Kv11.1 channel (hERG) and the corresponding IKr current is a major component of cardiac repolarization and sinoatrial pacemaking. Dysfunctions in hERG channels are associated with cardiac arrhythmias and remains a driving force to study the structure, biophysics and pharmacology of this channel. Several compounds that block hERG channels have been developed. In this study, we focused on BeKm-1, a toxin which is highly selective for the hERG channel.

To study hERG channels at high temporal and spatial resolution, we developed a photo-protected analog of BeKm-1 that enables control of hERG using light.

We developed a photo-protected BeKm-1 analog (BeKm-1-Lys18Nvoc) which is cleaved by UV-light at 365nm. Using a hERG stable cell line and high-throughput automated patch-clamp (Syncropatch 384, Nanion) we validated several properties of the BeKm-1 analog blockage. To demonstrate spatial control of cardiomyocyte function, hiPS-derived cardiomyocytes were plated on CardioExcyte96 to record extrafield potentials.

We first validated physico-chemical properties of BeKm-1-Nvoc compared to BeKm-1 using HPLC analyses. Patch-clamp experiments displayed no inhibition of hERG current by BeKm-1-Nvoc at concentrations for which wild-type Bekm-1 is maximally inhibiting. Illumination of BeKm-1-Nvoc (100nM) at 365nm allows cleavage of the protecting group and strong inhibition of hERG current. The block of hERG is reversible after washes. Illumination of BeKm-1-Nvoc on hiPS-derived cardiomyocytes induces prolongation of extrafied potential which reflects an increase in repolarization time. Study of effects of photoactivation of BeKm-1 on mouse and zebrafish heart rates are ongoing.

We developed for the first time a photo-sensitive blocker of endogenous hERG channel which allows control of its activity with the spatiotemporal precision of light. Studies of implication of hERG on arrhythmias using this compound are ongoing.