Looger, L.L., Lalonde, S., and Frommer, W.B.
Genetically encoded FRET sensors for visualizing metabolites with subcellular resolution in living cells.  Plant Physiology 138: 555-557 (2005).

What tools are there to determine the concentration of a particular molecular species in a physiological environment? Is it possible to visualize how its concentration varies across an organ, tissue, or cell? Is there a way to detect how metabolite levels change in response to environmental stimuli? Can these changes be monitored in real time? Can multiple analytes be measured simultaneously? Can these measurements be performed for a variety of structural and functional analyte classes? These are the central questions in the young field of metabolomics. No currently available technology addresses these issues in a satisfactory manner. Nonaqueous fractionation is static, invasive, has no cellular resolution, and is sensitive to artifacts. Spectroscopic methods such as nuclear magnetic resonance imaging and positron emission tomography provide dynamic data, but poor spatial resolution. The development of genetically encoded molecular sensors, which transduce an interaction of the target molecule with a recognition element into a macroscopic observable, via allosteric regulation of one or more reporter elements, may provide answers to some of the questions. The recognition element may simply bind the target, bind and enzymatically convert the target, or may serve as a substrate for the target, as in the use of a specific target sequence in the construction of a protease sensor (Nagai and Miyawaki, 2004). The most common reporter element is a sterically separated donor-acceptor fluorescence resonance energy transfer (FRET) pair of spectral variants of the green fluorescent protein (GFP; Fehr et al., 2002), although single fluorescent proteins (Doi and Yanagawa, 1999) or enzymes (Guntas and Ostermeier, 2004) are viable as well. Some molecular sensors additionally employ a conformational actuator (most commonly a peptide which binds to one conformational state of the recognition element) to magnify the allosteric effect upon and resulting output of the reporter element.