Increased Coupled Gating of L-Type Ca2+ Channels During Hypertension and Timothy Syndrome
RATIONALE:L-Type (Cav1.2) Ca channels are critical regulators of muscle and neural function. Although Cav1.2 channel activity varies regionally, little is known about the mechanisms underlying this heterogeneity. OBJECTIVE:To test the hypothesis that Cav1.2 channels can gate coordinately. METHODS AN...
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| Veröffentlicht in: | Circulation research 2010-03, Vol.106 (4), p.748-756 |
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| creator | Navedo, Manuel F Cheng, Edward P Yuan, Can Votaw, Scott Molkentin, Jeffery D Scott, John D Santana, Luis F |
| description | RATIONALE:L-Type (Cav1.2) Ca channels are critical regulators of muscle and neural function. Although Cav1.2 channel activity varies regionally, little is known about the mechanisms underlying this heterogeneity.
OBJECTIVE:To test the hypothesis that Cav1.2 channels can gate coordinately.
METHODS AND RESULTS:We used optical and electrophysiological approaches to record Cav1.2 channel activity in cardiac, smooth muscle, and tsA-201 cells expressing Cav1.2 channels. Consistent with our hypothesis, we found that small clusters of Cav1.2 channels can open and close in tandem. Fluorescence resonance energy transfer and electrophysiological studies suggest that this coupling of Cav1.2 channels involves transient interactions between neighboring channels via their C termini. The frequency of coupled gating events increases in hypertensive smooth muscle and in cells expressing a mutant Cav1.2 channel that causes arrhythmias and autism in humans with Timothy syndrome (LQT8).
CONCLUSIONS:Coupled gating of Cav1.2 channels may represent a novel mechanism for the regulation of Ca influx and excitability in neurons, cardiac, and arterial smooth muscle under physiological and pathological conditions. |
| doi_str_mv | 10.1161/CIRCRESAHA.109.213363 |
| format | Article |
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OBJECTIVE:To test the hypothesis that Cav1.2 channels can gate coordinately.
METHODS AND RESULTS:We used optical and electrophysiological approaches to record Cav1.2 channel activity in cardiac, smooth muscle, and tsA-201 cells expressing Cav1.2 channels. Consistent with our hypothesis, we found that small clusters of Cav1.2 channels can open and close in tandem. Fluorescence resonance energy transfer and electrophysiological studies suggest that this coupling of Cav1.2 channels involves transient interactions between neighboring channels via their C termini. The frequency of coupled gating events increases in hypertensive smooth muscle and in cells expressing a mutant Cav1.2 channel that causes arrhythmias and autism in humans with Timothy syndrome (LQT8).
CONCLUSIONS:Coupled gating of Cav1.2 channels may represent a novel mechanism for the regulation of Ca influx and excitability in neurons, cardiac, and arterial smooth muscle under physiological and pathological conditions.</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/CIRCRESAHA.109.213363</identifier><identifier>PMID: 20110531</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>A Kinase Anchor Proteins - genetics ; A Kinase Anchor Proteins - metabolism ; Animals ; Arterial hypertension. Arterial hypotension ; Biological and medical sciences ; Blood and lymphatic vessels ; Calcium Channels, L-Type - drug effects ; Calcium Channels, L-Type - genetics ; Calcium Channels, L-Type - metabolism ; Calcium Signaling - drug effects ; Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors ; Calcium-Calmodulin-Dependent Protein Kinases - metabolism ; Calmodulin - metabolism ; Cardiac dysrhythmias ; Cardiology. Vascular system ; Cells, Cultured ; Enzyme Activation ; Enzyme Activators - pharmacology ; Fluorescence Resonance Energy Transfer ; Fundamental and applied biological sciences. Psychology ; Heart ; Humans ; Hypertension - genetics ; Hypertension - metabolism ; Hypertension - physiopathology ; Ion Channel Gating - drug effects ; Long QT Syndrome - genetics ; Long QT Syndrome - metabolism ; Long QT Syndrome - physiopathology ; Medical sciences ; Membrane Potentials ; Mice ; Mice, Knockout ; Microscopy, Confocal ; Muscle, Smooth, Vascular - drug effects ; Muscle, Smooth, Vascular - metabolism ; Mutation ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Myocytes, Smooth Muscle - drug effects ; Myocytes, Smooth Muscle - metabolism ; Patch-Clamp Techniques ; Protein Kinase C-alpha - genetics ; Protein Kinase C-alpha - metabolism ; Protein Kinase Inhibitors - pharmacology ; Protein Structure, Tertiary ; Protein Transport ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Recombinant Fusion Proteins - metabolism ; Time Factors ; Transfection ; Vertebrates: cardiovascular system</subject><ispartof>Circulation research, 2010-03, Vol.106 (4), p.748-756</ispartof><rights>2010 American Heart Association, Inc.</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22516069$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20110531$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Navedo, Manuel F</creatorcontrib><creatorcontrib>Cheng, Edward P</creatorcontrib><creatorcontrib>Yuan, Can</creatorcontrib><creatorcontrib>Votaw, Scott</creatorcontrib><creatorcontrib>Molkentin, Jeffery D</creatorcontrib><creatorcontrib>Scott, John D</creatorcontrib><creatorcontrib>Santana, Luis F</creatorcontrib><title>Increased Coupled Gating of L-Type Ca2+ Channels During Hypertension and Timothy Syndrome</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>RATIONALE:L-Type (Cav1.2) Ca channels are critical regulators of muscle and neural function. Although Cav1.2 channel activity varies regionally, little is known about the mechanisms underlying this heterogeneity.
OBJECTIVE:To test the hypothesis that Cav1.2 channels can gate coordinately.
METHODS AND RESULTS:We used optical and electrophysiological approaches to record Cav1.2 channel activity in cardiac, smooth muscle, and tsA-201 cells expressing Cav1.2 channels. Consistent with our hypothesis, we found that small clusters of Cav1.2 channels can open and close in tandem. Fluorescence resonance energy transfer and electrophysiological studies suggest that this coupling of Cav1.2 channels involves transient interactions between neighboring channels via their C termini. The frequency of coupled gating events increases in hypertensive smooth muscle and in cells expressing a mutant Cav1.2 channel that causes arrhythmias and autism in humans with Timothy syndrome (LQT8).
CONCLUSIONS:Coupled gating of Cav1.2 channels may represent a novel mechanism for the regulation of Ca influx and excitability in neurons, cardiac, and arterial smooth muscle under physiological and pathological conditions.</description><subject>A Kinase Anchor Proteins - genetics</subject><subject>A Kinase Anchor Proteins - metabolism</subject><subject>Animals</subject><subject>Arterial hypertension. Arterial hypotension</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Calcium Channels, L-Type - drug effects</subject><subject>Calcium Channels, L-Type - genetics</subject><subject>Calcium Channels, L-Type - metabolism</subject><subject>Calcium Signaling - drug effects</subject><subject>Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors</subject><subject>Calcium-Calmodulin-Dependent Protein Kinases - metabolism</subject><subject>Calmodulin - metabolism</subject><subject>Cardiac dysrhythmias</subject><subject>Cardiology. Vascular system</subject><subject>Cells, Cultured</subject><subject>Enzyme Activation</subject><subject>Enzyme Activators - pharmacology</subject><subject>Fluorescence Resonance Energy Transfer</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Heart</subject><subject>Humans</subject><subject>Hypertension - genetics</subject><subject>Hypertension - metabolism</subject><subject>Hypertension - physiopathology</subject><subject>Ion Channel Gating - drug effects</subject><subject>Long QT Syndrome - genetics</subject><subject>Long QT Syndrome - metabolism</subject><subject>Long QT Syndrome - physiopathology</subject><subject>Medical sciences</subject><subject>Membrane Potentials</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microscopy, Confocal</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Mutation</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Smooth Muscle - drug effects</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Patch-Clamp Techniques</subject><subject>Protein Kinase C-alpha - genetics</subject><subject>Protein Kinase C-alpha - metabolism</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Structure, Tertiary</subject><subject>Protein Transport</subject><subject>Rabbits</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Time Factors</subject><subject>Transfection</subject><subject>Vertebrates: cardiovascular system</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUtPwzAQhC0EglL4CSBfOKEUrx9JfEGqQmkrVUKCcuBkuY7TBFKnslOq_nuCyvOyK-18O4cZhC6ADABiuMmmj9nj6Gk4GQ6AyAEFxmJ2gHogKI-4SOAQ9QghMkoYIyfoNIRXQoAzKo_RCSUARDDooZepM97qYHOcNZt13e2xbiu3xE2BZ9F8t7Y40_QaZ6V2ztYB3238pzzpFN9aF6rGYe1yPK9WTVvu8NPO5b5Z2TN0VOg62POv3UfP96N5NolmD-NpNpxFr4wDizhnSQ7UMJnaxcJwvhA8MWlKBFBLZJqmlNnECC2ZKUg3SJHHMtFx2sUgBLA-ut37rjeLlc2Nda3XtVr7aqX9TjW6Uv8VV5Vq2bwrmjLOIekMLv8a_Hx-h9QBV1-ADkbXhdfOVOGXowJiEsuOk3tu29St9eGt3mytV6XVdVsqIOqzOPVbXHeSal8c-wCGOYl3</recordid><startdate>20100305</startdate><enddate>20100305</enddate><creator>Navedo, Manuel F</creator><creator>Cheng, Edward P</creator><creator>Yuan, Can</creator><creator>Votaw, Scott</creator><creator>Molkentin, Jeffery D</creator><creator>Scott, John D</creator><creator>Santana, Luis F</creator><general>American Heart Association, Inc</general><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>5PM</scope></search><sort><creationdate>20100305</creationdate><title>Increased Coupled Gating of L-Type Ca2+ Channels During Hypertension and Timothy Syndrome</title><author>Navedo, Manuel F ; Cheng, Edward P ; Yuan, Can ; Votaw, Scott ; Molkentin, Jeffery D ; Scott, John D ; Santana, Luis F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-j3413-4437d12c398ebbc44b547c880512e0988823e7c5a93cf093c0fd697a681165513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>A Kinase Anchor Proteins - genetics</topic><topic>A Kinase Anchor Proteins - metabolism</topic><topic>Animals</topic><topic>Arterial hypertension. Arterial hypotension</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Calcium Channels, L-Type - drug effects</topic><topic>Calcium Channels, L-Type - genetics</topic><topic>Calcium Channels, L-Type - metabolism</topic><topic>Calcium Signaling - drug effects</topic><topic>Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors</topic><topic>Calcium-Calmodulin-Dependent Protein Kinases - metabolism</topic><topic>Calmodulin - metabolism</topic><topic>Cardiac dysrhythmias</topic><topic>Cardiology. Vascular system</topic><topic>Cells, Cultured</topic><topic>Enzyme Activation</topic><topic>Enzyme Activators - pharmacology</topic><topic>Fluorescence Resonance Energy Transfer</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Heart</topic><topic>Humans</topic><topic>Hypertension - genetics</topic><topic>Hypertension - metabolism</topic><topic>Hypertension - physiopathology</topic><topic>Ion Channel Gating - drug effects</topic><topic>Long QT Syndrome - genetics</topic><topic>Long QT Syndrome - metabolism</topic><topic>Long QT Syndrome - physiopathology</topic><topic>Medical sciences</topic><topic>Membrane Potentials</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microscopy, Confocal</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Mutation</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Smooth Muscle - drug effects</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Patch-Clamp Techniques</topic><topic>Protein Kinase C-alpha - genetics</topic><topic>Protein Kinase C-alpha - metabolism</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Structure, Tertiary</topic><topic>Protein Transport</topic><topic>Rabbits</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Recombinant Fusion Proteins - metabolism</topic><topic>Time Factors</topic><topic>Transfection</topic><topic>Vertebrates: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Navedo, Manuel F</creatorcontrib><creatorcontrib>Cheng, Edward P</creatorcontrib><creatorcontrib>Yuan, Can</creatorcontrib><creatorcontrib>Votaw, Scott</creatorcontrib><creatorcontrib>Molkentin, Jeffery D</creatorcontrib><creatorcontrib>Scott, John D</creatorcontrib><creatorcontrib>Santana, Luis F</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Navedo, Manuel F</au><au>Cheng, Edward P</au><au>Yuan, Can</au><au>Votaw, Scott</au><au>Molkentin, Jeffery D</au><au>Scott, John D</au><au>Santana, Luis F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased Coupled Gating of L-Type Ca2+ Channels During Hypertension and Timothy Syndrome</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>2010-03-05</date><risdate>2010</risdate><volume>106</volume><issue>4</issue><spage>748</spage><epage>756</epage><pages>748-756</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><abstract>RATIONALE:L-Type (Cav1.2) Ca channels are critical regulators of muscle and neural function. Although Cav1.2 channel activity varies regionally, little is known about the mechanisms underlying this heterogeneity.
OBJECTIVE:To test the hypothesis that Cav1.2 channels can gate coordinately.
METHODS AND RESULTS:We used optical and electrophysiological approaches to record Cav1.2 channel activity in cardiac, smooth muscle, and tsA-201 cells expressing Cav1.2 channels. Consistent with our hypothesis, we found that small clusters of Cav1.2 channels can open and close in tandem. Fluorescence resonance energy transfer and electrophysiological studies suggest that this coupling of Cav1.2 channels involves transient interactions between neighboring channels via their C termini. The frequency of coupled gating events increases in hypertensive smooth muscle and in cells expressing a mutant Cav1.2 channel that causes arrhythmias and autism in humans with Timothy syndrome (LQT8).
CONCLUSIONS:Coupled gating of Cav1.2 channels may represent a novel mechanism for the regulation of Ca influx and excitability in neurons, cardiac, and arterial smooth muscle under physiological and pathological conditions.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>20110531</pmid><doi>10.1161/CIRCRESAHA.109.213363</doi><tpages>9</tpages></addata></record> |
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| subjects | A Kinase Anchor Proteins - genetics A Kinase Anchor Proteins - metabolism Animals Arterial hypertension. Arterial hypotension Biological and medical sciences Blood and lymphatic vessels Calcium Channels, L-Type - drug effects Calcium Channels, L-Type - genetics Calcium Channels, L-Type - metabolism Calcium Signaling - drug effects Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors Calcium-Calmodulin-Dependent Protein Kinases - metabolism Calmodulin - metabolism Cardiac dysrhythmias Cardiology. Vascular system Cells, Cultured Enzyme Activation Enzyme Activators - pharmacology Fluorescence Resonance Energy Transfer Fundamental and applied biological sciences. Psychology Heart Humans Hypertension - genetics Hypertension - metabolism Hypertension - physiopathology Ion Channel Gating - drug effects Long QT Syndrome - genetics Long QT Syndrome - metabolism Long QT Syndrome - physiopathology Medical sciences Membrane Potentials Mice Mice, Knockout Microscopy, Confocal Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - metabolism Mutation Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - metabolism Patch-Clamp Techniques Protein Kinase C-alpha - genetics Protein Kinase C-alpha - metabolism Protein Kinase Inhibitors - pharmacology Protein Structure, Tertiary Protein Transport Rabbits Rats Rats, Sprague-Dawley Recombinant Fusion Proteins - metabolism Time Factors Transfection Vertebrates: cardiovascular system |
| title | Increased Coupled Gating of L-Type Ca2+ Channels During Hypertension and Timothy Syndrome |
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