As a versatile intracellular second messenger, calcium ion (Ca2+) regulates a plethora of physiological processes. To achieve precise control over Ca2+ signals in living cells and organisms, a set of optogenetic tools have recently been crafted by engineering photosensitive domains into intracellular signaling proteins, G-protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), and Ca2+ channels. We highlight herein the optogenetic engineering strategies, kinetic properties, advantages and limitations of these genetically-encoded Ca2+ channel actuators (GECAs) and modulators. In parallel, we present exemplary applications in both excitable and non-excitable cells and tissues. Furthermore, we briefly discuss potential solutions for wireless optogenetics to accelerate the in vivo applications of GECAs under physiological conditions, with an emphasis on integrating near-infrared (NIR) light-excitable upconversion nanoparticles (UCNPs) and bioluminescence with optogenetics.
Keywords: CRISPRa; CRY2; Calcium signaling; Ion channel; LOV2; NFAT; Near-infrared light; genetically-encoded calcium channel actuators; immune response; neuromodulation; optogenetics; protein design and engineering; synthetic biology; upconversion nanoparticles.