Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome
L-type calcium channel CaV1.2 plays an essential role in cardiac function. The gain-of-function mutations in CaV1.2 have been reported to be associated with Timothy syndrome, a disease characterized by QT prolongation and syndactyly. Previously we demonstrated that roscovitine, a cyclin-dependent ki...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-07-01
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| Series: | Stem Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671117302357 |
| _version_ | 1811227380959674368 |
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| author | LouJin Song Seon-hye E. Park Yehuda Isseroff Kumi Morikawa Masayuki Yazawa |
| author_facet | LouJin Song Seon-hye E. Park Yehuda Isseroff Kumi Morikawa Masayuki Yazawa |
| author_sort | LouJin Song |
| collection | DOAJ |
| description | L-type calcium channel CaV1.2 plays an essential role in cardiac function. The gain-of-function mutations in CaV1.2 have been reported to be associated with Timothy syndrome, a disease characterized by QT prolongation and syndactyly. Previously we demonstrated that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the phenotypes in induced pluripotent stem cell-derived cardiomyocytes from Timothy syndrome patients. However, exactly how roscovitine rescued the phenotypes remained unclear. Here we report a mechanism potentially underlying the therapeutic effects of roscovitine on Timothy syndrome cardiomyocytes. Our results using roscovitine analogs and CDK inhibitors and constructs demonstrated that roscovitine exhibits its therapeutic effects in part by inhibiting CDK5. The outcomes of this study allowed us to identify a molecular mechanism whereby CaV1.2 channels are regulated by CDK5. This study provides insights into the regulation of cardiac calcium channels and the development of future therapeutics for Timothy syndrome patients. |
| first_indexed | 2024-04-12T09:41:37Z |
| format | Article |
| id | doaj.art-e83c48c9291d40b38fd509cbf4f957e1 |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-04-12T09:41:37Z |
| publishDate | 2017-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-e83c48c9291d40b38fd509cbf4f957e12022-12-22T03:38:04ZengElsevierStem Cell Reports2213-67112017-07-0191505710.1016/j.stemcr.2017.05.028Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy SyndromeLouJin Song0Seon-hye E. Park1Yehuda Isseroff2Kumi Morikawa3Masayuki Yazawa4Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USAColumbia Stem Cell Initiative, Columbia University, New York, NY 10032, USAColumbia Stem Cell Initiative, Columbia University, New York, NY 10032, USAColumbia Stem Cell Initiative, Columbia University, New York, NY 10032, USAColumbia Stem Cell Initiative, Columbia University, New York, NY 10032, USAL-type calcium channel CaV1.2 plays an essential role in cardiac function. The gain-of-function mutations in CaV1.2 have been reported to be associated with Timothy syndrome, a disease characterized by QT prolongation and syndactyly. Previously we demonstrated that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the phenotypes in induced pluripotent stem cell-derived cardiomyocytes from Timothy syndrome patients. However, exactly how roscovitine rescued the phenotypes remained unclear. Here we report a mechanism potentially underlying the therapeutic effects of roscovitine on Timothy syndrome cardiomyocytes. Our results using roscovitine analogs and CDK inhibitors and constructs demonstrated that roscovitine exhibits its therapeutic effects in part by inhibiting CDK5. The outcomes of this study allowed us to identify a molecular mechanism whereby CaV1.2 channels are regulated by CDK5. This study provides insights into the regulation of cardiac calcium channels and the development of future therapeutics for Timothy syndrome patients.http://www.sciencedirect.com/science/article/pii/S2213671117302357cardiac arrhythmiaiPSCdisease modelingcalcium handlingdrug testTimothy syndromeCDK5 |
| spellingShingle | LouJin Song Seon-hye E. Park Yehuda Isseroff Kumi Morikawa Masayuki Yazawa Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome Stem Cell Reports cardiac arrhythmia iPSC disease modeling calcium handling drug test Timothy syndrome CDK5 |
| title | Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome |
| title_full | Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome |
| title_fullStr | Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome |
| title_full_unstemmed | Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome |
| title_short | Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome |
| title_sort | inhibition of cdk5 alleviates the cardiac phenotypes in timothy syndrome |
| topic | cardiac arrhythmia iPSC disease modeling calcium handling drug test Timothy syndrome CDK5 |
| url | http://www.sciencedirect.com/science/article/pii/S2213671117302357 |
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