This is only true when there is an inversion of orbital symmetry during the transition (Electronic states have symmetries that are either even, gerade or “ g” states, or uneven, ungerade, or “ u” states). Quantum theory says that absorption of light occurs when the transition moment between the ground state and the excited state is non-zero. One can immediately appreciate that 2P uncaging is potentially very advantageous for glutamate neurophysiology, as uncaging becomes pin-point due the nature of non-linear excitation (Figure (Figure1A 1A). Thus, in complex biological preparations, such as brain slices this can lead to large clouds of glutamate release outside the site of interest. But the same quantity of glutamate will be released in every plane above and below this point because of linear excitation. Of course lenses with a high numerical aperture will produce focused light, thus glutamate concentrations will be maximal at the focal point. The challenge for using 1P uncaging of glutamate for high-resolution functional mapping is that normal excitation must release the neurotransmitter wherever light hits the solution of caged compound. Beyond low-resolution functional mapping of receptors (Eder et al., 2004), 1P uncaging has been widely used for studying circuit connectivity by many laboratories (Shepherd, 2012). And so laser uncaging of neurotransmitters became a topic of active research for neurophysiologists using one-photon (1P) photolysis (Eder et al., 2004). For neuroscience, the work of the Hess group was crucial, as they developed the first caged neurotransmitters (Wilcox et al., 1990 Wieboldt et al., 1994a, b Niu et al., 1996 Breitinger et al., 2000). As an interesting aside I would like to point out that Barltrop was a natural product chemist who did a sabbatical with Melvin Calvin in the 1950s, with whom he must have started to think about using light for synthetic organic chemistry, and that Barltrop's work eventually lead to the gene chip revolution (McGall et al., 1997).
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All these caged compounds were designed for photolysis with near-UV light using the ortho-nitrobenzyl photochemical protecting group introduced by Barltrop et al. Henry Lester, George Hess, David Trentham and Roger Tsien and their co-workers all made seminal contributions to the field with the development of caged cGMP (Lester et al., 1979), carbamoylcholine (Walker et al., 1986), IP 3 (Walker et al., 1987), and Ca 2+ (Tsien and Zucker, 1986) in the 1980–86 period.
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The simplicity of term remains attractive, so I use it in the way Hoffman did, to mean a functional cage.Īfter the initial success of caged ATP in the study of the Na,K-ATPase (Kaplan and Hollis, 1980), other biologists became interested in caged compounds. And we should not forget, of course, those involved in animal husbandry use the term in a literal way. The term “caged compounds” was coined by a physiologist (Joe Hoffman) who was unaware of the term “caged” was used in chemistry to mean box-like structures. Conceptually simple in its design, the strategy is to block a crucial functionality of the biomolecule that is required for its activity with the “caging chromophore.” Irradiation cuts this bond, releasing the caged substrate. Originating in 1978 with caged ATP (Kaplan et al., 1978), all important biological signaling molecules and cations have been controlled by uncaging (Ellis-Davies, 2007). Caged compounds are, by definition, biological molecules which have been rendered inert by covalent attachment of a photochemical protecting group (Ellis-Davies, 2000).