{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T14:34:40Z","timestamp":1782398080365,"version":"3.54.5"},"reference-count":38,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2017,11,25]],"date-time":"2017-11-25T00:00:00Z","timestamp":1511568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01GM79629"],"award-info":[{"award-number":["R01GM79629"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["3R01GM079629-03S1"],"award-info":[{"award-number":["3R01GM079629-03S1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01GM097159"],"award-info":[{"award-number":["R01GM097159"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"American Heart Association Texas Affiliate Inc.","award":["14GRNT18750014"],"award-info":[{"award-number":["14GRNT18750014"]}]},{"DOI":"10.13039\/100000928","name":"Welch Foundation","doi-asserted-by":"publisher","award":["BI-1757"],"award-info":[{"award-number":["BI-1757"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In addition to gap junctional channels that mediate cell-to-cell communication, connexins form hemichannels that are present at the plasma membrane. Since hemichannels are permeable to small hydrophilic compounds, including metabolites and signaling molecules, their abnormal opening can cause or contribute to cell damage in disorders such as cardiac infarct, stroke, deafness, skin diseases, and cataracts. Therefore, hemichannels are potential pharmacological targets. A few aminoglycosides, well-known broad-spectrum antibiotics, have been shown to inhibit hemichannels. Here, we tested several commercially available aminoglycosides for inhibition of human connexin hemichannels using a cell-based bacterial growth complementation assay that we developed recently. We found that kanamycin A, kanamycin B, geneticin, neomycin, and paromomycin are effective inhibitors of hemichannels formed by connexins 26, 43, and 46 (Cx26, Cx43, and Cx46). Because of the &gt;70 years of clinical experience with aminoglycosides and the fact that several of the aminoglycosides tested here have been used in humans, they are promising starting points for the development of effective connexin hemichannel inhibitors.<\/jats:p>","DOI":"10.3390\/molecules22122063","type":"journal-article","created":{"date-parts":[[2017,11,27]],"date-time":"2017-11-27T11:07:08Z","timestamp":1511780828000},"page":"2063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Inhibition by Commercial Aminoglycosides of Human Connexin Hemichannels Expressed in Bacteria"],"prefix":"10.3390","volume":"22","author":[{"given":"Mariana","family":"Fiori","sequence":"first","affiliation":[{"name":"Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430-6551, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivasan","family":"Krishnan","sequence":"additional","affiliation":[{"name":"Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430-6551, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbey","family":"Kjellgren","sequence":"additional","affiliation":[{"name":"Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430-6551, USA"},{"name":"Honors College, McClellan Hall, Box 41017, Texas Tech University, Lubbock, TX 79409-1017, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-7568","authenticated-orcid":false,"given":"Luis","family":"Cuello","sequence":"additional","affiliation":[{"name":"Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430-6551, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8932-740X","authenticated-orcid":false,"given":"Guillermo","family":"Altenberg","sequence":"additional","affiliation":[{"name":"Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430-6551, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.bbamem.2012.02.007","article-title":"Evolutionary analyses of gap junction protein families","volume":"1828","author":"Abascal","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1002\/cphy.c110051","article-title":"Gap junctions","volume":"2","author":"Nielsen","year":"2012","journal-title":"Compr. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Paulis, L.E., Klein, A.M., Ghanem, A., Geelen, T., Coolen, B.F., Breitbach, M., Zimmermann, K., Nicolay, K., Fleischmann, B.K., and Roell, W. (2013). Embryonic cardiomyocyte, but not autologous stem cell transplantation, restricts infarct expansion, enhances ventricular function, and improves long-term survival. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061510"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3389\/fphys.2014.00071","article-title":"Functional analysis and regulation of purified connexin hemichannels","volume":"5","author":"Fiori","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Harris, A.L., and Locke, D. (2009). Permeability of connexin channels. Connexins: A Guide, Humana Press.","DOI":"10.1007\/978-1-59745-489-6"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.bbamem.2012.07.002","article-title":"Paracrine signaling through plasma membrane hemichannels","volume":"1828","author":"Wang","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"H1714","DOI":"10.1152\/ajpheart.00022.2007","article-title":"Hemichannels in cardiomyocytes open transiently during ischemia and contribute to reperfusion injury following brief ischemia","volume":"293","author":"Uemura","year":"2007","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.1017\/S1462399409001276","article-title":"Connexin-26 mutations in deafness and skin disease","volume":"11","author":"Lee","year":"2009","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"20","DOI":"10.3389\/fphys.2014.00020","article-title":"Connexin hemichannels in the lens","volume":"5","author":"Beyer","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.pharmthera.2015.06.005","article-title":"Connexin 43 is an emerging therapeutic target in ischemia\/reperfusion injury, cardioprotection and neuroprotection","volume":"153","author":"Schulz","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.2174\/0929867321666131228191714","article-title":"Role of connexins and pannexins in ischemic stroke","volume":"21","author":"Orellana","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1046\/j.1365-201X.2003.01198.x","article-title":"Do connexin 43 gap-junctional hemichannels activate and cause cell damage during ATP depletion of renal-tubule cells?","volume":"179","author":"Vergara","year":"2003","journal-title":"Acta Physiol. Scand."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1097\/01.mlg.0000241944.77192.d2","article-title":"A novel mechanism for connexin 26 mutation linked deafness: Cell death caused by leaky gap junction hemichannels","volume":"116","author":"Stong","year":"2006","journal-title":"Laryngoscope"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8647","DOI":"10.1074\/jbc.M413536200","article-title":"Membrane transport proteins with complete replacement of transmembrane helices with polyalanine sequences remain functional","volume":"280","author":"Bao","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00232-001-0115-0","article-title":"Inhibition of gap junction hemichannels by chloride channel blockers","volume":"185","author":"Eskandari","year":"2002","journal-title":"J. Membr. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Harris, A.L., and Locke, D. (2009). Pharmacology of connexin channels. Connexins: A Guide, Humana Press.","DOI":"10.1007\/978-1-59745-489-6"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.neuropharm.2013.03.020","article-title":"Connexin channel modulators and their mechanisms of action","volume":"75","author":"Verselis","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.pharmthera.2017.07.001","article-title":"Inhibitors of connexin and pannexin channels as potential therapeutics","volume":"180","author":"Willebrords","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3056","DOI":"10.2174\/138161210793292528","article-title":"Peptides targeting gap junctional structures","volume":"16","author":"Herve","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/j.1476-5381.2011.01244.x","article-title":"Pharmacological modulation of connexin-formed channels in cardiac pathophysiology","volume":"163","author":"Boengler","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e00177","DOI":"10.1042\/BSR20140089","article-title":"Functional hemichannels formed by human connexin 26 expressed in bacteria","volume":"35","author":"Fiori","year":"2015","journal-title":"Biosci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1177\/1087057116675321","article-title":"An Escherichia coli-based assay to assess the function of recombinant human hemichannels","volume":"22","author":"Krishnan","year":"2017","journal-title":"SLAS Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1007\/s002030050425","article-title":"Requirement of a large K+-uptake capacity and of extracytoplasmic protease activity for protamine resistance of Escherichia coli","volume":"167","author":"Stumpe","year":"1997","journal-title":"Arch. Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4238","DOI":"10.1128\/JB.186.13.4238-4245.2004","article-title":"Multiple paths for nonphysiological transport of K+ Escherichia coli","volume":"186","author":"Buurman","year":"2004","journal-title":"J. Bacteriol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1021\/bi048390f","article-title":"Electrostatic interaction of a K+ channel RCK domain with charged membrane surfaces","volume":"44","author":"Ptak","year":"2005","journal-title":"Biochemistry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0014-5793(03)00706-3","article-title":"MjK1, a K+ channel from M. jannaschii, mediates K+ uptake and K+ sensitivity in E. coli","volume":"547","author":"Hellmer","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1007\/s00424-016-1788-7","article-title":"Gap-junctional channel and hemichannel activity of two recently identified connexin 26 mutants associated with deafness","volume":"468","author":"Dalamon","year":"2016","journal-title":"Pflugers Arch.-Eur. J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3389\/fncel.2014.00265","article-title":"Extracellular gentamicin reduces the activity of connexin hemichannels and interferes with purinergic Ca2+ signaling in HeLa cells","volume":"8","author":"Figueroa","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Umezawa, S., and Hooper, I.R. (1982). Total synthesis and chemical modification of the aminoglycoside antibiotics. Aminoglycoside Antibiotics, Springer.","DOI":"10.1007\/978-3-642-68579-8"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Arya, D.P. (2007). Design, chemical synthesis, and antibacterial activity of kanamycin and neomycin class aminoglycoside antibiotics. Aminoglycoside Antibiotics: From Chemical Biology to Drug Discovery, John Wiley & Sons, Inc.","DOI":"10.1002\/9780470149676"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1128\/AAC.43.5.1003","article-title":"Aminoglycosides: Nephrotoxicity","volume":"43","author":"Tulkens","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1097\/MOO.0b013e32830e20b0","article-title":"Gap junctions and connexins in the inner ear: Their roles in homeostasis and deafness","volume":"16","author":"Nickel","year":"2008","journal-title":"Curr. Opin. Otolaryngol. Head Neck Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1515\/revneuro-2011-0065","article-title":"Glial hemichannels and their involvement in aging and neurodegenerative diseases","volume":"23","author":"Orellana","year":"2012","journal-title":"Rev. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s11481-012-9352-5","article-title":"The role of gap junction channels during physiologic and pathologic conditions of the human central nervous system","volume":"7","author":"Eugenin","year":"2012","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_35","first-page":"87","article-title":"A cell-based assay to assess hemichannel function","volume":"90","author":"Krishnan","year":"2017","journal-title":"Yale J. Biol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.febslet.2014.03.004","article-title":"Hunting for connexin hemichannels","volume":"588","author":"Saez","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"16030","DOI":"10.1073\/pnas.2530348100","article-title":"Molecular basis of calcium regulation in connexin-32 hemichannels","volume":"100","author":"Larrosa","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"E7986","DOI":"10.1073\/pnas.1609378113","article-title":"Mechanism of gating by calcium in connexin hemichannels","volume":"113","author":"Lopez","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/12\/2063\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:51:15Z","timestamp":1760208675000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/12\/2063"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,25]]},"references-count":38,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["molecules22122063"],"URL":"https:\/\/doi.org\/10.3390\/molecules22122063","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,25]]}}}