Optogenetic toolkit for precise control of calcium signaling

Calcium acts as a second messenger to regulate a myriad of cell functions, ranging from short-term muscle contraction and cell motility to long-term changes in gene expression and metabolism. To study the impact of Ca²⁺-modulated 'ON' and 'OFF' reactions in mammalian cells, pharmacological tools and 'caged' compounds are commonly used under various experimental conditions. The use of these reagents for precise control of Ca²⁺ signals, nonetheless, is impeded by lack of reversibility and specificity. The recently developed optogenetic tools, particularly those built upon engineered Ca²⁺ release-activated Ca²⁺ (CRAC) channels, provide exciting opportunities to remotely and non-invasively modulate Ca²⁺ signaling due to their superior spatiotemporal resolution and rapid reversibility. In this review, we briefly summarize the latest advances in the development of optogenetic tools (collectively termed as 'genetically encoded Ca²⁺ actuators', or GECAs) that are tailored for the interrogation of Ca²⁺ signaling, as well as their applications in remote neuromodulation and optogenetic immunomodulation. Our goal is to provide a general guide to choosing appropriate GECAs for optical control of Ca²⁺ signaling in cellulo, and in parallel, to stimulate further thoughts on evolving non-opsin-based optogenetics into a fully fledged technology for the study of Ca²⁺-dependent activities in vivo.