In the nervous system of all animals studied to date, including mammals, D-amino acids are present. As examples, D-Serine (D-Ser), D-aspartate (D-Asp) and D-glutamate (D-Glu) are present at high levels in specific brain regions, although their functions are not well understood. Because neurochemistry is well conserved across metazoan life, we find these molecules in a range of animals, and are studying their formation and function in cell to cell signaling. We are developing a range of analytical tools to characterize the chemical content of small brain regions, even down to individual neurons. Using capillary electrophoresis with laser induced fluorescence and mass spectrometry detection, we have determined which neurons synthesize D-Asp, and have measured the formation, transport and release of D-Asp in a stimulation dependent manner; we have even characterized the enzyme responsible for D-Asp formation. We are currently measuring the presence of other D-amino acids in neurons and endocrine structures and adapting sampling approaches to measure their activity-dependent release. Besides amino acids, neuropeptides are an important category of neuromodulatory compound. While proteins (and thus, their peptide products) are ribosomally translated using only L-amino acids, D-amino containing-peptides (DAACPs) do exist, although are difficult to characterize using mass spectrometry alone because the modification does not have an associated change in mass. We have developed a series of mass spectrometry approaches to identify DAACPs from complex mixtures of peptides. Our DAACP discovery funnel has already identified several candidate neuropeptides and more appear likely. Thus, this enigmatic post-translational modification to a peptide may be more common than previously thought.

Award Address  (ACS Award in Analytical Chemistry sponsored by Battelle Memorial Institute). Tools to measure D-amino acid signaling in the brain

248th National Meeting (2014)

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