Development of a light-switchable Orai1 channel and its applications in the drosophila model of Alzheimer’s disease

As important regulators of cell function, CRAC channels have been implicated in a myriad of human disorders．Optogenetic tools provide opportunities to remotely and noninvasively control CRAC channels with high spatiotemporal precision and rapid reversibility．However, the application of existing optogenetic toolkits is impeded by some drawbacks, such as absolute requirement of endogenous ORAI channels or easily crosstalk with other targets．To overcome these hurdles, we introduce a single-component, blue-light operated calcium channel (LOCa) by directly installing the LOV2 photoswitch into engineered Orai1 channels．Similar to CRAC channels, LOCa is highly selective for Ca²⁺．Without the need for extra cofactors, LOCa enables optical control of Ca²⁺ influx in a reversible manner．We applied LOCa to maintain the self-renewal of hematopoietic stem cells (HSCs), and established the feasibility of alleviating neurodegeneration syndromes with light in a drosophila model of amyloidosis, showing its potential as a novel interventional approach for CRAC related diseases．