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Action potential propagation causes Cx32 hemichannels in the Schwann cell paranode to open. As Cx32 hemichannels are directly sensitive to CO\n                    <jats:sub>2<\/jats:sub>\n                    , we have tested whether CO\n                    <jats:sub>2<\/jats:sub>\n                    produced in the axon, as a consequence of the energetic demands of action potential propagation, might gate Cx32 hemichannels. Using isolated sciatic nerve from the mouse, we found that the critical components required for intercellular CO\n                    <jats:sub>2<\/jats:sub>\n                    signaling are present (nodal mitochondria, the source of CO\n                    <jats:sub>2<\/jats:sub>\n                    ; a CO\n                    <jats:sub>2<\/jats:sub>\n                    -permeable aquaporin, AQP1; paranodal Cx32; and carbonic anhydrase). We have used a membrane impermeant fluorescent dye, FITC, to demonstrate the opening of Cx32 in Schwann cells in response to an external CO\n                    <jats:sub>2<\/jats:sub>\n                    stimulus or during action potential propagation in the isolated nerve. Pharmacological manipulations of AQP1 or carbonic anhydrase activity altered Cx32 gating during action potential firing. Expression of a modified Cx32 subunit, Cx32\n                    <jats:sup>DN<\/jats:sup>\n                    , that coassembles with Cx32\n                    <jats:sup>WT<\/jats:sup>\n                    , revealed that the activity-dependent dye loading of Schwann cells depended upon CO\n                    <jats:sub>2<\/jats:sub>\n                    binding to Cx32. CO\n                    <jats:sub>2<\/jats:sub>\n                    can, therefore, mediate neuron-to-glia signaling via connexins. CO\n                    <jats:sub>2<\/jats:sub>\n                    permeable aquaporins and carbonic anhydrase are key components of this signaling mechanism.\n                  <\/jats:p>","DOI":"10.7554\/elife.107085","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T14:30:38Z","timestamp":1754577038000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.107085","source":"Crossref","is-referenced-by-count":2,"title":["Activity-dependent CO2 production in the axon triggers opening of Connexin32 in the Schwann cell paranode"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2985-6841","authenticated-orcid":true,"given":"Jack","family":"Butler","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01a77tt86","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Sciences, University of Warwick","place":["Coventry, United 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