hERG inhibition

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zang's picture
hERG inhibition

In general, 2 voltage steps protocol is used for hERG assay.
Sometimes, I can see little effect of drug on the hERG current evoked by the 1st voltage step (+20 mV), but a huge inhibitory effect on the current evoked by 2nd voltage step (-50 mV).
How can I interpret this? Or, something wrong?

The FFM's picture
 The drug might be activity

 The drug might be activity dependent - in particular binding preferentially to the inactivated state.

In the first voltage step you are going from closed to open and rapidly to an inactivated state.  

In the second step you are going rapidly from an inactivated to an open state followed by a slow deactivation to closed state.

If the drug binds to the inactivated state then it will block while the cell is depolarized and the hERGs are inactivated and you will not see this effect on the first step of your protocol.  Upon hyperpolarization/repolarization where you would normally elicit a current when the channel goes from inactivated to open state, you see inhibited current as the drug inhibits the transition out of the inactivated state.