AbstractThe current optogenetic toolkit lacks a robust single-component Ca²⁺-selective ion channel tailored for remote control of Ca²⁺ signaling in mammals. Existing tools are either derived from engineered channelrhodopsin variants without strict Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ signals and hallmark Ca²⁺-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.