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Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome.
Song, LouJin; Park, Seon-Hye E; Isseroff, Yehuda; Morikawa, Kumi; Yazawa, Masayuki.
Afiliación
  • Song L; Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, NY 10032, USA; Department of Pharmacology, Columbia University, New York, NY 10032, USA.
  • Park SE; Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, NY 10032, USA.
  • Isseroff Y; Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, NY 10032, USA; College of Dental Medicine, Columbia University, New York, NY 10032, USA.
  • Morikawa K; Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, NY 10032, USA.
  • Yazawa M; Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, NY 10032, USA; Department of Pharmacology, Columbia University, New York, NY 10032, USA. Electronic address: my2387@cumc.columbia.edu.
Stem Cell Reports ; 9(1): 50-57, 2017 07 11.
Article en En | MEDLINE | ID: mdl-28648896
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Purinas / Trastorno Autístico / Síndrome de QT Prolongado / Sindactilia / Miocitos Cardíacos / Inhibidores de Proteínas Quinasas / Quinasa 5 Dependiente de la Ciclina Límite: Humans Idioma: En Revista: Stem Cell Reports Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Purinas / Trastorno Autístico / Síndrome de QT Prolongado / Sindactilia / Miocitos Cardíacos / Inhibidores de Proteínas Quinasas / Quinasa 5 Dependiente de la Ciclina Límite: Humans Idioma: En Revista: Stem Cell Reports Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos