{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T04:06:13Z","timestamp":1787630773286,"version":"build-2736575974"},"reference-count":90,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,9,24]],"date-time":"2020-09-24T00:00:00Z","timestamp":1600905600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,9,24]],"date-time":"2020-09-24T00:00:00Z","timestamp":1600905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute","award":["AG009524"],"award-info":[{"award-number":["AG009524"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Na<jats:sup>+<\/jats:sup>\u2013K<jats:sup>+<\/jats:sup>\u20132Cl<jats:sup>\u2212<\/jats:sup> Cotransporter (NKCC1) is a protein that aids in the active transport of sodium, potassium, and chloride ions across cell membranes. It has been shown that long-term systemic treatment with aldosterone (ALD) can enhance NKCC1 protein expression and activity in the aging cochlea resulting in improved hearing. In the present work, we used a cell line with confirmed NKCC1 expression to demonstrate that in vitro application of ALD increased outward voltage-gated potassium currents significantly, and simultaneously upregulated whole lysate and membrane portion NKCC1 protein expression. These ALD-induced changes were blocked by applying the mineralocorticoid receptor antagonist eplerenone. However, application of the NKCC1 inhibitor bumetanide or the potassium channel antagonist Tetraethyl ammonium had no effect. In addition, NKKC1 mRNA levels remained stable, indicating that ALD modulates NKCC1 protein expression via the activation of mineralocorticoid receptors and post-transcriptional modifications. Further, in vitro electrophysiology experiments, with ALD in the presence of NKCC1, K<jats:sup>+<\/jats:sup> channel and mineralocorticoid receptor inhibitors, revealed interactions between NKCC1 and outward K<jats:sup>+<\/jats:sup> channels, mediated by a mineralocorticoid receptor-ALD complex. These results provide evidence of the therapeutic potential of ALD for the prevention\/treatment of inner ear disorders such as age-related hearing loss.<\/jats:p>","DOI":"10.1038\/s41598-020-72450-4","type":"journal-article","created":{"date-parts":[[2020,9,24]],"date-time":"2020-09-24T10:04:50Z","timestamp":1600941890000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Aldosterone up-regulates voltage-gated potassium currents and NKCC1 protein membrane fractions"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8729-6112","authenticated-orcid":false,"given":"Parveen","family":"Bazard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harish K.","family":"Chittam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Parks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E.","family":"Taylor-Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkat R.","family":"Bhethanabotla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7423-6257","authenticated-orcid":false,"given":"Robert D.","family":"Frisina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph P.","family":"Walton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,24]]},"reference":[{"key":"72450_CR1","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1124\/pr.115.011106","volume":"68","author":"F Jaisser","year":"2016","unstructured":"Jaisser, F. & Farman, N. Emerging roles of the mineralocorticoid receptor in pathology: toward new paradigms in clinical pharmacology. Pharmacol. Rev. 68, 49\u201375 (2016).","journal-title":"Pharmacol. Rev."},{"key":"72450_CR2","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1007\/s00424-003-1049-4","volume":"446","author":"D Firsov","year":"2003","unstructured":"Firsov, D. & Muller, O. G. Aldosterone action in the heart. Pfl\u00fcgers Archiv Eur. J. Physiol. 446, 328\u2013333 (2003).","journal-title":"Pfl\u00fcgers Archiv Eur. J. Physiol."},{"key":"72450_CR3","doi-asserted-by":"publisher","first-page":"G909","DOI":"10.1152\/ajpgi.90312.2008","volume":"295","author":"MW Musch","year":"2008","unstructured":"Musch, M. W., Lucioni, A. & Chang, E. B. Aldosterone regulation of intestinal Na absorption involves SGK-mediated changes in NHE3 and Na+ pump activity. Am. J. Physiol. Gastrointestinal Liver Physiol. 295, G909\u2013G919 (2008).","journal-title":"Am. J. Physiol. Gastrointestinal Liver Physiol."},{"key":"72450_CR4","doi-asserted-by":"publisher","first-page":"C66","DOI":"10.1152\/ajpcell.00096.2013","volume":"306","author":"B Ding","year":"2014","unstructured":"Ding, B. et al. Direct control of Na+-K+-2Cl\u2212-cotransport protein (NKCC1) expression with aldosterone. Am. J. Physiol. - Cell Physiol. 306, C66\u2013C75. https:\/\/doi.org\/10.1152\/ajpcell.00096.2013 (2014).","journal-title":"Am. J. Physiol. - Cell Physiol."},{"key":"72450_CR5","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/361467a0","volume":"361","author":"CM Canessa","year":"1993","unstructured":"Canessa, C. M., Horisberger, J.-D. & Rossier, B. C. Epithelial sodium channel related to proteins involved in neurodegeneration. Nature 361, 467\u2013470. https:\/\/doi.org\/10.1038\/361467a0 (1993).","journal-title":"Nature"},{"key":"72450_CR6","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/367463a0","volume":"367","author":"CM Canessa","year":"1994","unstructured":"Canessa, C. M. et al. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature 367, 463\u2013467. https:\/\/doi.org\/10.1038\/367463a0 (1994).","journal-title":"Nature"},{"key":"72450_CR7","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1042\/CS20171525","volume":"132","author":"WC Valinsky","year":"2018","unstructured":"Valinsky, W. C., Touyz, R. M. & Shrier, A. Aldosterone, SGK1, and ion channels in the kidney. Clin. Sci. 132, 173\u2013183 (2018).","journal-title":"Clin. Sci."},{"key":"72450_CR8","doi-asserted-by":"crossref","unstructured":"Valinsky, W. C., Touyz, R. M. & Shrier, A. In Vitamins and hormones vol. 109 105\u2013131 (Elsevier, 2019).","DOI":"10.1016\/bs.vh.2018.10.004"},{"key":"72450_CR9","doi-asserted-by":"publisher","first-page":"L1013","DOI":"10.1152\/ajplung.00206.2012","volume":"303","author":"H-L Ji","year":"2012","unstructured":"Ji, H.-L. et al. \u03b4 ENaC: a novel divergent amiloride-inhibitable sodium channel. Lung Cell. Mol. Physiol. 303, L1013\u2013L1026. https:\/\/doi.org\/10.1152\/ajplung.00206.2012 (2012).","journal-title":"Lung Cell. Mol. Physiol."},{"key":"72450_CR10","doi-asserted-by":"publisher","first-page":"F463","DOI":"10.1152\/ajprenal.00171.2013","volume":"305","author":"D Wen","year":"2013","unstructured":"Wen, D., Cornelius, R. J., Yuan, Y. & Sansom, S. C. Regulation of BK-\u03b1 expression in the distal nephron by aldosterone and urine pH. Renal Physiol. 305, F463\u2013F476. https:\/\/doi.org\/10.1152\/ajprenal.00171.2013 (2013).","journal-title":"Renal Physiol."},{"key":"72450_CR11","doi-asserted-by":"publisher","first-page":"20163","DOI":"10.1074\/jbc.M116.735175","volume":"291","author":"WC Valinsky","year":"2016","unstructured":"Valinsky, W. C., Jolly, A., Miquel, P., Touyz, R. M. & Shrier, A. Aldosterone upregulates transient receptor potential melastatin 7 (TRPM7). J. Biol. Chem. 291, 20163\u201320172. https:\/\/doi.org\/10.1074\/jbc.M116.735175 (2016).","journal-title":"J. Biol. Chem."},{"key":"72450_CR12","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1016\/S0006-291X(03)01301-9","volume":"307","author":"M Palmada","year":"2003","unstructured":"Palmada, M., Embark, H. M., Wyatt, A. W., B\u00f6hmer, C. & Lang, F. Negative charge at the consensus sequence for the serum- and glucocorticoid-inducible kinase, SGK1, determines pH sensitivity of the renal outer medullary K+ channel, ROMK1. Biochem. Biophys. Res. Commun. 307, 967\u2013972. https:\/\/doi.org\/10.1016\/S0006-291X(03)01301-9 (2003).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"72450_CR13","doi-asserted-by":"publisher","first-page":"23066","DOI":"10.1074\/jbc.M212301200","volume":"278","author":"D Yoo","year":"2003","unstructured":"Yoo, D. et al. Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase A. J. Biol. Chem. 278, 23066\u201323075. https:\/\/doi.org\/10.1074\/jbc.M212301200 (2003).","journal-title":"J. Biol. Chem."},{"key":"72450_CR14","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1016\/j.kint.2016.12.010","volume":"91","author":"MV Mamenko","year":"2017","unstructured":"Mamenko, M. V. et al. The renal TRPV4 channel is essential for adaptation to increased dietary potassium. Kidney Int. 91, 1398\u20131409. https:\/\/doi.org\/10.1016\/j.kint.2016.12.010 (2017).","journal-title":"Kidney Int."},{"key":"72450_CR15","doi-asserted-by":"publisher","first-page":"2712","DOI":"10.1073\/pnas.051603198","volume":"98","author":"M Robert-Nicoud","year":"2001","unstructured":"Robert-Nicoud, M. et al. Transcriptome of a mouse kidney cortical collecting duct cell line: effects of aldosterone and vasopressin. Proc. Natl. Acad. Sci. 98, 2712. https:\/\/doi.org\/10.1073\/pnas.051603198 (2001).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"72450_CR16","doi-asserted-by":"publisher","first-page":"3936","DOI":"10.1096\/fj.09-134759","volume":"23","author":"T Ziera","year":"2009","unstructured":"Ziera, T. et al. Cnksr3 is a direct mineralocorticoid receptor target gene and plays a key role in the regulation of the epithelial sodium channel. FASEB 23, 3936\u20133946. https:\/\/doi.org\/10.1096\/fj.09-134759 (2009).","journal-title":"FASEB"},{"key":"72450_CR17","doi-asserted-by":"publisher","first-page":"C175","DOI":"10.1152\/ajpcell.1998.274.1.C175","volume":"274","author":"AS Mihailidou","year":"1998","unstructured":"Mihailidou, A. S., Buhagiar, K. A. & Rasmussen, H. H. Na+ influx and Na+-K+pump activation during short-term exposure of cardiac myocytes to aldosterone. Am. J. Physiol. Cell Physiol. 274, C175\u2013C181. https:\/\/doi.org\/10.1152\/ajpcell.1998.274.1.C175 (1998).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"72450_CR18","doi-asserted-by":"publisher","first-page":"R1533","DOI":"10.1152\/ajpregu.1991.261.6.R1533","volume":"261","author":"W Clauss","year":"1991","unstructured":"Clauss, W., Dantzer, V. & Skadhauge, E. Aldosterone modulates electrogenic Cl secretion in the colon of the hen (Gallus domesticus). Am. J. Physiol.-Regul. Integr. Comp. Physiol. 261, R1533\u2013R1541. https:\/\/doi.org\/10.1152\/ajpregu.1991.261.6.R1533 (1991).","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"72450_CR19","doi-asserted-by":"publisher","first-page":"10883","DOI":"10.1073\/pnas.0604607103","volume":"103","author":"AN Anselmo","year":"2006","unstructured":"Anselmo, A. N. et al. WNK1 and OSR1 regulate the Na+, K+, 2Cl\u2212 cotransporter in HeLa cells. Proc. Natl. Acad. Sci. 103, 10883\u201310888 (2006).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"72450_CR20","doi-asserted-by":"publisher","first-page":"e106692","DOI":"10.1371\/journal.pone.0106692","volume":"9","author":"MC Ko","year":"2014","unstructured":"Ko, M. C. et al. Inhibition of NKCC1 attenuated hippocampal LTP formation and inhibitory avoidance in rat. PLoS ONE 9, e106692 (2014).","journal-title":"PLoS ONE"},{"key":"72450_CR21","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.3346\/jkms.2000.15.S.S3","volume":"15","author":"T Gerelsaikhan","year":"2000","unstructured":"Gerelsaikhan, T. & Turner, R. J. Membrane topology and function of the secretory Na+-K+-2Cl-cotransporter (NKCC1). J. Korean Med. Sci. 15, S3 (2000).","journal-title":"J. Korean Med. Sci."},{"key":"72450_CR22","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1038\/ncpneuro0883","volume":"4","author":"KT Kahle","year":"2008","unstructured":"Kahle, K. T. et al. Roles of the cation\u2013chloride cotransporters in neurological disease. Nat. Clin. Pract. Neurol. 4, 490\u2013503 (2008).","journal-title":"Nat. Clin. Pract. Neurol."},{"key":"72450_CR23","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/9713","volume":"22","author":"E Delpire","year":"1999","unstructured":"Delpire, E., Lu, J., England, R., Dull, C. & Thorne, T. Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat. Genet. 22, 192\u2013195 (1999).","journal-title":"Nat. Genet."},{"key":"72450_CR24","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1093\/geront\/43.5.661","volume":"43","author":"DS Dalton","year":"2003","unstructured":"Dalton, D. S. et al. The impact of hearing loss on quality of life in older adults. Gerontologist 43, 661\u2013668 (2003).","journal-title":"Gerontologist"},{"key":"72450_CR25","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/S0378-5955(97)00006-3","volume":"106","author":"DR Frisina","year":"1997","unstructured":"Frisina, D. R. & Frisina, R. D. Speech recognition in noise and presbycusis: relations to possible neural mechanisms. Hear. Res. 106, 95\u2013104 (1997).","journal-title":"Hear. Res."},{"key":"72450_CR26","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0378-5955(01)00377-X","volume":"163","author":"GA Gates","year":"2002","unstructured":"Gates, G. A., Mills, D., Nam, B.-H., D\u2019Agostino, R. & Rubel, E. W. Effects of age on the distortion product otoacoustic emission growth functions. Hear. Res. 163, 53\u201360 (2002).","journal-title":"Hear. Res."},{"key":"72450_CR27","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1016\/S0140-6736(05)67423-5","volume":"366","author":"GA Gates","year":"2005","unstructured":"Gates, G. A. & Mills, J. H. Presbycusis. Lancet 366, 1111\u20131120 (2005).","journal-title":"Lancet"},{"key":"72450_CR28","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1080\/09638280210129162","volume":"24","author":"C Heine","year":"2002","unstructured":"Heine, C. & Browning, C. J. Communication and psychosocial consequences of sensory loss in older adults: overview and rehabilitation directions. Disab. Rehabil. 24, 763\u2013773 (2002).","journal-title":"Disab. Rehabil."},{"key":"72450_CR29","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1007\/s00405-010-1270-7","volume":"267","author":"Q Huang","year":"2010","unstructured":"Huang, Q. & Tang, J. Age-related hearing loss or presbycusis. Eur. Arch. Otorhinolaryngol. 267, 1179\u20131191 (2010).","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"72450_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/00034894931020S101","volume":"102","author":"HF Schuknecht","year":"1993","unstructured":"Schuknecht, H. F. & Gacek, M. R. Cochlear pathology in presbycusis. Ann. Otol. Rhinol. Laryngol. 102, 1\u201316 (1993).","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"72450_CR31","doi-asserted-by":"publisher","first-page":"1777","DOI":"10.1288\/00005537-197410000-00012","volume":"84","author":"HF Schuknecht","year":"1974","unstructured":"Schuknecht, H. F. et al. Atrophy of the stria vascularis, a common cause for hearing loss. Laryngoscope 84, 1777\u20131821 (1974).","journal-title":"Laryngoscope"},{"key":"72450_CR32","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.jcomdis.2007.03.008","volume":"40","author":"K Tremblay","year":"2007","unstructured":"Tremblay, K. & Ross, B. Effects of age and age-related hearing loss on the brain. J. Commun. Disord. 40, 305\u2013312 (2007).","journal-title":"J. Commun. Disord."},{"key":"72450_CR33","first-page":"141","volume":"7","author":"JF Willott","year":"1996","unstructured":"Willott, J. F. Anatomic and physiologic aging: a behavioral neuroscience perspective. Am. Acad. Audiol. 7, 141\u2013151 (1996).","journal-title":"Am. Acad. Audiol."},{"key":"72450_CR34","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1007\/s10162-010-0214-7","volume":"11","author":"H Lang","year":"2010","unstructured":"Lang, H. et al. Chronic reduction of endocochlear potential reduces auditory nerve activity: further confirmation of an animal model of metabolic presbyacusis. J. Assoc. Res. Otolaryngol. 11, 419\u2013434. https:\/\/doi.org\/10.1007\/s10162-010-0214-7 (2010).","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"72450_CR35","doi-asserted-by":"publisher","first-page":"9643","DOI":"10.1523\/JNEUROSCI.22-21-09643.2002","volume":"22","author":"RA Schmiedt","year":"2002","unstructured":"Schmiedt, R. A., Lang, H., Okamura, H.-O. & Schulte, B. A. Effects of furosemide applied chronically to the round window: a model of metabolic presbyacusis. J. Neurosci. 22, 9643\u20139650 (2002).","journal-title":"J. Neurosci."},{"key":"72450_CR36","doi-asserted-by":"publisher","first-page":"2572","DOI":"10.1016\/S0006-3495(00)76497-6","volume":"79","author":"S Takeuchi","year":"2000","unstructured":"Takeuchi, S., Ando, M. & Kakigi, A. Mechanism generating endocochlear potential: role played by intermediate cells in stria vascularis. Biophys. J . 79, 2572\u20132582 (2000).","journal-title":"Biophys. J ."},{"key":"72450_CR37","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/0378-5955(84)90057-1","volume":"14","author":"WF Sewell","year":"1984","unstructured":"Sewell, W. F. The effects of furosemide on the endocochlear potential and auditory-nerve fiber tuning curves in cats. Hear. Res. 14, 305\u2013314 (1984).","journal-title":"Hear. Res."},{"key":"72450_CR38","doi-asserted-by":"publisher","first-page":"1846","DOI":"10.1097\/01.mlg.0000234940.33569.39","volume":"116","author":"T Suzuki","year":"2006","unstructured":"Suzuki, T. et al. Age-dependent degeneration of the stria vascularis in human cochleae. Laryngoscope 116, 1846\u20131850. https:\/\/doi.org\/10.1097\/01.mlg.0000234940.33569.39 (2006).","journal-title":"Laryngoscope"},{"key":"72450_CR39","doi-asserted-by":"publisher","first-page":"2081","DOI":"10.18632\/aging.101045","volume":"8","author":"RD Frisina","year":"2016","unstructured":"Frisina, R. D., Ding, B., Zhu, X. & Walton, J. P. Age-related hearing loss: prevention of threshold declines, cell loss and apoptosis in spiral ganglion neurons. Aging (Albany NY) 8, 2081\u20132099 (2016).","journal-title":"Aging (Albany NY)"},{"key":"72450_CR40","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.heares.2016.05.001","volume":"336","author":"J Halonen","year":"2016","unstructured":"Halonen, J. et al. Long-term treatment with aldosterone slows the progression of age-related hearing loss. Hear. Res. 336, 63\u201371 (2016).","journal-title":"Hear. Res."},{"key":"72450_CR41","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1044\/1059-0889(2013\/13-0003)","volume":"22","author":"RD Frisina","year":"2013","unstructured":"Frisina, R. D. & Frisina, D. R. Physiological and neurobiological bases of age-related hearing loss: biotherapeutic implications. Am. J. Audiol. 22, 299\u2013302 (2013).","journal-title":"Am. J. Audiol."},{"key":"72450_CR42","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1002\/cne.10244","volume":"447","author":"CL Adamson","year":"2002","unstructured":"Adamson, C. L., Reid, M. A., Mo, Z.-L., Bowne-English, J. & Davis, R. L. Firing features and potassium channel content of murine spiral ganglion neurons vary with cochlear location. J. Comp. Neurol. 447, 331\u2013350. https:\/\/doi.org\/10.1002\/cne.10244 (2002).","journal-title":"J. Comp. Neurol."},{"key":"72450_CR43","doi-asserted-by":"publisher","first-page":"4333","DOI":"10.1073\/pnas.97.8.4333","volume":"97","author":"T Kharkovets","year":"2000","unstructured":"Kharkovets, T. et al. KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. Proc. Natl. Acad. Sci. 97, 4333. https:\/\/doi.org\/10.1073\/pnas.97.8.4333 (2000).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"72450_CR44","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/S0092-8674(00)80556-5","volume":"96","author":"C Kubisch","year":"1999","unstructured":"Kubisch, C. et al. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 96, 437\u2013446 (1999).","journal-title":"Cell"},{"key":"72450_CR45","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2015.00077","author":"W Sun","year":"2015","unstructured":"Sun, W. et al. Potassium channel activator attenuates salicylate-induced cochlear hearing loss potentially ameliorating tinnitus. Front. Neurol. https:\/\/doi.org\/10.3389\/fneur.2015.00077 (2015).","journal-title":"Front. Neurol."},{"key":"72450_CR46","doi-asserted-by":"publisher","first-page":"7803","DOI":"10.1038\/s41598-017-08141-4","volume":"7","author":"P Bazard","year":"2017","unstructured":"Bazard, P., Frisina, R. D., Walton, J. P. & Bhethanabotla, V. R. Nanoparticle-based plasmonic transduction for modulation of electrically excitable cells. Sci. Rep. 7, 7803 (2017).","journal-title":"Sci. Rep."},{"key":"72450_CR47","unstructured":"47Chittam, H. K. Modulation of whole cell currents in human neuroblastoma cells via the hormone aldosterone: an in vitro study (2016)."},{"key":"72450_CR48","doi-asserted-by":"crossref","unstructured":"Kovalevich, J., & Langford, D. In Neuronal cell culture 9\u201321 (Springer, Berlin, 2013).","DOI":"10.1007\/978-1-62703-640-5_2"},{"key":"72450_CR49","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1096\/fasebj.10.9.8801164","volume":"10","author":"R Lotan","year":"1996","unstructured":"Lotan, R. Retinoids in cancer chemoprevention. FASEB J. 10, 1031\u20131039 (1996).","journal-title":"FASEB J."},{"key":"72450_CR50","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1023\/A:1005733430435","volume":"31","author":"G Melino","year":"1997","unstructured":"Melino, G., Thiele, C. J., Knight, R. A. & Piacentini, M. Retinoids and the control of growth\/death decisions in human neuroblastoma cell lines. J. Neurooncol. 31, 65\u201383 (1997).","journal-title":"J. Neurooncol."},{"key":"72450_CR51","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/0045-6039(84)90038-1","volume":"14","author":"S P\u00e5hlman","year":"1984","unstructured":"P\u00e5hlman, S., Ruusala, A.-I., Abrahamsson, L., Mattsson, M. E. & Esscher, T. Retinoic acid-induced differentiation of cultured human neuroblastoma cells: a comparison with phorbolester-induced differentiation. Cell Differ. 14, 135\u2013144 (1984).","journal-title":"Cell Differ."},{"key":"72450_CR52","doi-asserted-by":"publisher","first-page":"13799","DOI":"10.1074\/jbc.M112.341214","volume":"287","author":"A Banno","year":"2012","unstructured":"Banno, A. et al. Subcellular localization of talin is regulated by inter-domain interactions. J. Biol. Chem. 287, 13799\u201313812 (2012).","journal-title":"J. Biol. Chem."},{"key":"72450_CR53","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1111\/j.1432-1033.1983.tb07668.x","volume":"135","author":"JA Lenstra","year":"1983","unstructured":"Lenstra, J. A. & Bloemendal, H. Topography of the total protein population from cultured cells upon fractionation by chemical extractions. Eur. J. Biochem. 135, 413\u2013423 (1983).","journal-title":"Eur. J. Biochem."},{"key":"72450_CR54","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1083\/jcb.200904140","volume":"187","author":"L-H Loo","year":"2009","unstructured":"Loo, L.-H. et al. Heterogeneity in the physiological states and pharmacological responses of differentiating 3T3-L1 preadipocytes. J. Cell Biol. 187, 375\u2013384 (2009).","journal-title":"J. Cell Biol."},{"key":"72450_CR55","doi-asserted-by":"crossref","unstructured":"Michelsen, U. & von Hagen, J. In Methods in Enzymology vol. 463 305\u2013328 (Elsevier, 2009).","DOI":"10.1016\/S0076-6879(09)63019-6"},{"key":"72450_CR56","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1251\/bpo20","volume":"3","author":"M Marone","year":"2001","unstructured":"Marone, M., Mozzetti, S., De Ritis, D., Pierelli, L. & Scambia, G. Semiquantitative RT-PCR analysis to assess the expression levels of multiple transcripts from the same sample. Biol. Proc. Online 3, 19 (2001).","journal-title":"Biol. Proc. Online"},{"key":"72450_CR57","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1677\/jme.1.01755","volume":"34","author":"S Bustin","year":"2005","unstructured":"Bustin, S., Benes, V., Nolan, T. & Pfaffl, M. Quantitative real-time RT-PCR\u2013a perspective. J. Mol. Endocrinol. 34, 597\u2013601 (2005).","journal-title":"J. Mol. Endocrinol."},{"key":"72450_CR58","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1152\/jn.1998.79.2.648","volume":"79","author":"P Tosetti","year":"1998","unstructured":"Tosetti, P., Taglietti, V. & Toselli, M. Functional changes in potassium conductances of the human neuroblastoma cell line SH-SY5Y during in vitro differentiation. J. Neurophysiol. 79, 648\u2013658 (1998).","journal-title":"J. Neurophysiol."},{"key":"72450_CR59","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.1172\/JCI1042","volume":"101","author":"JB Matthews","year":"1998","unstructured":"Matthews, J. B. et al. Na-K-2Cl cotransporter gene expression and function during enterocyte differentiation: modulation of Cl-secretory capacity by butyrate. J. Clin. Investig. 101, 2072 (1998).","journal-title":"J. Clin. Investig."},{"key":"72450_CR60","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1083\/jcb.201404136","volume":"206","author":"X Huang","year":"2014","unstructured":"Huang, X. & Jan, L. Y. Targeting potassium channels in cancer. J. Cell. Biol. 206, 151\u2013162 (2014).","journal-title":"J. Cell. Biol."},{"key":"72450_CR61","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/nrm1009","volume":"4","author":"R L\u00f6sel","year":"2003","unstructured":"L\u00f6sel, R. & Wehling, M. Nongenomic actions of steroid hormones. Nat. Rev. Mol. Cell Biol. 4, 46 (2003).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"72450_CR62","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/j.tins.2017.07.001","volume":"40","author":"Y Ben-Ari","year":"2017","unstructured":"Ben-Ari, Y. NKCC1 chloride importer antagonists attenuate many neurological and psychiatric disorders. Trends Neurosci. 40, 536\u2013554 (2017).","journal-title":"Trends Neurosci."},{"key":"72450_CR63","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1007\/s00424-014-1588-x","volume":"467","author":"K-T Lu","year":"2015","unstructured":"Lu, K.-T. et al. NKCC1 mediates traumatic brain injury-induced hippocampal neurogenesis through CREB phosphorylation and HIF-1\u03b1 expression. Pfl\u00fcgers Archiv \u2013 Eur. J. Physiol. 467, 1651\u20131661. https:\/\/doi.org\/10.1007\/s00424-014-1588-x (2015).","journal-title":"Pfl\u00fcgers Archiv \u2013 Eur. J. Physiol."},{"key":"72450_CR64","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1111\/apha.12832","volume":"220","author":"S Bandulik","year":"2017","unstructured":"Bandulik, S. Of channels and pumps: different ways to boost the aldosterone?. Acta Physiol. 220, 332\u2013360 (2017).","journal-title":"Acta Physiol."},{"key":"72450_CR65","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1038\/ki.1992.284","volume":"42","author":"CP Bastl","year":"1992","unstructured":"Bastl, C. P. & Hayslett, J. P. The cellular action of aldosterone in target epithelia. Kidney Int. 42, 250\u2013264 (1992).","journal-title":"Kidney Int."},{"key":"72450_CR66","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1097\/MNH.0b013e32833c34ec","volume":"19","author":"W-H Wang","year":"2010","unstructured":"Wang, W.-H., Yue, P., Sun, P. & Lin, D.-H. Regulation and function of potassium channels in aldosterone-sensitive distal nephron. Curr. Opin. Nephrol. Hypertens. 19, 463 (2010).","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"72450_CR67","doi-asserted-by":"publisher","first-page":"257","DOI":"10.3109\/10409238.2016.1172553","volume":"51","author":"DL Neverisky","year":"2016","unstructured":"Neverisky, D. L. & Abbott, G. W. Ion channel\u2013transporter interactions. Crit. Rev. Biochem. Mol. Biol. 51, 257\u2013267 (2016).","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"72450_CR68","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1111\/j.1469-7793.2001.0151k.x","volume":"537","author":"JP B\u00e9nitah","year":"2001","unstructured":"B\u00e9nitah, J. P., Perrier, E., G\u00f3mez, A. M. & Vassort, G. Effects of aldosterone on transient outward K+ current density in rat ventricular myocytes. J. Physiol. 537, 151\u2013160 (2001).","journal-title":"J. Physiol."},{"key":"72450_CR69","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1055\/s-0029-1243601","volume":"42","author":"S Bandulik","year":"2010","unstructured":"Bandulik, S., Penton, D., Barhanin, J. & Warth, R. TASK1 and TASK3 potassium channels: determinants of aldosterone secretion and adrenocortical zonation. Hormone Metab. Res. 42, 450\u2013457 (2010).","journal-title":"Hormone Metab. Res."},{"key":"72450_CR70","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1007\/s12013-012-9442-2","volume":"65","author":"T Wang","year":"2013","unstructured":"Wang, T. et al. Bumetanide hyperpolarizes Madin\u2013Darby canine kidney cells and enhances cellular gentamicin uptake by elevating cytosolic Ca2+ thus facilitating intermediate conductance Ca2+-activated potassium channels. Cell Biochem. Biophys. 65, 381\u2013398 (2013).","journal-title":"Cell Biochem. Biophys."},{"key":"72450_CR71","doi-asserted-by":"publisher","first-page":"C1388","DOI":"10.1152\/ajpcell.1996.270.5.C1388","volume":"270","author":"SN Orlov","year":"1996","unstructured":"Orlov, S. N., Tremblay, J. & Hamet, P. Cell volume in vascular smooth muscle is regulated by bumetanide-sensitive ion transport. Am. J. Physiol. Cell Physiol. 270, C1388\u2013C1397 (1996).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"72450_CR72","doi-asserted-by":"publisher","first-page":"C763","DOI":"10.1152\/ajpcell.1993.265.3.C763","volume":"265","author":"PB Perry","year":"1993","unstructured":"Perry, P. B. & O\u2019Neill, W. C. Swelling-activated K fluxes in vascular endothelial cells: volume regulation via K-Cl cotransport and K channels. Am. J. Physiol.-Cell Physiol. 265, C763\u2013C769 (1993).","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"72450_CR73","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/0304-4157(91)90005-H","volume":"1071","author":"B Sarkadi","year":"1991","unstructured":"Sarkadi, B. & Parker, J. C. Activation of ion transport pathways by changes in cell volume. Biochim. et Biophysica Acta \u2013Rev. Biomembr. 1071, 407\u2013427 (1991).","journal-title":"Biochim. et Biophysica Acta \u2013Rev. Biomembr."},{"key":"72450_CR74","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.mce.2011.07.019","volume":"350","author":"R Dooley","year":"2012","unstructured":"Dooley, R., Harvey, B. J. & Thomas, W. Non-genomic actions of aldosterone: from receptors and signals to membrane targets. Mol. Cell. Endocrinol. 350, 223\u2013234 (2012).","journal-title":"Mol. Cell. Endocrinol."},{"key":"72450_CR75","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s10741-005-2343-3","volume":"10","author":"GH Williams","year":"2005","unstructured":"Williams, G. H. Aldosterone biosynthesis, regulation, and classical mechanism of action. Heart Fail. Rev. 10, 7\u201313 (2005).","journal-title":"Heart Fail. Rev."},{"key":"72450_CR76","doi-asserted-by":"publisher","first-page":"30171","DOI":"10.1074\/jbc.M111.222893","volume":"286","author":"J Rinehart","year":"2011","unstructured":"Rinehart, J. et al. WNK2 kinase is a novel regulator of essential neuronal cation-chloride cotransporters. J. Biol. Chem. 286, 30171\u201330180 (2011).","journal-title":"J. Biol. Chem."},{"key":"72450_CR77","doi-asserted-by":"publisher","first-page":"28969","DOI":"10.1074\/jbc.271.46.28969","volume":"271","author":"L D'Andrea","year":"1996","unstructured":"D\u2019Andrea, L. et al. Na: K: 2Cl Cotransporter (NKCC) of Intestinal Epithelial Cells SURFACE EXPRESSION IN RESPONSE TO cAMP. J. Biol. Chem. 271, 28969\u201328976 (1996).","journal-title":"J. Biol. Chem."},{"key":"72450_CR78","doi-asserted-by":"publisher","first-page":"C1109","DOI":"10.1152\/ajpcell.1993.265.4.C1109","volume":"265","author":"J Matthews","year":"1993","unstructured":"Matthews, J. et al. Phorbol ester sequentially downregulates cAMP-regulated basolateral and apical Cl-transport pathways in T84 cells. Am. J. Physiol. Cell Physiol. 265, C1109\u2013C1117 (1993).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"72450_CR79","doi-asserted-by":"publisher","first-page":"C254","DOI":"10.1152\/ajpcell.1997.272.1.C254","volume":"272","author":"JB Matthews","year":"1997","unstructured":"Matthews, J. B., Smith, J. A. & Hrnjez, B. J. Effects of F-actin stabilization or disassembly on epithelial Cl-secretion and Na-K-2Cl cotransport. Am. J. Physiol. - Cell Physiol. 272, C254\u2013C262 (1997).","journal-title":"Am. J. Physiol. - Cell Physiol."},{"key":"72450_CR80","doi-asserted-by":"publisher","first-page":"C697","DOI":"10.1152\/ajpcell.1998.274.3.C697","volume":"274","author":"JB Matthews","year":"1998","unstructured":"Matthews, J. B., Smith, J. A., Mun, E. C. & Sicklick, J. K. Osmotic regulation of intestinal epithelial Na+-K+-Cl\u2212 cotransport: role of Cl\u2212 and F-actin. Am. J. Physiol. Cell Physiol. 274, C697\u2013C706 (1998).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"72450_CR81","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/S0039-6060(05)80317-4","volume":"118","author":"JB Matthews","year":"1995","unstructured":"Matthews, J. B., Smith, J. A. & Nguyen, H. Modulation of intestinal chloride secretion at basolateral transport sites: opposing effects of cyclic adenosine monophosphate and phorbol ester. Surgery 118, 147\u2013153 (1995).","journal-title":"Surgery"},{"key":"72450_CR82","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/S0002-9610(99)80109-3","volume":"169","author":"JB Matthews","year":"1995","unstructured":"Matthews, J. B., Tally, K. J. & Smith, J. A. Activation of intestinal Na-K-2Cl cotransport by 5\u2032-AMP requires F-actin remodeling. Am. J. Surg. 169, 50\u201356 (1995).","journal-title":"Am. J. Surg."},{"key":"72450_CR83","doi-asserted-by":"publisher","first-page":"G370","DOI":"10.1152\/ajpgi.1993.265.2.G370","volume":"265","author":"JB Matthews","year":"1993","unstructured":"Matthews, J. B. et al. Na (+)-K (+)-2Cl-cotransport and Cl-secretion evoked by heat-stable enterotoxin is microfilament dependent in T84 cells. Am. J. Physiol. \u2013 Gastrointest. Liver Physiol. 265, G370\u2013G378 (1993).","journal-title":"Am. J. Physiol. \u2013 Gastrointest. Liver Physiol."},{"key":"72450_CR84","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/S0039-6060(98)70144-8","volume":"124","author":"OC Farokhzad","year":"1998","unstructured":"Farokhzad, O. C., Mun, E. C., Sicklick, J. K., Smith, J. A. & Matthews, J. B. Effects of bryostatin 1, a novel anticancer agent, on intestinal transport and barrier function: role of protein kinase C. Surgery 124, 380\u2013387 (1998).","journal-title":"Surgery"},{"key":"72450_CR85","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1002\/(SICI)1097-4652(199912)181:3<489::AID-JCP13>3.0.CO;2-7","volume":"181","author":"OC Farokhzad","year":"1999","unstructured":"Farokhzad, O. C. et al. Protein kinase C activation downregulates the expression and function of the basolateral Na+\/K+\/2Cl\u2212 cotransporter. J. Cell. Physiol. 181, 489\u2013498 (1999).","journal-title":"J. Cell. Physiol."},{"key":"72450_CR86","doi-asserted-by":"publisher","first-page":"G142","DOI":"10.1152\/ajpgi.00483.2011","volume":"304","author":"PG Bouyer","year":"2012","unstructured":"Bouyer, P. G. et al. Capsaicin induces NKCC1 internalization and inhibits chloride secretion in colonic epithelial cells independently of TRPV1. Am. J. Physiol.-Gastrointest Liver Physiol. 304, G142\u2013G156 (2012).","journal-title":"Am. J. Physiol.-Gastrointest Liver Physiol."},{"key":"72450_CR87","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1172\/JCI10897","volume":"106","author":"MP Lee","year":"2000","unstructured":"Lee, M. P. et al. Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. J. Clin. Investig. 106, 1447\u20131455 (2000).","journal-title":"J. Clin. Investig."},{"key":"72450_CR88","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/ng0297-186","volume":"15","author":"N Neyroud","year":"1997","unstructured":"Neyroud, N. et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat. Genet. 15, 186 (1997).","journal-title":"Nat. Genet."},{"key":"72450_CR89","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1016\/S0896-6273(00)80255-X","volume":"17","author":"DE Vetter","year":"1996","unstructured":"Vetter, D. E. et al. Inner ear defects induced by null mutationof the isk Gene. Neuron 17, 1251\u20131264 (1996).","journal-title":"Neuron"},{"key":"72450_CR90","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1002\/glia.22629","volume":"62","author":"BR Larsen","year":"2014","unstructured":"Larsen, B. R. et al. Contributions of the Na+\/K+-ATPase, NKCC1, and Kir4.1 to hippocampal K+ clearance and volume responses. Glia 62, 608\u2013622 (2014).","journal-title":"Glia"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-72450-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-72450-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-72450-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T19:16:11Z","timestamp":1670354171000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-72450-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,24]]},"references-count":90,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["72450"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-72450-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,24]]},"assertion":[{"value":"11 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 July 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 September 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Drs. Ding, Frisina, Zhu and Walton hold a patent (not yet licensed) on the use of aldosterone and anti-inflammatories to treat age-related hearing loss. There are no other actual or perceived conflicts for the authors of this manuscript regarding funding source agencies, NIH or others, for the research reported in this manuscript.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15604"}}