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Like fluorescence sensing techniques, methods to manipulate proteins with light have produced great advances in recent years. Ion channels have been one of the principal protein targets of photoswitched manipulation. In combination with fluorescence detection of cell signaling, this has enabled non-invasive, all-optical experiments on cell and tissue function, both in vitro and in vivo. Optical manipulation of channels has also provided insights into the mechanism of channel function. Optical control elements can be classified according to their molecular reversibility as non-reversible phototriggers where light breaks a chemical bond (e.g. caged ligands) and as photoswitches that reversibly photoisomerize. Synthetic photoswitches constitute nanoscale actuators that can alter channel function using three different strategies. These include (1) nanotoggles, which are tethered photoswitchable ligands that either activate channels (agonists) or inhibit them (blockers or antagonists), (2) nanokeys, which are untethered (freely diffusing) photoswitchable ligands, and (3) nanotweezers, which are photoswitchable crosslinkers. The properties of such photoswitches are discussed here, with a focus on tethered photoswitchable ligands. The recent literature on optical manipulation of ion channels is reviewed for the different channel families, with special emphasis on the understanding of ligand binding and gating processes, applications in nanobiotechnology, and with attention to future prospects in the field.
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