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However, some membranes are impermeable to CO\n 2<\/jats:sub>\n and NH\n 3<\/jats:sub>\n , whereas some aquaporin (AQP) water channels\u2014tetramers with hydrophobic central pores\u2014are permeable to CO\n 2<\/jats:sub>\n , NH\n 3<\/jats:sub>\n or both. Nevertheless, we understand neither the routes that CO\n 2<\/jats:sub>\n and NH\n 3<\/jats:sub>\n take through AQP tetramers, nor the basis of CO\n 2<\/jats:sub>\n \/NH\n 3<\/jats:sub>\n selectivity. Here, we show\u2014for human AQP1 (hAQP1)\u2014that virtually all NH\n 3<\/jats:sub>\n and H\n 2<\/jats:sub>\n O pass through the hydrophilic, monomeric pores. However, CO\n 2<\/jats:sub>\n passes through both the monomeric pores and another pathway. We expressed hAQP1 in\n Xenopus<\/jats:italic>\n oocytes and used microelectrodes to monitor the maximal surface\u2010pH transient (\u0394pH\n S<\/jats:sub>\n ) caused by CO\n 2<\/jats:sub>\n or NH\n 3<\/jats:sub>\n influxes. We found that p\u2010chloromercuribenzene sulfonate (pCMBS)\u2014which reacts with C189 in the monomeric pore\u2014eliminates the entire hAQP1\u2010dependent (*) NH\n 3<\/jats:sub>\n signal (\u0394pH\n S<\/jats:sub>\n *)\n NH3<\/jats:sub>\n , but only half of the signals for CO\n 2<\/jats:sub>\n (\u0394pH\n S<\/jats:sub>\n *)\n CO2<\/jats:sub>\n or osmotic water permeability\n P<\/jats:italic>\n f<\/jats:sub>\n *. 4,4'\u2010diisothiocyanatostilbene\u20102,2'\u2010disulfonate (DIDS), eliminates the remaining (\u0394pH\n S<\/jats:sub>\n *)\n CO2<\/jats:sub>\n but has no effect on (\u0394pH\n S<\/jats:sub>\n *)\n NH3<\/jats:sub>\n or\n P<\/jats:italic>\n f<\/jats:sub>\n *. Together, the two drugs completely eliminate the CO\n 2<\/jats:sub>\n permeability of hAQP1. When we express hAQP1 in\n Pichia pastoris<\/jats:italic>\n , treat spheroplasts with DIDS and examine hAQP1 by SDS\u2010PAGE, reactivity with an anti\u2010DIDS antibody shows that DIDS crosslinks hAQP1 monomers. Our results provide the first evidence that a molecule can move through an AQP via a route other than the monomeric pore, and raise the possibility that selectivity depends on the extent to which CO\n 2<\/jats:sub>\n \/NH\n 3<\/jats:sub>\n moves through monomeric pores versus an alternate pathway (e.g., the central pore).\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n Some membranes have negligible CO\n 2<\/jats:sub>\n permeability in the absence of protein channels like aquaporin\u20101 (AQP1).\n <\/jats:p>\n <\/jats:list-item>\n \n \n We confirm that, during CO\n 2<\/jats:sub>\n influx, heterologous expression of human AQP1 (hAQP1) in\n Xenopus<\/jats:italic>\n oocytes increases the magnitude of the transient surface\u2010pH increase by an amount (\u0394pH\n S<\/jats:sub>\n *)\n CO2<\/jats:sub>\n , measured with microelectrodes. During NH\n 3<\/jats:sub>\n influx, hAQP1 expression increases the magnitude of the transient pH\n S<\/jats:sub>\n decrease by (\u0394pH\n S<\/jats:sub>\n *)\n NH3<\/jats:sub>\n .\n <\/jats:p>\n <\/jats:list-item>\n \n \n p\u2010chloromercuribenzene sulfonate (pCMBS), which reacts with C189 in the monomeric pore, reduces (\u0394pH\n S<\/jats:sub>\n *)\n CO2<\/jats:sub>\n by half; (\u0394pH\n S<\/jats:sub>\n *)\n NH3<\/jats:sub>\n , to zero; and AQP1\u2010dependent osmotic water permeability (\n P<\/jats:italic>\n f<\/jats:sub>\n *), by half.\n <\/jats:p>\n <\/jats:list-item>\n \n \n 4,4'\u2010diisothiocyanatostilbene\u20102,2'\u2010disulfonate (DIDS) reduces (\u0394pH\n S<\/jats:sub>\n *)\n CO2<\/jats:sub>\n by half, but has no effect on (\u0394pH\n S<\/jats:sub>\n *)\n NH3<\/jats:sub>\n or\n P<\/jats:italic>\n f<\/jats:sub>\n *. DIDS crosslinks AQP1 monomers expressed in\n Pichia pastoris<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:list-item>\n \n \n Together, pCMBS+DIDS reduce (\u0394pH\n S<\/jats:sub>\n *)\n CO2<\/jats:sub>\n to zero. The C189S mutation of AQP1 eliminates the effects of pCMBS, but not of DIDS. Our results thus show that CO\n 2<\/jats:sub>\n traverses AQP1 via the monomeric pore plus a novel DIDS\u2010sensitive route that may be the central pore.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp289556","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T04:39:54Z","timestamp":1764909594000},"page":"336-365","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mechanism of CO\n 2<\/sub>\n and NH\n 3<\/sub>\n transport through human aquaporin 1: Evidence for parallel CO\n 2<\/sub>\n pathways"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0386-4248","authenticated-orcid":false,"given":"Raif","family":"Musa\u2010Aziz","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Institute of Biomedical Sciences University of S\u00e3o Paulo S\u00e3o Paulo Brazil"},{"name":"Department of Physiology and Biophysics Case Western Reserve University School of Medicine Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Ryan","family":"Geyer","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Case Western Reserve University School of Medicine Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1928-4392","authenticated-orcid":false,"given":"Seong\u2010Ki","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Case Western Reserve University School of Medicine Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8519-6991","authenticated-orcid":false,"given":"Fraser J.","family":"Moss","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Case Western Reserve University School of Medicine Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4741-7287","authenticated-orcid":false,"given":"Walter F.","family":"Boron","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Case Western Reserve University School of Medicine Cleveland OH USA"},{"name":"Department of Medicine Case Western Reserve University School of Medicine Cleveland OH USA"},{"name":"Department of Biochemistry Case Western Reserve University School of Medicine Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.275.5305.1490"},{"issue":"5","key":"e_1_2_6_3_1","first-page":"C1605","article-title":"Aquaporin\u20101 acts as an O2 channel. 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