Aldosterone up-regulates voltage-gated potassium currents and NKCC1 protein membrane fractions
Na + –K + –2Cl − 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 resul...
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| Veröffentlicht in: | Scientific reports 2020-09, Vol.10 (1), p.15604, Article 15604 |
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| creator | Bazard, Parveen Ding, Bo Chittam, Harish K. Zhu, Xiaoxia Parks, Thomas A. Taylor-Clark, Thomas E. Bhethanabotla, Venkat R. Frisina, Robert D. Walton, Joseph P. |
| description | Na
+
–K
+
–2Cl
−
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
+
channel and mineralocorticoid receptor inhibitors, revealed interactions between NKCC1 and outward K
+
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. |
| doi_str_mv | 10.1038/s41598-020-72450-4 |
| format | Article |
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+
–K
+
–2Cl
−
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
+
channel and mineralocorticoid receptor inhibitors, revealed interactions between NKCC1 and outward K
+
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.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-72450-4</identifier><identifier>PMID: 32973172</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/443 ; 692/4017 ; Aldosterone - pharmacology ; Cell Membrane - metabolism ; Gene Expression Regulation - drug effects ; Humanities and Social Sciences ; Humans ; Ion Channel Gating - drug effects ; multidisciplinary ; Neuroblastoma - metabolism ; Neuroblastoma - pathology ; Potassium - metabolism ; Receptors, Mineralocorticoid - metabolism ; Science ; Science (multidisciplinary) ; Solute Carrier Family 12, Member 2 - metabolism ; Tumor Cells, Cultured ; Up-Regulation</subject><ispartof>Scientific reports, 2020-09, Vol.10 (1), p.15604, Article 15604</ispartof><rights>The Author(s) 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-4fa60122a90af5b076688ce61452daa88efb963ac739672b50cde33ffcfd56ad3</citedby><cites>FETCH-LOGICAL-c483t-4fa60122a90af5b076688ce61452daa88efb963ac739672b50cde33ffcfd56ad3</cites><orcidid>0000-0001-8729-6112 ; 0000-0002-7423-6257</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515911/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515911/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32973172$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bazard, Parveen</creatorcontrib><creatorcontrib>Ding, Bo</creatorcontrib><creatorcontrib>Chittam, Harish K.</creatorcontrib><creatorcontrib>Zhu, Xiaoxia</creatorcontrib><creatorcontrib>Parks, Thomas A.</creatorcontrib><creatorcontrib>Taylor-Clark, Thomas E.</creatorcontrib><creatorcontrib>Bhethanabotla, Venkat R.</creatorcontrib><creatorcontrib>Frisina, Robert D.</creatorcontrib><creatorcontrib>Walton, Joseph P.</creatorcontrib><title>Aldosterone up-regulates voltage-gated potassium currents and NKCC1 protein membrane fractions</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Na
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–K
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−
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
+
channel and mineralocorticoid receptor inhibitors, revealed interactions between NKCC1 and outward K
+
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.</description><subject>631/443</subject><subject>692/4017</subject><subject>Aldosterone - pharmacology</subject><subject>Cell Membrane - metabolism</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Ion Channel Gating - drug effects</subject><subject>multidisciplinary</subject><subject>Neuroblastoma - metabolism</subject><subject>Neuroblastoma - pathology</subject><subject>Potassium - metabolism</subject><subject>Receptors, Mineralocorticoid - metabolism</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Solute Carrier Family 12, Member 2 - metabolism</subject><subject>Tumor Cells, Cultured</subject><subject>Up-Regulation</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp9kMtKxDAUhoMozqC-gAvpC0Rz7WUjDIM3HHSjW8NpmtRK25SkHfDtjVYH3ZjNSTjn_3L4EDql5JwSnl8EQWWRY8IIzpiQBIs9tGRESMw4Y_u_7gt0EsIbiUeyQtDiEC04KzJOM7ZEL6u2cmE03vUmmQbsTT21MJqQbF07Qm1wHV9VMrgRQmimLtGT96YfQwJ9lTzcr9c0GbwbTdMnnelKDxFkPeixcX04RgcW2mBOvusRer6-elrf4s3jzd16tcFa5HzEwkJKKGNQELCyJFma5rk2KRWSVQB5bmxZpBx0xos0Y6UkujKcW6ttJVOo-BG6nLnDVHam0nFBD60afNOBf1cOGvW30zevqnZblcmokdIIYDNAexeCN3aXpUR9ClezcBWFqy_hSsTQ2e9fd5EfvXGAzwMhtvraePXmJt9HE_9hPwBGio7q</recordid><startdate>20200924</startdate><enddate>20200924</enddate><creator>Bazard, Parveen</creator><creator>Ding, Bo</creator><creator>Chittam, Harish K.</creator><creator>Zhu, Xiaoxia</creator><creator>Parks, Thomas A.</creator><creator>Taylor-Clark, Thomas E.</creator><creator>Bhethanabotla, Venkat R.</creator><creator>Frisina, Robert D.</creator><creator>Walton, Joseph P.</creator><general>Nature Publishing Group UK</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8729-6112</orcidid><orcidid>https://orcid.org/0000-0002-7423-6257</orcidid></search><sort><creationdate>20200924</creationdate><title>Aldosterone up-regulates voltage-gated potassium currents and NKCC1 protein membrane fractions</title><author>Bazard, Parveen ; Ding, Bo ; Chittam, Harish K. ; Zhu, Xiaoxia ; Parks, Thomas A. ; Taylor-Clark, Thomas E. ; Bhethanabotla, Venkat R. ; Frisina, Robert D. ; Walton, Joseph P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-4fa60122a90af5b076688ce61452daa88efb963ac739672b50cde33ffcfd56ad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>631/443</topic><topic>692/4017</topic><topic>Aldosterone - pharmacology</topic><topic>Cell Membrane - metabolism</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Ion Channel Gating - drug effects</topic><topic>multidisciplinary</topic><topic>Neuroblastoma - metabolism</topic><topic>Neuroblastoma - pathology</topic><topic>Potassium - metabolism</topic><topic>Receptors, Mineralocorticoid - metabolism</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Solute Carrier Family 12, Member 2 - metabolism</topic><topic>Tumor Cells, Cultured</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bazard, Parveen</creatorcontrib><creatorcontrib>Ding, Bo</creatorcontrib><creatorcontrib>Chittam, Harish K.</creatorcontrib><creatorcontrib>Zhu, Xiaoxia</creatorcontrib><creatorcontrib>Parks, Thomas A.</creatorcontrib><creatorcontrib>Taylor-Clark, Thomas E.</creatorcontrib><creatorcontrib>Bhethanabotla, Venkat R.</creatorcontrib><creatorcontrib>Frisina, Robert D.</creatorcontrib><creatorcontrib>Walton, Joseph P.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bazard, Parveen</au><au>Ding, Bo</au><au>Chittam, Harish K.</au><au>Zhu, Xiaoxia</au><au>Parks, Thomas A.</au><au>Taylor-Clark, Thomas E.</au><au>Bhethanabotla, Venkat R.</au><au>Frisina, Robert D.</au><au>Walton, Joseph P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aldosterone up-regulates voltage-gated potassium currents and NKCC1 protein membrane fractions</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-09-24</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>15604</spage><pages>15604-</pages><artnum>15604</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Na
+
–K
+
–2Cl
−
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
+
channel and mineralocorticoid receptor inhibitors, revealed interactions between NKCC1 and outward K
+
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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32973172</pmid><doi>10.1038/s41598-020-72450-4</doi><orcidid>https://orcid.org/0000-0001-8729-6112</orcidid><orcidid>https://orcid.org/0000-0002-7423-6257</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 631/443 692/4017 Aldosterone - pharmacology Cell Membrane - metabolism Gene Expression Regulation - drug effects Humanities and Social Sciences Humans Ion Channel Gating - drug effects multidisciplinary Neuroblastoma - metabolism Neuroblastoma - pathology Potassium - metabolism Receptors, Mineralocorticoid - metabolism Science Science (multidisciplinary) Solute Carrier Family 12, Member 2 - metabolism Tumor Cells, Cultured Up-Regulation |
| title | Aldosterone up-regulates voltage-gated potassium currents and NKCC1 protein membrane fractions |
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