Abstract
Kv1.5 channels carry ultra-rapid delayed rectifier K+ currents in excitable cells, including neurons and cardiac myocytes. In the current study, the effects of cholinesterase inhibitor donepezil on cloned Kv1.5 channels expressed in HEK29 cells were explored using whole-cell recording technique. Exposure to donepezil resulted in a rapid and reversible block of Kv1.5 currents, with an IC50 value of 72.5 μM. The mutant R476V significantly reduced the binding affinity of donepezil to Kv1.5 channels, showing the target site in the outer mouth region. Donepezil produced a significant delay in the duration of activation and deactivation, and mutant R476V potentiated these effects without altering activation curves. In response to slowed deactivation time course, a typical crossover of Kv1.5 tail currents was clearly evident after bath application of donepezil. In addition, both this chemical and mutant R476V accelerated current decay during channel inactivation in a voltage-dependent way, but barely changed the inactivation and recovery curves. The presence of donepezil exhibited the use-dependent block of Kv1.5 currents in response to a series of depolarizing pulses. Our data indicate that donepezil can directly block Kv1.5 channels in its open and closed states.
Highlights
We examined the actions of donepezil on the recovery rate of Kv1.5 channels using a dual pulse protocol
We showed a result that donepezil, a potent inhibitor of acetylcholinesterase, blocked Kv1.5 channels expressed in HEK293 cells in voltage- and concentration-dependent ways
Earlier publications unfold that chemicals, such as nifedipine[24] and celecoxib[32], have an inhibitory effect on both closed and open states of Kv2.1 channels
Summary
The effect of 80 μM donepezil on R476V variant currents was significantly weaker than that on wild type currents (n = 5, Student’s t-test, p < 0.05), suggesting that the outer mouth of Kv1.5 channels is the binding site of this chemical. At a holding potential of −80 mV, the deactivation tail currents were elicited by a series of 500 ms test pulses from −110 mV to −40 mV after a conditioning prepulse of +40 mV.
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