A """"""""caged"""""""" molecule is a photosensitive, but temporarily inert, precursor of a biologically active molecule. Light absorption transforms the precursor into a molecule with full bioactivity. Because a light beam can be easily focused and steered, and photochemical reactions are extremely fast, caged molecules are versatile tools for using light to manipulate biology with exceptionally high spatial and temporal resolution. The long-term objective is to develop a broad spectrum of novel photochemical tools that will enable cellular physiologists to use light to probe and control dynamic signaling processes in living cells and tissues. The proposed research has four foci: 1) Develop new """"""""cages"""""""" that a) are strongly activated by light, b) show fast kinetics of product release on photolysis, c) give high yield of product when photolyzed, and d) are chemically and metabolically stable in the absence of light. 2) Develop new probes for cellular signaling, specifically cage neurotransmitters, lipid messengers, as well as probes that permit """"""""photochemical knock-out"""""""" of neurotransmitter receptors and transporters, and ion channels. 3) Develop and optimize two probes of intracellular calcium signaling: a caged calcium and a caged """"""""anti- calcium"""""""" for using light to rapidly generate and ablate intracellular calcium signals, respectively. 4) Apply the developed probes to cellular physiology research in the areas of signal processing by nerve terminals and dendrites, synaptic plasticity, and calcium regulation of cell excitability.
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