Biophysics of ion channel kinetics and state dependent inhibition
Please notice these positions are no longer vacant.

Gating kinetics and drug-channel interaction
L-type calcium channels are the therapeutic targets for calcium antagonists. These compounds block L-channels more efficiently in the open and/or inactivated states. Mutational analysis provided first insights into the location of the drug binding and gating determinants. Variations in channel inactivation affect the rates of drug binding and dissociation. Co-expression of Cav1.2 with different β subunits modulating inactivation is of particular interest: changes in inactivation are accompanied by changes in the drug affinity while the drug-binding pocket remains unchanged. We investigate drug binding and dissociation processes. We will focus on the most intriguing process: how drug molecules escape from the closed channel conformation (dissociation of trapped drugs). We expect that systematic study of trapping and escaping will shad the light onto molecular mechanisms of interaction of blockers with the channel pore.

Physico-chemical properties of drug molecule and block of HERG channels.
HERG channel blockers bind to their putative receptor site in the pore in the open and inactivated channel conformations. Channel closure may "trap" a drug molecule inside the channel and delay or even prevent drug dissociation at rest. Slow recovery from block suggests that drug dissociation from HERG channels is determined by the conformational state. We will analyse dissociation of various HERG blockers from the closed channel conformation under different conditions (e.g. different membrane voltages and temperature) and also make use of HERG channels with mutations in the gating structures.