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| Content Provider | Springer Nature Link |
|---|---|
| Author | López Izquierdo, Angélica Aréchiga Figueroa, Iván A. More Galindo, Eloy G. Ponce Balbuena, Daniela Rodríguez Martínez, Martín Ferrer Villada, Tania Rodríguez Menchaca, Aldo A. Heyden, Marcel A G Sánchez Chapula, José A. |
| Copyright Year | 2011 |
| Abstract | Cardiac inward rectifier potassium currents determine the resting membrane potential and contribute repolarization capacity during phase 3 repolarization. Quinacrine is a cationic amphiphilic drug. In this work, the effects of quinacrine were studied on cardiac Kir channels expressed in HEK 293 cells and on the inward rectifier potassium currents, IK1 and IKATP, in cardiac myocytes. We found that quinacrine differentially inhibited Kir channels, Kir6.2 ∼ Kir2.3 > Kir2.1. In addition, we found in cardiac myocytes that quinacrine inhibited IKATP > IK1. We presented evidence that quinacrine displays a double action towards strong inward rectifier Kir2.x channels, i.e., direct pore block and interference in phosphatidylinositol 4,5-bisphosphate, PIP2–Kir channel interaction. Pore block is evident in Kir2.1 and 2.3 channels as rapid block; channel block involves residues E224 and E299 facing the cytoplasmic pore of Kir2.1. The interference of the drug with the interaction of Kir2.x and Kir6.2/SUR2A channels and PIP2 is suggested from four sources of evidence: (1) Slow onset of current block when quinacrine is applied from either the inside or the outside of the channel. (2) Mutation of Kir2.3(I213L) and mutation of Kir6.2(C166S) increase their affinity for PIP2 and lowers its sensitivity for quinacrine. (3) Mutations of Kir2.1(L222I and K182Q) which decreased its affinity for PIP2 increased its sensitivity for quinacrine. (4) Co-application of quinacrine with PIP2 lowers quinacrine-mediated current inhibition. In conclusion, our data demonstrate how an old drug provides insight into a dual a blocking mechanism of Kir carried inward rectifier channels. |
| Starting Page | 505 |
| Ending Page | 517 |
| Page Count | 13 |
| File Format | |
| ISSN | 00316768 |
| Journal | Pflügers Archiv |
| Volume Number | 462 |
| Issue Number | 4 |
| e-ISSN | 14322013 |
| Language | English |
| Publisher | Springer-Verlag |
| Publisher Date | 2011-07-22 |
| Publisher Place | Berlin, Heidelberg |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Quinacrine Inward rectifier potassium channels Phosphatidylinositol 4,5-bisphosphate, PIP2 Kir2.1 Kir2.3 Kir6.2 Human Physiology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Physiology Physiology (medical) Clinical Biochemistry |
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