mediated current. Despite disrupted NBCe1 function in RTN\u2010adjacent astrocytes from these conditional knockout mice, CO\n                      <jats:sub>2<\/jats:sub>\n                      \u2010induced activation of RTN neurons or astrocytes\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      , and CO\n                      <jats:sub>2<\/jats:sub>\n                      \u2010stimulated breathing, were indistinguishable from NBCe1\u2010intact littermates; hypoxia\u2010stimulated breathing and sighs were likewise unaffected. We obtained a more widespread deletion of NBCe1 in brainstem astrocytes by using tamoxifen\u2010treated Aldh1l1\u2010Cre\/ERT2;\n                      <jats:italic>Slc4a4<\/jats:italic>\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      mice. Again, there was no difference in effects of CO\n                      <jats:sub>2<\/jats:sub>\n                      or hypoxia on breathing or on neuron\/astrocyte activation in NBCe1\u2010deleted mice. These data indicate that astrocytic NBCe1 is not required for the respiratory responses to these chemoreceptor stimuli in mice, and that any physiologically relevant astrocytic contributions must involve NBCe1\u2010independent mechanisms.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15635-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            The electrogenic NBCe1 transporter is proposed to mediate local astrocytic CO\n                            <jats:sub>2<\/jats:sub>\n                            \/H+ sensing that enables excitatory modulation of nearby retrotrapezoid nucleus (RTN) neurons to support chemosensory control of breathing.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We used two different Cre mouse lines for cell\u2010specific and\/or temporally regulated deletion of the NBCe1 gene (Slc4a4) in astrocytes to test this hypothesis.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            In both mouse lines,\n                            <jats:italic>Slc4a4<\/jats:italic>\n                            was depleted from RTN\u2010associated astrocytes but CO\n                            <jats:sub>2<\/jats:sub>\n                            \u2010induced Fos expression (i.e. cell activation) in RTN neurons and local astrocytes was intact.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Likewise, respiratory chemoreflexes evoked by changes in CO\n                            <jats:sub>2<\/jats:sub>\n                            or O\n                            <jats:sub>2<\/jats:sub>\n                            were unaffected by loss of astrocytic Slc4a4.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>These data do not support the previously proposed role for NBCe1 in respiratory chemosensitivity mediated by astrocytes.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp284960","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T14:50:01Z","timestamp":1688050201000},"page":"3667-3686","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The astrocytic Na\n                    <sup>+<\/sup>\n                    \u2010HCO\n                    <sub>3<\/sub>\n                    <sup>\u2212<\/sup>\n                    cotransporter, NBCe1, is dispensable for respiratory chemosensitivity"],"prefix":"10.1113","volume":"601","author":[{"given":"Keyong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Virginia Charlottesville VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3604-6655","authenticated-orcid":false,"given":"Elizabeth 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