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. 2008 May;131(5):399-405.
doi: 10.1085/jgp.200709946. Epub 2008 Apr 14.

Ion channels as drug targets: the next GPCRs

Gregory J Kaczorowski  1 , Owen B McManus, Birgit T Priest, Maria L Garcia
Affiliations

Ion channels as drug targets: the next GPCRs

Gregory J Kaczorowski et al. J Gen Physiol. 2008 May.
No abstract available

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Figures

Figure 1.
Figure 1.
A functional, membrane potential FRET-based assay for Nav1.7 channels. In the absence of other ionic conductances that can hyperpolarize the cell, heterologous expression of Nav1.7 channels provides a system where at the cell resting membrane potential most channels will reside in the nonconducting inactivated state. Removal of fast inactivation by the addition of veratridine shifts the channel's equilibrium to the conductive, open state that allows sodium entry leading to cell depolarization. The changes in voltage can be monitored with a pair of FRET voltage-sensing dyes, coumarin and oxonol. Cell depolarization alters the distribution of oxonol across the membrane, causing a change in the FRET signal. In the presence of a Nav1.7 inhibitor, channel equilibrium shifts toward the inactivated, drug-bound conformation, reducing the number of channels that will be available for veratridine modification, and preventing the agonist-induced FRET signal. The dose–response curve for the veratridine-induced change in FRET signal is steep, suggesting that modification of a small number of Nav1.7 channels is sufficient to cause cell depolarization.
Figure 2.
Figure 2.
1-Benzazepin-2-one Nav1 inhibitors. The structures of two 1-benzazepin-2-one Nav1 inhibitors are illustrated together with their potencies for hNav1.5, hNav1.7, and hNav1.8 channels as determined in functional membrane potential, FRET-based assays. The estimated potencies of these compounds for the inactivated state of hNav1.5 and hNav1.7 channels, as determined from electrophysiological recordings, are also presented. Note that only compound 2 displays selectivity for the hNav1.7 channel. Both compounds are weaker inhibitors of the hNav1.8 channel.
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