Engineering of a bona fide light-operated calcium channel.

The current optogenetic toolkit lacks a robust single-component Ca-selective ion channel tailored for remote control of Ca signaling in mammals. Existing tools are either derived from engineered channelrhodopsin variants without strict Ca selectivity or based on the stromal interaction molecule 1 (STIM1) that might crosstalk with other targets. Here, we describe the design of a light-operated Ca channel (designated LOCa) by inserting a plant-derived photosensory module into the intracellular loop of an engineered ORAI1 channel. LOCa displays biophysical features reminiscent of the ORAI1 channel, which enables precise optical control over Ca signals and hallmark Ca-dependent physiological responses. Furthermore, we demonstrate the use of LOCa to modulate aberrant hematopoietic stem cell self-renewal, transcriptional programming, cell suicide, as well as neurodegeneration in a Drosophila model of amyloidosis.