Light-gated ion channels (channelrhodopsins; ChR) can be used to precisely control the electrical activity of genetically targeted cell populations with light. While non-selective cation ChR are widely used to elicit action potentials (AP) in excitable cells, the recently identified class of K+-selective ChR (KCR) are promising tools for optogenetic AP inhibition. One of the most K+-selective KCR identified to date is Wobblia lunata inhibitory ChR (WiChR), which - by combining high light sensitivity and prolonged channel opening with efficient expression in neurons and cardiomyocytes - enables reliable suppression of AP firing in response to blue light pulses. However, a detailed understanding of WiChR photoactivation and its conducting states has so far been missing. Here, we introduce the first model of the WiChR photocycle, designed to quantitatively reproduce and predict its photocurrents, as well as resulting changes in membrane voltage. We combined electrophysiological recordings with simultaneous imaging of intracellular K+ concentration under varied light-stimulation protocols that serve as a basis for computational modelling of putative photocycle transitions. We show that WiChR photocurrents can be fully described by a simple unbranched photocycle model, composed of two closed and two open states of near-constant high K+ selectivity, which are further shaped by changes in intracellular K+ concentration during extended illumination. These changes are promoted by the large photocurrent amplitudes observed in WiChR-expressing cells, and differ substantially among individual cells and across cell types, underlining the importance of the optogenetically targeted host system. Our model presents a framework for assessing and predicting WiChR photoresponses, and will be useful for guiding the design of optimized stimulation protocols for future application of WiChR and other KCR.
Ohnemus et al. (2026) studied this question.