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Glycine Transporter 2 (GlyT2) inhibitors have shown considerable potential as analgesics for the treatment of neuropathic pain but also display considerable side effects. One potential source of side effects is irreversible inhibition. In this study, we have characterized the mechanism of ORG25543 inhibition of GlyT2 by first considering three potential ligand binding sites on GlyT2—the substrate site, the vestibule allosteric site and the lipid allosteric site. The three sites were tested using a combination of molecular dynamics simulations and analysis of the inhibition of glycine transport of a series point mutated GlyT2 using electrophysiological methods. We demonstrate that the lipid allosteric site on GlyT2 is the most likely binding site for ORG25543. We also demonstrate that cholesterol derived from the cell membrane can form specific interactions with inhibitor‐bound transporters to form an allosteric network of regulatory sites. These observations will guide the future design of GlyT2 inhibitors with the objective of minimising on‐target side effects and improving the therapeutic window for the treatment of patients suffering from neuropathic pain. [ABSTRACT FROM AUTHOR]

The accumulation of iron in dopaminergic neurons can cause oxidative stress and dopaminergic neuron degeneration. Iron chelation therapy may reduce dopaminergic neurodegeneration, but chelators should be targeted towards dopaminergic cells. In this work, two series of compounds based on 8-hydroxyquinoline and deferiprone, iron chelators that have amphetamine-like structures, have been designed, synthesized and characterized. Each of these compounds chelated iron ions in aqueous solution. The hydroxyquinoline-based compounds exhibited stronger iron-binding constants than those of the deferiprone derivatives. The hydroxyquinoline-based compounds also exhibited greater free radical scavenging activities compared to the deferiprone derivatives. Molecular dynamics simulations showed that the hydroxyquinoline-based compounds generally bound well within human dopamine transporter cavities. Thus, these compounds are excellent candidates for future exploration as drugs against diseases that are affected by iron-induced dopaminergic neuron damage, such as Parkinson's disease. [ABSTRACT FROM AUTHOR]

Spontaneous Ca(2+) release from intracellular stores is important for various physiological and pathological processes. In cardiac muscle cells, spontaneous store overload-induced Ca(2+) release (SOICR) can result in Ca(2+) waves, a major cause of ventricular tachyarrhythmias (VTs) and sudden death. The molecular mechanism underlying SOICR has been a mystery for decades. Here we show that a point mutation, E4872A, in the helix bundle crossing region (the proposed gate) of the cardiac ryanodine receptor (RyR2) completely abolishes luminal, but not cytosolic, Ca(2+) activation of RyR2. The introduction of metal-binding histidines at this site converts RyR2 into a luminal Ni(2+)-gated channel. Mouse hearts harboring a heterozygous RyR2 mutation at this site (E4872Q) are resistant to SOICR and are completely protected against Ca(2+)-triggered VTs. These data show that the RyR2 gate directly senses luminal (store) Ca(2+), explaining the regulation of RyR2 by luminal Ca(2+), the initiation of Ca(2+) waves and Ca(2+)-triggered arrhythmias. This newly identified store-sensing gate structure is conserved in all RyR and inositol 1,4,5-trisphosphate receptor isoforms.

Hydrazones—consisting of a dynamic imine bond and an acidic NH proton—have recently emerged as versatile photoswitches underpinned by their ability to form thermally bistable isomers, (Z) and (E), respectively. Herein, we introduce two photoresponsive homopolymers containing structurally different hydrazones as main‐chain repeating units, synthesized via head‐to‐tail Acyclic Diene METathesis (ADMET) polymerization. Their key difference lies in the hydrazone design, specifically the location of the aliphatic arm connecting the rotor of the hydrazone photoswitch to the aliphatic polymer backbone. Critically, we demonstrate that their main photoresponsive property, i.e. their hydrodynamic volume, changes in opposite directions upon photoisomerization (λ=410 nm) in dilute solution. Further, the polymers—independent of the design of the individual hydrazone monomer—feature a photoswitchable glass transition temperature (Tg) by close to 10 °C. The herein established design strategy allows to photochemically manipulate macromolecular properties by simple structural changes. [ABSTRACT FROM AUTHOR]

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A coarse-grain model of the epithelial plasma membrane was developed from high-resolution lipidomic data and simulated using the MARTINI force field to characterize its biophysical properties. Plasmalogen lipids, Forssman glycosphingolipids, and hydroxylated Forssman glycosphingolipids and sphingomyelin were systematically added to determine their structural effects. Plasmalogen lipids have a minimal effect on the overall biophysical properties of the epithelial plasma membrane. In line with the hypothesized role of Forssman lipids in the epithelial apical membrane, the introduction of Forssman lipids initiates the formation of glycosphingolipid-rich nanoscale lipid domains, which also include phosphatidylethanolamine (PE), sphingomyelin (SM), and cholesterol (CHOL). This decreases the lateral diffusion in the extracellular leaflet, as well as the area per lipid of domain forming lipids, most notably PE. Finally, hydroxylation of the Forssman glycosphingolipids and sphingomyelin further modulates the lateral organization of the membrane. Through comparison to the previously studied average and neuronal plasma membranes, the impact of membrane lipid composition on membrane properties was characterized. Overall, this study furthers our understanding of the biophysical properties of complex membranes and the impact of lipid diversity in modulating membrane properties. [ABSTRACT FROM AUTHOR]