Small-Molecule Fluorescent Sensors for Investigating Zinc Metalloneurochemistry

Abstract

ConspectusMetal ions are involved in many neurobiological processes relevant to human health and disease. 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 categories: proteinbound and loosely-bound. The latter pool is also referred to as histochemically observable, chelatable, labile, or mobile zinc. The neurophysiological and neuropathological significance of such 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 suitable 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 mobile 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. We used several of these probes to image Zn(II) distribution, uptake, and mobilization in a variety of cell types, including neuronal cultures. Goals for the future include developing strategies for multi-color imaging, further defining the quenching and turn-on mechanisms of the sensors, and employing the probes to elucidate the functional significance of Zn(II) in neurobiology. Introduction"Metalloneurochemistry" defines a field at the intersection of inorganic chemistry and neuroscience and includes explorations of metal ions as neurotransmitters, as co-factors in neuroproteins, and as neurotoxins. 1 Most early investigations of metal ions in the central nervous system focused on the neuromodulatory roles of K(I) and Ca(II). The importance of d-block metals, including Mn(II), Fe(II), Cu(II), and Zn(II), in neurobiology has emerged recently. 2,3 We are primarily interested in Zn(II), the second most abundant d-block metal ion in the human brain. 4 In certain substructures of the mammalian hippocampus, "mobile" Zn(II) is co-localized with glutamate in presynaptic vesicles. 5 This Zn(II) pool has been implicated in both neurophysiology and disease, but details of its functional significance remain unclear. 6-8 Some questions include: (i) Is Zn(II) a neurotransmitter? (ii) What factors govern Zn (II) release into the synapse 9-12 in physiological and pathological contexts? (iii) What ligands coordinate vesicular and synaptic Zn(II)? (iv) How and why does Zn(II) influence signaling cascades and synaptic plasticity? Studies of these phenomena require a combination of chemistry, biology, electrophysiology, and optical imaging. To facilitate such investigations, we...

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