Mitochondrial ROMK channel is a molecular component of mitoK(ATP)
Activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) has been implicated in the mechanism of cardiac ischemic preconditioning, yet its molecular composition is unknown. To use an unbiased proteomic analysis of the mitochondrial inner membrane to identify the mitochondrial K(+...
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| Veröffentlicht in: | Circulation research 2012-08, Vol.111 (4), p.446-454 |
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| creator | Foster, D Brian Ho, Alice S Rucker, Jasma Garlid, Anders O Chen, Ling Sidor, Agnieszka Garlid, Keith D O'Rourke, Brian |
| description | Activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) has been implicated in the mechanism of cardiac ischemic preconditioning, yet its molecular composition is unknown.
To use an unbiased proteomic analysis of the mitochondrial inner membrane to identify the mitochondrial K(+) channel underlying mitoK(ATP).
Mass spectrometric analysis was used to identify KCNJ1(ROMK) in purified bovine heart mitochondrial inner membrane and ROMK mRNA was confirmed to be present in neonatal rat ventricular myocytes and adult hearts. ROMK2, a short form of the channel, is shown to contain an N-terminal mitochondrial targeting signal, and a full-length epitope-tagged ROMK2 colocalizes with mitochondrial ATP synthase β. The high-affinity ROMK toxin, tertiapin Q, inhibits mitoK(ATP) activity in isolated mitochondria and in digitonin-permeabilized cells. Moreover, short hairpin RNA-mediated knockdown of ROMK inhibits the ATP-sensitive, diazoxide-activated component of mitochondrial thallium uptake. Finally, the heart-derived cell line, H9C2, is protected from cell death stimuli by stable ROMK2 overexpression, whereas knockdown of the native ROMK exacerbates cell death.
The findings support ROMK as the pore-forming subunit of the cytoprotective mitoK(ATP) channel. |
| doi_str_mv | 10.1161/CIRCRESAHA.112.266445 |
| format | Article |
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To use an unbiased proteomic analysis of the mitochondrial inner membrane to identify the mitochondrial K(+) channel underlying mitoK(ATP).
Mass spectrometric analysis was used to identify KCNJ1(ROMK) in purified bovine heart mitochondrial inner membrane and ROMK mRNA was confirmed to be present in neonatal rat ventricular myocytes and adult hearts. ROMK2, a short form of the channel, is shown to contain an N-terminal mitochondrial targeting signal, and a full-length epitope-tagged ROMK2 colocalizes with mitochondrial ATP synthase β. The high-affinity ROMK toxin, tertiapin Q, inhibits mitoK(ATP) activity in isolated mitochondria and in digitonin-permeabilized cells. Moreover, short hairpin RNA-mediated knockdown of ROMK inhibits the ATP-sensitive, diazoxide-activated component of mitochondrial thallium uptake. Finally, the heart-derived cell line, H9C2, is protected from cell death stimuli by stable ROMK2 overexpression, whereas knockdown of the native ROMK exacerbates cell death.
The findings support ROMK as the pore-forming subunit of the cytoprotective mitoK(ATP) channel.</description><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/CIRCRESAHA.112.266445</identifier><identifier>PMID: 22811560</identifier><language>eng</language><publisher>United States</publisher><subject>Adenosine Triphosphate - metabolism ; Animals ; Animals, Newborn ; Apoptosis ; Bee Venoms - pharmacology ; Cattle ; CHO Cells ; Cricetinae ; Cricetulus ; Cytoprotection ; Diazoxide - pharmacology ; Gene Expression Regulation ; Humans ; Mass Spectrometry ; Mitochondria, Heart - drug effects ; Mitochondria, Heart - metabolism ; Mitochondria, Heart - pathology ; Mitochondrial Membranes - drug effects ; Mitochondrial Membranes - metabolism ; Mitochondrial Proton-Translocating ATPases - metabolism ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; Necrosis ; Potassium Channel Blockers - pharmacology ; Potassium Channels - drug effects ; Potassium Channels - genetics ; Potassium Channels - metabolism ; Potassium Channels, Inwardly Rectifying - drug effects ; Potassium Channels, Inwardly Rectifying - genetics ; Potassium Channels, Inwardly Rectifying - metabolism ; Proteomics - methods ; Rats ; RNA Interference ; RNA, Messenger - metabolism ; Thallium - metabolism ; Time Factors ; Transfection</subject><ispartof>Circulation research, 2012-08, Vol.111 (4), p.446-454</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22811560$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Foster, D Brian</creatorcontrib><creatorcontrib>Ho, Alice S</creatorcontrib><creatorcontrib>Rucker, Jasma</creatorcontrib><creatorcontrib>Garlid, Anders O</creatorcontrib><creatorcontrib>Chen, Ling</creatorcontrib><creatorcontrib>Sidor, Agnieszka</creatorcontrib><creatorcontrib>Garlid, Keith D</creatorcontrib><creatorcontrib>O'Rourke, Brian</creatorcontrib><title>Mitochondrial ROMK channel is a molecular component of mitoK(ATP)</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>Activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) has been implicated in the mechanism of cardiac ischemic preconditioning, yet its molecular composition is unknown.
To use an unbiased proteomic analysis of the mitochondrial inner membrane to identify the mitochondrial K(+) channel underlying mitoK(ATP).
Mass spectrometric analysis was used to identify KCNJ1(ROMK) in purified bovine heart mitochondrial inner membrane and ROMK mRNA was confirmed to be present in neonatal rat ventricular myocytes and adult hearts. ROMK2, a short form of the channel, is shown to contain an N-terminal mitochondrial targeting signal, and a full-length epitope-tagged ROMK2 colocalizes with mitochondrial ATP synthase β. The high-affinity ROMK toxin, tertiapin Q, inhibits mitoK(ATP) activity in isolated mitochondria and in digitonin-permeabilized cells. Moreover, short hairpin RNA-mediated knockdown of ROMK inhibits the ATP-sensitive, diazoxide-activated component of mitochondrial thallium uptake. Finally, the heart-derived cell line, H9C2, is protected from cell death stimuli by stable ROMK2 overexpression, whereas knockdown of the native ROMK exacerbates cell death.
The findings support ROMK as the pore-forming subunit of the cytoprotective mitoK(ATP) channel.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Apoptosis</subject><subject>Bee Venoms - pharmacology</subject><subject>Cattle</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cytoprotection</subject><subject>Diazoxide - pharmacology</subject><subject>Gene Expression Regulation</subject><subject>Humans</subject><subject>Mass Spectrometry</subject><subject>Mitochondria, Heart - drug effects</subject><subject>Mitochondria, Heart - metabolism</subject><subject>Mitochondria, Heart - pathology</subject><subject>Mitochondrial Membranes - drug effects</subject><subject>Mitochondrial Membranes - metabolism</subject><subject>Mitochondrial Proton-Translocating ATPases - metabolism</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Necrosis</subject><subject>Potassium Channel Blockers - pharmacology</subject><subject>Potassium Channels - drug effects</subject><subject>Potassium Channels - genetics</subject><subject>Potassium Channels - metabolism</subject><subject>Potassium Channels, Inwardly Rectifying - drug effects</subject><subject>Potassium Channels, Inwardly Rectifying - genetics</subject><subject>Potassium Channels, Inwardly Rectifying - metabolism</subject><subject>Proteomics - methods</subject><subject>Rats</subject><subject>RNA Interference</subject><subject>RNA, Messenger - metabolism</subject><subject>Thallium - metabolism</subject><subject>Time Factors</subject><subject>Transfection</subject><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kM9LwzAcxYMgbk7_BCXHeejMNz_a7FjKdGMbkzrPJU1SVkmb2rQH_3snztPjwec9eA-hByALgBies02e5av3dJ2ePV3QOOZcXKEpCMojLhKYoNsQPgkBzujyBk0olQAiJlOU7uvB65NvTV8rh_PDfov1SbWtdbgOWOHGO6tHp3qsfdP51rYD9hVuzrHtPD2-Pd2h60q5YO8vOkMfL6tjto52h9dNlu6iDjgMEYiKMy2J0oZzoOVSGaU040JwKWSyTAyhMQMiLTdaUKp1BcxUXCW8tCXRbIbmf71d779GG4aiqYO2zqnW-jEUQNjvGZLIM_p4Qceysabo-rpR_XfxP5v9AF6vV70</recordid><startdate>20120803</startdate><enddate>20120803</enddate><creator>Foster, D Brian</creator><creator>Ho, Alice S</creator><creator>Rucker, Jasma</creator><creator>Garlid, Anders O</creator><creator>Chen, Ling</creator><creator>Sidor, Agnieszka</creator><creator>Garlid, Keith D</creator><creator>O'Rourke, Brian</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20120803</creationdate><title>Mitochondrial ROMK channel is a molecular component of mitoK(ATP)</title><author>Foster, D Brian ; Ho, Alice S ; Rucker, Jasma ; Garlid, Anders O ; Chen, Ling ; Sidor, Agnieszka ; Garlid, Keith D ; O'Rourke, Brian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p141t-15f43c80acd4412b9adaac34554858797d0263108e4dc522ccf13df4a74beb0c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adenosine Triphosphate - metabolism</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Apoptosis</topic><topic>Bee Venoms - pharmacology</topic><topic>Cattle</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Cytoprotection</topic><topic>Diazoxide - pharmacology</topic><topic>Gene Expression Regulation</topic><topic>Humans</topic><topic>Mass Spectrometry</topic><topic>Mitochondria, Heart - drug effects</topic><topic>Mitochondria, Heart - metabolism</topic><topic>Mitochondria, Heart - pathology</topic><topic>Mitochondrial Membranes - drug effects</topic><topic>Mitochondrial Membranes - metabolism</topic><topic>Mitochondrial Proton-Translocating ATPases - metabolism</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - pathology</topic><topic>Necrosis</topic><topic>Potassium Channel Blockers - pharmacology</topic><topic>Potassium Channels - drug effects</topic><topic>Potassium Channels - genetics</topic><topic>Potassium Channels - metabolism</topic><topic>Potassium Channels, Inwardly Rectifying - drug effects</topic><topic>Potassium Channels, Inwardly Rectifying - genetics</topic><topic>Potassium Channels, Inwardly Rectifying - metabolism</topic><topic>Proteomics - methods</topic><topic>Rats</topic><topic>RNA Interference</topic><topic>RNA, Messenger - metabolism</topic><topic>Thallium - metabolism</topic><topic>Time Factors</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Foster, D Brian</creatorcontrib><creatorcontrib>Ho, Alice S</creatorcontrib><creatorcontrib>Rucker, Jasma</creatorcontrib><creatorcontrib>Garlid, Anders O</creatorcontrib><creatorcontrib>Chen, Ling</creatorcontrib><creatorcontrib>Sidor, Agnieszka</creatorcontrib><creatorcontrib>Garlid, Keith D</creatorcontrib><creatorcontrib>O'Rourke, Brian</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Foster, D Brian</au><au>Ho, Alice S</au><au>Rucker, Jasma</au><au>Garlid, Anders O</au><au>Chen, Ling</au><au>Sidor, Agnieszka</au><au>Garlid, Keith D</au><au>O'Rourke, Brian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitochondrial ROMK channel is a molecular component of mitoK(ATP)</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>2012-08-03</date><risdate>2012</risdate><volume>111</volume><issue>4</issue><spage>446</spage><epage>454</epage><pages>446-454</pages><eissn>1524-4571</eissn><abstract>Activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) has been implicated in the mechanism of cardiac ischemic preconditioning, yet its molecular composition is unknown.
To use an unbiased proteomic analysis of the mitochondrial inner membrane to identify the mitochondrial K(+) channel underlying mitoK(ATP).
Mass spectrometric analysis was used to identify KCNJ1(ROMK) in purified bovine heart mitochondrial inner membrane and ROMK mRNA was confirmed to be present in neonatal rat ventricular myocytes and adult hearts. ROMK2, a short form of the channel, is shown to contain an N-terminal mitochondrial targeting signal, and a full-length epitope-tagged ROMK2 colocalizes with mitochondrial ATP synthase β. The high-affinity ROMK toxin, tertiapin Q, inhibits mitoK(ATP) activity in isolated mitochondria and in digitonin-permeabilized cells. Moreover, short hairpin RNA-mediated knockdown of ROMK inhibits the ATP-sensitive, diazoxide-activated component of mitochondrial thallium uptake. Finally, the heart-derived cell line, H9C2, is protected from cell death stimuli by stable ROMK2 overexpression, whereas knockdown of the native ROMK exacerbates cell death.
The findings support ROMK as the pore-forming subunit of the cytoprotective mitoK(ATP) channel.</abstract><cop>United States</cop><pmid>22811560</pmid><doi>10.1161/CIRCRESAHA.112.266445</doi><tpages>9</tpages></addata></record> |
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| source | Journals@Ovid Ovid Autoload; MEDLINE; American Heart Association Journals; EZB-FREE-00999 freely available EZB journals |
| subjects | Adenosine Triphosphate - metabolism Animals Animals, Newborn Apoptosis Bee Venoms - pharmacology Cattle CHO Cells Cricetinae Cricetulus Cytoprotection Diazoxide - pharmacology Gene Expression Regulation Humans Mass Spectrometry Mitochondria, Heart - drug effects Mitochondria, Heart - metabolism Mitochondria, Heart - pathology Mitochondrial Membranes - drug effects Mitochondrial Membranes - metabolism Mitochondrial Proton-Translocating ATPases - metabolism Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Necrosis Potassium Channel Blockers - pharmacology Potassium Channels - drug effects Potassium Channels - genetics Potassium Channels - metabolism Potassium Channels, Inwardly Rectifying - drug effects Potassium Channels, Inwardly Rectifying - genetics Potassium Channels, Inwardly Rectifying - metabolism Proteomics - methods Rats RNA Interference RNA, Messenger - metabolism Thallium - metabolism Time Factors Transfection |
| title | Mitochondrial ROMK channel is a molecular component of mitoK(ATP) |
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