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Tytuł:
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Identification and functional study of genetic polymorphisms in cyclic nucleotide phosphodiesterase 3A (PDE3A).
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Autorzy:
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Kim YR; Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University, Busan, South Korea.
Yi M; Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University, Busan, South Korea.; Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Cho SA; Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University, Busan, South Korea.
Kim WY; Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University, Busan, South Korea.
Min J; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
Shin JG; Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University, Busan, South Korea.; Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Inje University College of Medicine, Inje University, Busan, 47392, South Korea.
Lee SJ; Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University, Busan, South Korea.
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Źródło:
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Annals of human genetics [Ann Hum Genet] 2021 Mar; Vol. 85 (2), pp. 80-91. Date of Electronic Publication: 2020 Nov 28.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: <2010-> : Oxford : Wiley-Blackwell
Original Publication: Oxford : Blackwell
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MeSH Terms:
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Cilostazol/*administration & dosage
Cyclic AMP/*genetics
Cyclic Nucleotide Phosphodiesterases, Type 3/*genetics
Platelet Activation/*drug effects
Adult ; Blood Platelets/drug effects ; Cilostazol/adverse effects ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Mutation, Missense/genetics ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Platelet Activation/genetics ; Platelet Aggregation Inhibitors/administration & dosage ; Platelet Aggregation Inhibitors/adverse effects ; Polymorphism, Genetic/genetics ; Signal Transduction/drug effects ; Exome Sequencing
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References:
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Grant Information:
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Z99 ES999999 United States ImNIH Intramural NIH HHS
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Contributed Indexing:
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Keywords: adenylyl cyclase; cilostazol; genetic polymorphisms; phosphodiesterase 3A (PDE3A); single nucleotide polymorphism
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Substance Nomenclature:
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0 (Platelet Aggregation Inhibitors)
E0399OZS9N (Cyclic AMP)
EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
EC 3.1.4.17 (PDE3A protein, human)
N7Z035406B (Cilostazol)
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Entry Date(s):
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Date Created: 20201129 Date Completed: 20210802 Latest Revision: 20230530
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Update Code:
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20240105
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PubMed Central ID:
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PMC10225158
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DOI:
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10.1111/ahg.12411
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PMID:
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33249558
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Phosphodiesterase 3A (PDE3A) is an enzyme that plays an important role in the regulation of cyclic adenosine monophosphate (cAMP)-mediated intracellular signaling in cardiac myocytes and platelets. PDE3A hydrolyzes cAMP, which results in a decrease in intracellular cAMP levels and leads to platelet activation. Whole-exome sequencing of 50 DNA samples from a healthy Korean population revealed a total of 13 single nucleotide polymorphisms including five missense variants, D12N, Y497C, H504Q, C707R, and A980V. Recombinant proteins for the five variants of PDE3A (and wild-type protein) were expressed in a FreeStyle 293 expression system with site-directed mutagenesis. The expression of the recombinant PDE3A proteins was confirmed with Western blotting. Catalytic activity of the PDE3A missense variants and wild-type enzyme was measured with a PDE-based assay. Effects of the missense variants on the inhibition of PDE3A activity by cilostazol were also investigated. All variant proteins showed reduced activity (33-53%; p < .0001) compared to the wild-type protein. In addition, PDE3A activity was inhibited by cilostazol in a dose-dependent manner and was further suppressed in the missense variants. Specifically, the PDE3A Y497C showed significantly reduced activity, consistent with the predictions of in silico analyses. The present study provides evidence that individuals carrying the PDE3A Y497C variant may have lower enzyme activity for cAMP hydrolysis, which could cause interindividual variation in cAMP-mediated physiological functions.
(© 2020 John Wiley & Sons Ltd/University College London.)
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