Regulation of SR and mitochondrial Ca 2+ signaling by L-type Ca 2+ channels and Na/Ca exchanger in hiPSC-CMs
While signaling of cardiac SR by surface membrane proteins (I & I ) is well studied, the regulation of mitochondrial Ca by plasmalemmal proteins remains less explored. Here we have examined the signaling of mitochondria and SR by surface-membrane calcium-transporting proteins, using genetically...
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| Veröffentlicht in: | Cell calcium (Edinburgh) 2025-01, Vol.125, p.102985 |
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| creator | Zhang, Xiao-Hua Morad, Martin |
| description | While signaling of cardiac SR by surface membrane proteins (I
& I
) is well studied, the regulation of mitochondrial Ca
by plasmalemmal proteins remains less explored. Here we have examined the signaling of mitochondria and SR by surface-membrane calcium-transporting proteins, using genetically engineered targeted fluorescent probes, mito-GCamP6 and R-CEPIA1er.
In voltage-clamped and TIRF-imaged cardiomyocytes, low Na
induced SR Ca
release was suppressed by short pre-exposures to ∼100 nM FCCP, suggesting mitochondrial Ca
contribution to low Na
triggered SR Ca
release. Even though low Na
- or caffeine-triggered SR Ca
release activated global mitochondrial Ca
uptake, focal mitochondrial Ca
signals varied in kinetics and magnitude, showing uptake or release of calcium, depending on cellular location of mitochondria. In spontaneously pacing cells, sustained caffeine exposures depleted the SR Ca
content activating mitochondrial Ca
uptake followed by sustained mitochondrial pacing. Spontaneous hiPSCCMs pacing was strongly suppressed by L-type calcium channels blockers, but not by inhibiting SERCA2a by CPA.
Spontaneous hiPSCCMs pacing is triggered by influx of calcium through L-type Ca
channel that gates the release of SR pools supplemented by NCX-mediated mitochondrial calcium contribution. |
| doi_str_mv | 10.1016/j.ceca.2024.102985 |
| format | Article |
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& I
) is well studied, the regulation of mitochondrial Ca
by plasmalemmal proteins remains less explored. Here we have examined the signaling of mitochondria and SR by surface-membrane calcium-transporting proteins, using genetically engineered targeted fluorescent probes, mito-GCamP6 and R-CEPIA1er.
In voltage-clamped and TIRF-imaged cardiomyocytes, low Na
induced SR Ca
release was suppressed by short pre-exposures to ∼100 nM FCCP, suggesting mitochondrial Ca
contribution to low Na
triggered SR Ca
release. Even though low Na
- or caffeine-triggered SR Ca
release activated global mitochondrial Ca
uptake, focal mitochondrial Ca
signals varied in kinetics and magnitude, showing uptake or release of calcium, depending on cellular location of mitochondria. In spontaneously pacing cells, sustained caffeine exposures depleted the SR Ca
content activating mitochondrial Ca
uptake followed by sustained mitochondrial pacing. Spontaneous hiPSCCMs pacing was strongly suppressed by L-type calcium channels blockers, but not by inhibiting SERCA2a by CPA.
Spontaneous hiPSCCMs pacing is triggered by influx of calcium through L-type Ca
channel that gates the release of SR pools supplemented by NCX-mediated mitochondrial calcium contribution.</description><identifier>EISSN: 1532-1991</identifier><identifier>DOI: 10.1016/j.ceca.2024.102985</identifier><identifier>PMID: 39693912</identifier><language>eng</language><publisher>Netherlands</publisher><subject>Caffeine - pharmacology ; Calcium - metabolism ; Calcium Channels, L-Type - metabolism ; Calcium Signaling - drug effects ; Humans ; Induced Pluripotent Stem Cells - cytology ; Induced Pluripotent Stem Cells - metabolism ; Mitochondria - drug effects ; Mitochondria - metabolism ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Sarcoplasmic Reticulum - metabolism ; Sodium - metabolism ; Sodium-Calcium Exchanger - metabolism</subject><ispartof>Cell calcium (Edinburgh), 2025-01, Vol.125, p.102985</ispartof><rights>Copyright © 2024 Elsevier Ltd. All rights reserved.</rights><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/39693912$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Xiao-Hua</creatorcontrib><creatorcontrib>Morad, Martin</creatorcontrib><title>Regulation of SR and mitochondrial Ca 2+ signaling by L-type Ca 2+ channels and Na/Ca exchanger in hiPSC-CMs</title><title>Cell calcium (Edinburgh)</title><addtitle>Cell Calcium</addtitle><description>While signaling of cardiac SR by surface membrane proteins (I
& I
) is well studied, the regulation of mitochondrial Ca
by plasmalemmal proteins remains less explored. Here we have examined the signaling of mitochondria and SR by surface-membrane calcium-transporting proteins, using genetically engineered targeted fluorescent probes, mito-GCamP6 and R-CEPIA1er.
In voltage-clamped and TIRF-imaged cardiomyocytes, low Na
induced SR Ca
release was suppressed by short pre-exposures to ∼100 nM FCCP, suggesting mitochondrial Ca
contribution to low Na
triggered SR Ca
release. Even though low Na
- or caffeine-triggered SR Ca
release activated global mitochondrial Ca
uptake, focal mitochondrial Ca
signals varied in kinetics and magnitude, showing uptake or release of calcium, depending on cellular location of mitochondria. In spontaneously pacing cells, sustained caffeine exposures depleted the SR Ca
content activating mitochondrial Ca
uptake followed by sustained mitochondrial pacing. Spontaneous hiPSCCMs pacing was strongly suppressed by L-type calcium channels blockers, but not by inhibiting SERCA2a by CPA.
Spontaneous hiPSCCMs pacing is triggered by influx of calcium through L-type Ca
channel that gates the release of SR pools supplemented by NCX-mediated mitochondrial calcium contribution.</description><subject>Caffeine - pharmacology</subject><subject>Calcium - metabolism</subject><subject>Calcium Channels, L-Type - metabolism</subject><subject>Calcium Signaling - drug effects</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells - cytology</subject><subject>Induced Pluripotent Stem Cells - metabolism</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Sarcoplasmic Reticulum - metabolism</subject><subject>Sodium - metabolism</subject><subject>Sodium-Calcium Exchanger - metabolism</subject><issn>1532-1991</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjskKwjAURYMgzj_gQt5e2mZwyrooLlRE3cuzjW0kTUtTwf69A7p2deHcc-ESMmTUZ5TNgpsfqQh9TvnkBbhcTBukw6aCe0xK1iZd526UUinmrEXaQs6kkIx3iDmo5G6w0rmF_ArHA6CNIdNVHqW5jUuNBkIEPganE4tG2wQuNWy8qi7Ut4lStFYZ95nuMHhR9XjDRJWgLaR6fwy9cOv6pHlF49Tgmz0yWi1P4dor7pdMxeei1BmW9fl3T_wVntFZSXo</recordid><startdate>202501</startdate><enddate>202501</enddate><creator>Zhang, Xiao-Hua</creator><creator>Morad, Martin</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>202501</creationdate><title>Regulation of SR and mitochondrial Ca 2+ signaling by L-type Ca 2+ channels and Na/Ca exchanger in hiPSC-CMs</title><author>Zhang, Xiao-Hua ; Morad, Martin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_396939123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Caffeine - pharmacology</topic><topic>Calcium - metabolism</topic><topic>Calcium Channels, L-Type - metabolism</topic><topic>Calcium Signaling - drug effects</topic><topic>Humans</topic><topic>Induced Pluripotent Stem Cells - cytology</topic><topic>Induced Pluripotent Stem Cells - metabolism</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Sarcoplasmic Reticulum - metabolism</topic><topic>Sodium - metabolism</topic><topic>Sodium-Calcium Exchanger - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Xiao-Hua</creatorcontrib><creatorcontrib>Morad, Martin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Cell calcium (Edinburgh)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Xiao-Hua</au><au>Morad, Martin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of SR and mitochondrial Ca 2+ signaling by L-type Ca 2+ channels and Na/Ca exchanger in hiPSC-CMs</atitle><jtitle>Cell calcium (Edinburgh)</jtitle><addtitle>Cell Calcium</addtitle><date>2025-01</date><risdate>2025</risdate><volume>125</volume><spage>102985</spage><pages>102985-</pages><eissn>1532-1991</eissn><abstract>While signaling of cardiac SR by surface membrane proteins (I
& I
) is well studied, the regulation of mitochondrial Ca
by plasmalemmal proteins remains less explored. Here we have examined the signaling of mitochondria and SR by surface-membrane calcium-transporting proteins, using genetically engineered targeted fluorescent probes, mito-GCamP6 and R-CEPIA1er.
In voltage-clamped and TIRF-imaged cardiomyocytes, low Na
induced SR Ca
release was suppressed by short pre-exposures to ∼100 nM FCCP, suggesting mitochondrial Ca
contribution to low Na
triggered SR Ca
release. Even though low Na
- or caffeine-triggered SR Ca
release activated global mitochondrial Ca
uptake, focal mitochondrial Ca
signals varied in kinetics and magnitude, showing uptake or release of calcium, depending on cellular location of mitochondria. In spontaneously pacing cells, sustained caffeine exposures depleted the SR Ca
content activating mitochondrial Ca
uptake followed by sustained mitochondrial pacing. Spontaneous hiPSCCMs pacing was strongly suppressed by L-type calcium channels blockers, but not by inhibiting SERCA2a by CPA.
Spontaneous hiPSCCMs pacing is triggered by influx of calcium through L-type Ca
channel that gates the release of SR pools supplemented by NCX-mediated mitochondrial calcium contribution.</abstract><cop>Netherlands</cop><pmid>39693912</pmid><doi>10.1016/j.ceca.2024.102985</doi></addata></record> |
| fulltext | fulltext |
| identifier | EISSN: 1532-1991 |
| ispartof | Cell calcium (Edinburgh), 2025-01, Vol.125, p.102985 |
| issn | 1532-1991 |
| language | eng |
| recordid | cdi_pubmed_primary_39693912 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Caffeine - pharmacology Calcium - metabolism Calcium Channels, L-Type - metabolism Calcium Signaling - drug effects Humans Induced Pluripotent Stem Cells - cytology Induced Pluripotent Stem Cells - metabolism Mitochondria - drug effects Mitochondria - metabolism Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Sarcoplasmic Reticulum - metabolism Sodium - metabolism Sodium-Calcium Exchanger - metabolism |
| title | Regulation of SR and mitochondrial Ca 2+ signaling by L-type Ca 2+ channels and Na/Ca exchanger in hiPSC-CMs |
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