In This Issue pubs.acs.org/chemneuro
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D-AMINO
ACIDS IN BRAIN TISSUE
stapled AID peptides act as selective inhibitors of the Cavα− Cavβ interaction, thereby modulating VGIC function.
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Amino acids are essential biomolecules, and it has long been known that nature favors the L-enantiomer of these chiral building blocks for proteins. Increasingly, however, biological roles for naturally occurring D-amino acids are being discovered. In mammals specifically, D-amino acids appear to play various regulatory roles in the central nervous system. In this issue, Weatherly and co-workers (DOI: 10.1021/ acschemneuro.6b00398) report the D- and L-amino acid levels in mouse hippocampus, cortex, and blood. In brain tissue, both D- and L-amino acid concentrations exceeded those of blood by at least 10-fold. However, D-amino acid levels were found up to 2000 times higher in the brain compared to blood, with most Damino acids being more abundant in the hippocampus than the cortex. This result suggests there may be regional differences in D-amino acid synthesis and degradation in the brain.
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The neuronal porosome complex is composed of an intricate network of lipids and proteins, comprising a key component of the synaptosome in mediating neurotransmission. It has been hypothesized that the particular composition of the lipids present in the porosome plays a key role in regulating transport through the synaptosome membrane. In this issue, Lewis et al. (DOI: 10.1021/acschemneuro.7b00030) analyze the lipidome of the synaptosome, synaptosomal membrane, and synaptic vesicle isolated from rat brain using mass spectrometry, electron microscopy, and atomic force microscopy. Lipidomics mass spectrometry studies revealed stark differences in the lipid composition of these three compartments, and the distribution of specific lipids across compartments is highly asymmetrical. For example, the enrichment of sphingolipids in synaptic vesicles, but not the synaptosomal membrane, suggests these compounds may play a role in neurotransmission. The distinct lipid profiles of the synaptosomal membrane and synaptic vesicles suggest differential roles for these lipids beyond structural support and compartmentalization, and that these compartments are tightly regulated.
STAPLING VOLTAGE-GATED ION CHANNELS
Electrical signaling in the central nervous system is regulated by voltage-gated ion channels (VGICs), which function via the formation of pore-forming subunits in the plasma membrane mediated by protein−protein interactions. Key sites in these multiprotein interactions, such as those between the voltagegated calcium channel (Cav) α-interaction domain (AID) and the β-subunit, represent important drug targets for treating cardiovascular diseases, chronic pain, and epilepsy. Here, Findeisen et al. (DOI: 10.1021/acschemneuro.6b00454) target and modulate this pore-forming interaction with stapled peptides. By engineering AID peptides stapled with a meta-xylyl bridge between two cysteines, the authors created an AID with increased α-helicity that retains its native binding to the Cavβ subunit, as confirmed by circular dichroism spectroscopy and X-ray crystallography. Additionally, the © 2017 American Chemical Society
NEW INSIGHTS INTO THE NEUROLOGICAL LIPIDOME
Published: June 21, 2017 1118
DOI: 10.1021/acschemneuro.7b00206 ACS Chem. Neurosci. 2017, 8, 1118−1118
