Just as metals provide the structure necessary to build skyscrapers, so do metals form an indispensable component of cells. Without the added zing that metals provide, proteins would be so many decorative molecular curlicues. It is fair to say that life would simply not be possible without the spice of particular inorganic elements albeit a dash. It has been known for quite a while that the synaptic vesicles of certain glutamatergic pathways contain remarkably high concentrations of zinc. The zinc in these vesicles unlike most of the zinc in the cell is not tightly bound but appears to be only in weak association with other molecules. The precise role of this synaptic zinc has served to tantalize neurobiologists for a number of years but has not as yet yielded up its full secret. Our primary interest is in defining the role of synaptic zinc in both normal and pathological physiology. Towards this end we bring to bear a number of techniques on whole brains, slices, isolated neurons and Xenopus oocytes; fluorometric imaging, electrophysiology, fluorescence spectroscopy and nanochemistry.
We currently focus on the following problems:
- What is the role of the vesicular zinc found in certain glutaminergic neurons?
- Can zinc act as a second messenger?
- How does zinc make its way from the extracellular space to populate proteins and the synaptic vesicles?
An additional focus of our research is on the development of new techniques for exploring the neurophysiology of the brain. We have given particular attention to developing techniques for imaging neuronal activity, because it provides a possible way of visualizing the choreography of ensembles of neurons during activity, as it is probably the spatio-temporal pattern of neural activity that is at the heart of mental activity. We are developing new chemical probes for imaging neuronal activity, transition metals and ways of delivering these probes to specific cellular populations.
Keywords: synapse, hippocampus, fluorescent, zinc, imaging, signaling.
Nydegger I, Rumschik SM, Zhao J & Kay AR. 2012, Evidence for an Extracellular Zinc-Veneer in Rodent Brains from Experiments with Zn-Ionophores and ZnT3 Knockouts. ACS Chemical Neuroscience
Rumschik SM, Nydegger I, Zhao J, Kay AR., 2009, The interplay between inorganic phosphate and amino acids determines zinc solubility in brain slices. J Neurochem. 108(5):1300-8.
Zhao J, Bertoglio BA, Devinney MJ Jr, Dineley KE, Kay AR., 2009, The interaction of biological and noxious transition metals with the zinc probes FluoZin-3 and Newport Green. Anal Biochem. 384(1):34-41.
Kay, A. R., Neyton, J. & Paoletti, P. 2006. A startling role for synaptic zinc. Neuron 52, 572-4.
Kay, A. R. 2006. Imaging synaptic zinc: promises and perils. Trends in Neuroscience 29, 200-206.
Kay, A. R. & Tóth, K. 2006. The influence of location of a fluorescent zinc-probe in brain slices on its response to synaptic activation. J. Neurophysiol. 95, 1949-1956.
Kay, A. R. 2003. Evidence for chelatable zinc in the extracellular space of the hippocampus, but little evidence for synaptic release of Zn. J. Neurosci. 23: 6847-6855.
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Kay, A. R., Alfonso, A., Alford, S., Cline, H. T., Holgado, A. M., Sakmann, B., Snitsarev, V. A., Stricker, T. P., Takahashi, M., Wu, L.-G. 1999. Imaging synaptic activity in intact brain and slices with FM1-43 in C. elegans, Lamprey and Rat. Neuron, 24:809-817.