Please use this identifier to cite or link to this item:
|Author(s):||Harley, Carol A|
Jones, David K
Fernandes, Andreia S
Robertson, Gail A
|Title:||Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain|
|Publisher:||National Academy of Sciences|
|Abstract:||The human human ether-à-go-go-related gene (hERG) potassium channel plays a critical role in the repolarization of the cardiac action potential. Changes in hERG channel function underlie long QT syndrome (LQTS) and are associated with cardiac arrhythmias and sudden death. A striking feature of this channel and KCNH channels in general is the presence of an N-terminal Per-Arnt-Sim (PAS) domain. In other proteins, PAS domains bind ligands and modulate effector domains. However, the PAS domains of KCNH channels are orphan receptors. We have uncovered a family of positive modulators of hERG that specifically bind to the PAS domain. We generated two single-chain variable fragments (scFvs) that recognize different epitopes on the PAS domain. Both antibodies increase the rate of deactivation but have different effects on channel activation and inactivation. Importantly, we show that both antibodies, on binding to the PAS domain, increase the total amount of current that permeates the channel during a ventricular action potential and significantly reduce the action potential duration recorded in human cardiomyocytes. Overall, these molecules constitute a previously unidentified class of positive modulators and establish that allosteric modulation of hERG channel function through ligand binding to the PAS domain can be attained.|
|Source:||Proceedings of the National Academy of Sciences, vol. 113(35), p.9916-21|
|Document Type:||Artigo em Revista Científica Internacional|
|Appears in Collections:||I3S - Artigo em Revista Científica Internacional|
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.