Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts
We previously demonstrated that defective interdomain interaction between N-terminal (0 to 600) and central regions (2000 to 2500) of ryanodine receptor 2 (RyR2) induces Ca2+ leak in failing hearts and that K201 (JTV519) inhibits the Ca2+ leak by correcting the defective interdomain interaction. In...
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| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 2008-02, Vol.117 (6), p.762-772 |
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| creator | YAMAMOTO, Takeshi YANO, Masafumi XIAOJUAN XU UCHINOUMI, Hitoshi TATEISHI, Hiroki MOCHIZUKI, Mamoru ODA, Tetsuro KOBAYASHI, Shigeki IKEMOTO, Noriaki MATSUZAKI, Masunori |
| description | We previously demonstrated that defective interdomain interaction between N-terminal (0 to 600) and central regions (2000 to 2500) of ryanodine receptor 2 (RyR2) induces Ca2+ leak in failing hearts and that K201 (JTV519) inhibits the Ca2+ leak by correcting the defective interdomain interaction. In the present report, we identified the K201-binding domain and characterized the role of this novel domain in the regulation of the RyR2 channel.
An assay using a quartz-crystal microbalance technique (a very sensitive mass-measuring technique) revealed that K201 specifically bound to recombinant RyR2 fragments 1741 to 2270 and 1981 to 2520 but not to other RyR2 fragments from the 1 to 2750 region (1 to 610, 494 to 1000, 741 to 1260, 985 to 1503, 1245 to 1768, 2234 to 2750). By further analysis of the fragment(1741-2270), K201 was found to specifically bind to its subfragment(2114-2149). With the use of the peptide matching this subfragment (DP(2114-2149)) as a carrier, the RyR2 was fluorescently labeled with methylcoumarin acetate (MCA) in a site-directed manner. After tryptic digestion, the major MCA-labeled fragment of RyR2 (155 kDa) was detected by an antibody raised against the central region (Ab(2132)). Moreover, of several recombinant RyR2 fragments, only fragment(2234-2750) was specifically MCA labeled; this suggests that the K201-binding domain(2114-2149) binds with domain(2234-2750). Addition of DP(2114-2149) to the MCA-labeled sarcoplasmic reticulum interfered with the interaction between domain(2114-2149) and domain(2234-2750), causing domain unzipping, as evidenced by an increased accessibility of the bound MCA to a large-size fluorescence quencher. In failing cardiomyocytes, the frequency of spontaneous Ca2+ spark was markedly increased compared with normal cardiomyocytes, whereas incorporation of DP(2114-2149) markedly decreased the frequency of spontaneous Ca2+ spark.
We first identified the K201-binding site as domain(2114-2149) of RyR2. Interruption of the interdomain interaction between the domain(2114-2149) and central domain(2234-2750) seems to mediate stabilization of RyR2 in failing hearts, which may lead to a novel therapeutic strategy against heart failure and perhaps lethal arrhythmia. |
| doi_str_mv | 10.1161/circulationaha.107.718957 |
| format | Article |
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An assay using a quartz-crystal microbalance technique (a very sensitive mass-measuring technique) revealed that K201 specifically bound to recombinant RyR2 fragments 1741 to 2270 and 1981 to 2520 but not to other RyR2 fragments from the 1 to 2750 region (1 to 610, 494 to 1000, 741 to 1260, 985 to 1503, 1245 to 1768, 2234 to 2750). By further analysis of the fragment(1741-2270), K201 was found to specifically bind to its subfragment(2114-2149). With the use of the peptide matching this subfragment (DP(2114-2149)) as a carrier, the RyR2 was fluorescently labeled with methylcoumarin acetate (MCA) in a site-directed manner. After tryptic digestion, the major MCA-labeled fragment of RyR2 (155 kDa) was detected by an antibody raised against the central region (Ab(2132)). Moreover, of several recombinant RyR2 fragments, only fragment(2234-2750) was specifically MCA labeled; this suggests that the K201-binding domain(2114-2149) binds with domain(2234-2750). Addition of DP(2114-2149) to the MCA-labeled sarcoplasmic reticulum interfered with the interaction between domain(2114-2149) and domain(2234-2750), causing domain unzipping, as evidenced by an increased accessibility of the bound MCA to a large-size fluorescence quencher. In failing cardiomyocytes, the frequency of spontaneous Ca2+ spark was markedly increased compared with normal cardiomyocytes, whereas incorporation of DP(2114-2149) markedly decreased the frequency of spontaneous Ca2+ spark.
We first identified the K201-binding site as domain(2114-2149) of RyR2. Interruption of the interdomain interaction between the domain(2114-2149) and central domain(2234-2750) seems to mediate stabilization of RyR2 in failing hearts, which may lead to a novel therapeutic strategy against heart failure and perhaps lethal arrhythmia.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/circulationaha.107.718957</identifier><identifier>PMID: 18227387</identifier><identifier>CODEN: CIRCAZ</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Amino Acid Sequence ; Animals ; Annexin A5 - chemistry ; Annexin A5 - metabolism ; Binding Sites ; Biological and medical sciences ; Blood and lymphatic vessels ; Calcium - metabolism ; Cardiology. Vascular system ; Cardiovascular system ; Disease Models, Animal ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Dogs ; Heart Failure - metabolism ; Linear Models ; Medical sciences ; Miscellaneous ; Molecular Sequence Data ; Myocytes, Cardiac - metabolism ; Pharmacology. Drug treatments ; Ryanodine Receptor Calcium Release Channel - chemistry ; Ryanodine Receptor Calcium Release Channel - metabolism ; Sarcoplasmic Reticulum ; Sequence Homology, Amino Acid ; Thiazepines - metabolism</subject><ispartof>Circulation (New York, N.Y.), 2008-02, Vol.117 (6), p.762-772</ispartof><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c534t-13bee38654d9d4338e701c5861b4b90344cbd39dc4aafb6e9f3d1667648612f13</citedby><cites>FETCH-LOGICAL-c534t-13bee38654d9d4338e701c5861b4b90344cbd39dc4aafb6e9f3d1667648612f13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3674,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20086626$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18227387$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>YAMAMOTO, Takeshi</creatorcontrib><creatorcontrib>YANO, Masafumi</creatorcontrib><creatorcontrib>XIAOJUAN XU</creatorcontrib><creatorcontrib>UCHINOUMI, Hitoshi</creatorcontrib><creatorcontrib>TATEISHI, Hiroki</creatorcontrib><creatorcontrib>MOCHIZUKI, Mamoru</creatorcontrib><creatorcontrib>ODA, Tetsuro</creatorcontrib><creatorcontrib>KOBAYASHI, Shigeki</creatorcontrib><creatorcontrib>IKEMOTO, Noriaki</creatorcontrib><creatorcontrib>MATSUZAKI, Masunori</creatorcontrib><title>Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>We previously demonstrated that defective interdomain interaction between N-terminal (0 to 600) and central regions (2000 to 2500) of ryanodine receptor 2 (RyR2) induces Ca2+ leak in failing hearts and that K201 (JTV519) inhibits the Ca2+ leak by correcting the defective interdomain interaction. In the present report, we identified the K201-binding domain and characterized the role of this novel domain in the regulation of the RyR2 channel.
An assay using a quartz-crystal microbalance technique (a very sensitive mass-measuring technique) revealed that K201 specifically bound to recombinant RyR2 fragments 1741 to 2270 and 1981 to 2520 but not to other RyR2 fragments from the 1 to 2750 region (1 to 610, 494 to 1000, 741 to 1260, 985 to 1503, 1245 to 1768, 2234 to 2750). By further analysis of the fragment(1741-2270), K201 was found to specifically bind to its subfragment(2114-2149). With the use of the peptide matching this subfragment (DP(2114-2149)) as a carrier, the RyR2 was fluorescently labeled with methylcoumarin acetate (MCA) in a site-directed manner. After tryptic digestion, the major MCA-labeled fragment of RyR2 (155 kDa) was detected by an antibody raised against the central region (Ab(2132)). Moreover, of several recombinant RyR2 fragments, only fragment(2234-2750) was specifically MCA labeled; this suggests that the K201-binding domain(2114-2149) binds with domain(2234-2750). Addition of DP(2114-2149) to the MCA-labeled sarcoplasmic reticulum interfered with the interaction between domain(2114-2149) and domain(2234-2750), causing domain unzipping, as evidenced by an increased accessibility of the bound MCA to a large-size fluorescence quencher. In failing cardiomyocytes, the frequency of spontaneous Ca2+ spark was markedly increased compared with normal cardiomyocytes, whereas incorporation of DP(2114-2149) markedly decreased the frequency of spontaneous Ca2+ spark.
We first identified the K201-binding site as domain(2114-2149) of RyR2. Interruption of the interdomain interaction between the domain(2114-2149) and central domain(2234-2750) seems to mediate stabilization of RyR2 in failing hearts, which may lead to a novel therapeutic strategy against heart failure and perhaps lethal arrhythmia.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Annexin A5 - chemistry</subject><subject>Annexin A5 - metabolism</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Calcium - metabolism</subject><subject>Cardiology. Vascular system</subject><subject>Cardiovascular system</subject><subject>Disease Models, Animal</subject><subject>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</subject><subject>Dogs</subject><subject>Heart Failure - metabolism</subject><subject>Linear Models</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Molecular Sequence Data</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Ryanodine Receptor Calcium Release Channel - chemistry</subject><subject>Ryanodine Receptor Calcium Release Channel - metabolism</subject><subject>Sarcoplasmic Reticulum</subject><subject>Sequence Homology, Amino Acid</subject><subject>Thiazepines - metabolism</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9vEzEUxC0EoqHwFZA5wG2D_9t7jLaURIqoFKXnldd-2xht7GA7h357tiSCI6enGf1m3mEQ-kTJklJFv7qQ3XmyNaRoD3ZJiV5qalqpX6EFlUw0QvL2NVoQQtpGc8Zu0LtSfs5ScS3fohtqGNPc6AU6bTzEGsbg_tThNOK9zU9Q8V062hDLi1MPgDubfbAO755tTD5EwDtwcKop45pwl3IGV3F3sDHChO9CSdlDxiHiexumEJ_wGmyu5T16M9qpwIfrvUWP99_23brZPnzfdKtt4yQXtaF8AOBGSeFbLzg3oAl10ig6iKElXAg3eN56J6wdBwXtyD1VSisxI2yk_BZ9ufSecvp1hlL7YygOpslGSOfSa8IMJUr8F2REtlIZOYPtBXQ5lZJh7E85HG1-7inpX3bpu82ue9yu9puHH6v1arZ1f9llzn68PjkPR_D_ktchZuDzFbDF2WnMNrpQ_nKMEKMUU_w3SniZbw</recordid><startdate>20080212</startdate><enddate>20080212</enddate><creator>YAMAMOTO, Takeshi</creator><creator>YANO, Masafumi</creator><creator>XIAOJUAN XU</creator><creator>UCHINOUMI, Hitoshi</creator><creator>TATEISHI, Hiroki</creator><creator>MOCHIZUKI, Mamoru</creator><creator>ODA, Tetsuro</creator><creator>KOBAYASHI, Shigeki</creator><creator>IKEMOTO, Noriaki</creator><creator>MATSUZAKI, Masunori</creator><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>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7X8</scope></search><sort><creationdate>20080212</creationdate><title>Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts</title><author>YAMAMOTO, Takeshi ; YANO, Masafumi ; XIAOJUAN XU ; UCHINOUMI, Hitoshi ; TATEISHI, Hiroki ; MOCHIZUKI, Mamoru ; ODA, Tetsuro ; KOBAYASHI, Shigeki ; IKEMOTO, Noriaki ; MATSUZAKI, Masunori</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c534t-13bee38654d9d4338e701c5861b4b90344cbd39dc4aafb6e9f3d1667648612f13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Annexin A5 - chemistry</topic><topic>Annexin A5 - metabolism</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Calcium - metabolism</topic><topic>Cardiology. Vascular system</topic><topic>Cardiovascular system</topic><topic>Disease Models, Animal</topic><topic>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</topic><topic>Dogs</topic><topic>Heart Failure - metabolism</topic><topic>Linear Models</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Molecular Sequence Data</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Ryanodine Receptor Calcium Release Channel - chemistry</topic><topic>Ryanodine Receptor Calcium Release Channel - metabolism</topic><topic>Sarcoplasmic Reticulum</topic><topic>Sequence Homology, Amino Acid</topic><topic>Thiazepines - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>YAMAMOTO, Takeshi</creatorcontrib><creatorcontrib>YANO, Masafumi</creatorcontrib><creatorcontrib>XIAOJUAN XU</creatorcontrib><creatorcontrib>UCHINOUMI, Hitoshi</creatorcontrib><creatorcontrib>TATEISHI, Hiroki</creatorcontrib><creatorcontrib>MOCHIZUKI, Mamoru</creatorcontrib><creatorcontrib>ODA, Tetsuro</creatorcontrib><creatorcontrib>KOBAYASHI, Shigeki</creatorcontrib><creatorcontrib>IKEMOTO, Noriaki</creatorcontrib><creatorcontrib>MATSUZAKI, Masunori</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>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>YAMAMOTO, Takeshi</au><au>YANO, Masafumi</au><au>XIAOJUAN XU</au><au>UCHINOUMI, Hitoshi</au><au>TATEISHI, Hiroki</au><au>MOCHIZUKI, Mamoru</au><au>ODA, Tetsuro</au><au>KOBAYASHI, Shigeki</au><au>IKEMOTO, Noriaki</au><au>MATSUZAKI, Masunori</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2008-02-12</date><risdate>2008</risdate><volume>117</volume><issue>6</issue><spage>762</spage><epage>772</epage><pages>762-772</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><coden>CIRCAZ</coden><abstract>We previously demonstrated that defective interdomain interaction between N-terminal (0 to 600) and central regions (2000 to 2500) of ryanodine receptor 2 (RyR2) induces Ca2+ leak in failing hearts and that K201 (JTV519) inhibits the Ca2+ leak by correcting the defective interdomain interaction. In the present report, we identified the K201-binding domain and characterized the role of this novel domain in the regulation of the RyR2 channel.
An assay using a quartz-crystal microbalance technique (a very sensitive mass-measuring technique) revealed that K201 specifically bound to recombinant RyR2 fragments 1741 to 2270 and 1981 to 2520 but not to other RyR2 fragments from the 1 to 2750 region (1 to 610, 494 to 1000, 741 to 1260, 985 to 1503, 1245 to 1768, 2234 to 2750). By further analysis of the fragment(1741-2270), K201 was found to specifically bind to its subfragment(2114-2149). With the use of the peptide matching this subfragment (DP(2114-2149)) as a carrier, the RyR2 was fluorescently labeled with methylcoumarin acetate (MCA) in a site-directed manner. After tryptic digestion, the major MCA-labeled fragment of RyR2 (155 kDa) was detected by an antibody raised against the central region (Ab(2132)). Moreover, of several recombinant RyR2 fragments, only fragment(2234-2750) was specifically MCA labeled; this suggests that the K201-binding domain(2114-2149) binds with domain(2234-2750). Addition of DP(2114-2149) to the MCA-labeled sarcoplasmic reticulum interfered with the interaction between domain(2114-2149) and domain(2234-2750), causing domain unzipping, as evidenced by an increased accessibility of the bound MCA to a large-size fluorescence quencher. In failing cardiomyocytes, the frequency of spontaneous Ca2+ spark was markedly increased compared with normal cardiomyocytes, whereas incorporation of DP(2114-2149) markedly decreased the frequency of spontaneous Ca2+ spark.
We first identified the K201-binding site as domain(2114-2149) of RyR2. Interruption of the interdomain interaction between the domain(2114-2149) and central domain(2234-2750) seems to mediate stabilization of RyR2 in failing hearts, which may lead to a novel therapeutic strategy against heart failure and perhaps lethal arrhythmia.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>18227387</pmid><doi>10.1161/circulationaha.107.718957</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Sequence Animals Annexin A5 - chemistry Annexin A5 - metabolism Binding Sites Biological and medical sciences Blood and lymphatic vessels Calcium - metabolism Cardiology. Vascular system Cardiovascular system Disease Models, Animal Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Dogs Heart Failure - metabolism Linear Models Medical sciences Miscellaneous Molecular Sequence Data Myocytes, Cardiac - metabolism Pharmacology. Drug treatments Ryanodine Receptor Calcium Release Channel - chemistry Ryanodine Receptor Calcium Release Channel - metabolism Sarcoplasmic Reticulum Sequence Homology, Amino Acid Thiazepines - metabolism |
| title | Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts |
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