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Protein Kinase A-Dependent Biophysical Phenotype for V227F-KCNJ2 Mutation in Catecholaminergic Polymorphic Ventricular Tachycardia
| Content Provider | Scilit |
|---|---|
| Author | Vega, Amanda L. Tester, David J. Ackerman, Michael J. Makielski, Jonathan C. |
| Copyright Year | 2009 |
| Description | Journal: Circulation: Arrhythmia and Electrophysiology Background— KCNJ2 encodes Kir2.1, a pore-forming subunit of the cardiac inward rectifier current, I$ _{K1}$ . KCNJ2 mutations are associated with Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia. The aim of this study was to characterize the biophysical and cellular phenotype of a KCNJ2 missense mutation, V227F, found in a patient with catecholaminergic polymorphic ventricular tachycardia. Methods and Results— Kir2.1-wild-type (WT) and V227F channels were expressed individually and together in Cos-1 cells to measure I$ _{K1}$ by voltage clamp. Unlike typical Andersen-Tawil syndrome-associated KCNJ2 mutations, which show dominant negative loss of function, Kir2.1WT+V227F coexpression yielded I$ _{K1}$ indistinguishable from Kir2.1-WT under basal conditions. To simulate catecholamine activity, a protein kinase A (PKA)-stimulating cocktail composed of forskolin and 3-isobutyl-1-methylxanthine was used to increase PKA activity. This PKA-simulated catecholaminergic stimulation caused marked reduction of outward I$ _{K1}$ compared with Kir2.1-WT. PKA-induced reduction in I$ _{K1}$ was eliminated by mutating the phosphorylation site at serine 425 (S425N). Conclusions— Heteromeric Kir2.1-V227F and WT channels showed an unusual latent loss of function biophysical phenotype that depended on PKA-dependent Kir2.1 phosphorylation. This biophysical phenotype, distinct from typical Andersen-Tawil syndrome mutations, suggests a specific mechanism for PKA-dependent I$ _{K1}$ dysfunction for this KCNJ2 mutation, which correlates with adrenergic conditions underlying the clinical arrhythmia. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766080/pdf https://www.ahajournals.org/doi/pdf/10.1161/CIRCEP.109.872309 |
| Ending Page | 547 |
| Page Count | 8 |
| Starting Page | 540 |
| ISSN | 19413149 |
| e-ISSN | 19413084 |
| DOI | 10.1161/circep.109.872309 |
| Journal | Circulation: Arrhythmia and Electrophysiology |
| Issue Number | 5 |
| Volume Number | 2 |
| Language | English |
| Publisher | Ovid Technologies (Wolters Kluwer Health) |
| Publisher Date | 2009-10-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Circulation: Arrhythmia and Electrophysiology Peripheral Vascular Disease Arrhythmia (mechanisms) Andersen-tawil Syndrome Catecholaminergic Polymorphic Ventricular Tachycardia |
| Content Type | Text |
| Resource Type | Article |
| Subject | Physiology (medical) Cardiology and Cardiovascular Medicine |
