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Analytical biochemistry (1)
Molecular and cellular neurosciences (1)
Beacham, Daniel (2)
Austin, Christopher P. (1)
Catterall, William A. (1)
Chen, Yuan (1)
Hooten, Elizabeth (1)
Huang, Ruili (1)
Scheuer, Todd (1)
Shahane, Sampada A. (1)
Sharp, Elizabeth M. (1)
Shou, Louie (1)
Southall, Noel (1)
Titus, Steven A. (1)
Xia, Menghang (1)
Yu, Frank H. (1)
Zhao, Yong (1)
Zheng, Wei (1)
Year of Publication
Functional Properties and Differential Neuromodulation of Nav1.6 Channels
Yu, Frank H.
Sharp, Elizabeth M.
Catterall, William A.
Molecular and cellular neurosciences
The voltage-gated sodium channel Nav1.6 plays unique roles in the nervous system, but its functional properties and neuromodulation are not as well established as for NaV1.2 channels. We found no significant differences in voltage-dependent activation or fast inactivation between NaV1.6 and NaV1.2 channels expressed in non-excitable cells. In contrast, the voltage dependence of slow inactivation was more positive for Nav1.6 channels, they conducted substantially larger persistent sodium currents than Nav1.2 channels, and they were much less sensitive to inhibtion by phosphorylation by cAMP-dependent protein kinase and protein kinase C. Resurgent sodium current, a hallmark of Nav1.6 channels in neurons, was not observed for NaV1.6 expressed alone or with the auxiliary β4 subunit. The unique properties of NaV1.6 channels, together with the resurgent currents that they conduct in neurons, make these channels well-suited to provide the driving force for sustained repetitive firing, a crucial property of neurons.
A new homogeneous high-throughput screening assay for profiling compound activity on the human ether-a-go-go-related gene channel
Titus, Steven A.
Shahane, Sampada A.
Austin, Christopher P.
Long QT syndrome, either inherited or acquired from drug treatments, can result in ventricular arrhythmia (torsade de pointes) and sudden death. Human ether-a-go-go-related gene (hERG) channel inhibition by drugs is now recognized as a common reason for the acquired form of long QT syndrome. It has been reported that more than 100 known drugs inhibit the activity of the hERG channel. Since 1997, several drugs have been withdrawn from the market due to the long QT syndrome caused by hERG inhibition. Food and Drug Administration regulations now require safety data on hERG channels for investigative new drug (IND) applications. The assessment of compound activity on the hERG channel has now become an important part of the safety evaluation in the process of drug discovery. During the past decade, several in vitro assay methods have been developed and significant resources have been used to characterize hERG channel activities. However, evaluation of compound activities on hERG have not been performed for large compound collections due to technical difficulty, lack of throughput, and/or lack of biological relevance to function. Here we report a modified form of the FluxOR thallium flux assay, capable of measuring hERG activity in a homogeneous 1536-well plate format. To validate the assay, we screened a 7-point dilution series of the LOPAC 1280 library collection and reported rank order potencies of ten common hERG inhibitors. A correlation was also observed for the hERG channel activities of 10 known hERG inhibitors determined in this thallium flux assay and in the patch clamp experiment. Our findings indicate that this thallium flux assay can be used as an alternative method to profile large-volume compound libraries for compound activity on the hERG channel.
Human ether-a-go-go-related gene (hERG); Quantitative high-throughput screening; (qHTS); FluxOR; Thallium flux; Baculovirus; BacMam
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