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Small-molecule fluorescent sensors for investigating zinc metalloneurochemistry.

ABSTRACT: The metalloneurochemistry of Zn(II) is of substantial current interest. Zinc is the second most abundant d-block metal ion in the human brain, and its distribution varies with relatively high concentrations found in the hippocampus. Brain zinc is generally divided into two types, protein-bound and loosely bound, the latter also being termed histochemically observable, chelatable, labile, or mobile zinc. The neurophysiological and neuropathological significance of mobile Zn(II) remains enigmatic. Studies of Zn(II) distribution, translocation, and function in vivo require tools for its detection. Because Zn(II) has a closed-shell d(10) configuration and no convenient spectroscopic signature, fluorescence is a well-suited method for monitoring Zn(II) in biological contexts. This Account summarizes work by our laboratory addressing the design, preparation, characterization, and use of small-molecule fluorescent sensors for imaging Zn(II) in living cells and samples of brain tissue. These sensors provide "turn-on" or ratiometric Zn(II) detection in aqueous solution at neutral pH. By making alterations to the Zn(II)-binding unit and fluorophore platform, we have devised sensors with varied photophysical and metal-binding properties. Several of these probes have been applied to image Zn(II) distribution, uptake, and mobilization in a variety of cell types, including neuronal cultures.

SUBMITTER: Nolan EM

PROVIDER: S-EPMC2646817 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Small-molecule fluorescent sensors for investigating zinc metalloneurochemistry.

Nolan Elizabeth M EM Lippard Stephen J SJ

Accounts of chemical research 20090101 1

The metalloneurochemistry of Zn(II) is of substantial current interest. Zinc is the second most abundant d-block metal ion in the human brain, and its distribution varies with relatively high concentrations found in the hippocampus. Brain zinc is generally divided into two types, protein-bound and loosely bound, the latter also being termed histochemically observable, chelatable, labile, or mobile zinc. The neurophysiological and neuropathological significance of mobile Zn(II) remains enigmatic. ...[more]

PMID: 18989940

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Project description:Treatment of aqueous zinc solutions with incremental additions of a ditopic fluorescent sensor of the Zinpyr family, based on pyridine/pyrazine-containing metal recognition units, affords a fluorescence titration curve with a sharp maximum at a sensor:Zn(2+) ratio of 0.5 (Zhang, X-a.; Hayes, D.; Smith, S. J.; Friedle, S.; Lippard, S. J. J. Am. Chem. Soc.2008, 130, 15788-15789). This fluorescence response enables the quantification of readily chelatable zinc in biological samples by a simple titration protocol. In the present work a new set of ditopic fluorescence zinc sensors functionalized with pyridine/pyrazine-containing metal chelating units is described, and through detailed studies the principles governing the characteristic OFF-ON-OFF fluorescence behavior and quantification capabilities of the family are delineated. Incorporation of carboxylate/ester groups in the 6 position of the fluorescein allows for control of the spatial distribution of the sensor for selective extra- or intracellular imaging of mobile zinc, without introducing significant changes in zinc-binding properties. A combination of spectrophotometric and potentiometric measurements provided a complete description of the H(+)- and Zn(2+)-binding properties of the compounds and their correlation with the observed fluorescence profile. The first zinc-binding event has an apparent affinity, K(1)', of 1.9 × 10(9)-3.1 × 10(9) M(-1), whereas for coordination of the second Zn(2+) ion, responsible for fluorescence turn-on, the apparent formation constant, K(2)', is 5.5 × 10(7)-6.9 × 10(7) M(-1). A detailed chemical and mathematical analysis of the system demonstrated that the difference in emission efficiencies of the dimetalated (LZn(2)) vs monometalated (LZn) and metal-free (L) forms, a consequence of the combined quenching effects of the two metal-chelating units, significantly influences the shape of the titration curve. The scope of the titration method was investigated mathematically, and a lower boundary for the range of concentrations that can be determined was established as a function of the magnitude of K(2)'. Our results suggest that the principles governing the response of the ZPP1 series are applicable to other analogues of the Zinpyr family. Moreover, they may guide the design of other ditopic sensors suitable for determining the concentrations of a wide range of mobile metal ions and other chemical signaling agents of relevance in biological systems.

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Small-molecule fluorescent sensors for investigating zinc metalloneurochemistry.

Publications

Small-molecule fluorescent sensors for investigating zinc metalloneurochemistry.

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