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Issue 17, 2018
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Competition between Li+ and Na+ in sodium transporters and receptors: Which Na+-Binding sites are “therapeutic” Li+ targets?

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Abstract

Sodium (Na+) acts as an indispensable allosteric regulator of the activities of biologically important neurotransmitter transporters and G-protein coupled receptors (GPCRs), which comprise well-known drug targets for psychiatric disorders and addictive behavior. How selective these allosteric Na+-binding sites are for the cognate cation over abiogenic Li+, a first-line drug to treat bipolar disorder, is unclear. Here, we reveal how properties of the host protein and its binding cavity affect the outcome of the competition between Li+ and Na+ for allosteric binding sites in sodium transporters and receptors. We show that rigid Na+-sites that are crowded with multiple protein ligands are well-protected against Li+ attack, but their flexible counterparts or buried Na+-sites containing only one or two protein ligands are vulnerable to Li+ substitution. These findings suggest a novel possible mode of Li+ therapeutic action: By displacing Na+ bound by ≤2 protein ligands in buried GPCR sites and stabilizing the receptor's inactive state, Li+ could prohibit conformational changes to an active state, leading to lower cytosolic levels of activated guanine nucleotide-binding proteins, which are hyperactive/overexpressed in bipolar disorder patients.

Graphical abstract: Competition between Li+ and Na+ in sodium transporters and receptors: Which Na+-Binding sites are “therapeutic” Li+ targets?

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Publication details

The article was received on 13 Dec 2017, accepted on 02 Apr 2018 and first published on 02 Apr 2018


Article type: Edge Article
DOI: 10.1039/C7SC05284G
Citation: Chem. Sci., 2018,9, 4093-4103
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    Competition between Li+ and Na+ in sodium transporters and receptors: Which Na+-Binding sites are “therapeutic” Li+ targets?

    T. Dudev, K. Mazmanian and C. Lim, Chem. Sci., 2018, 9, 4093
    DOI: 10.1039/C7SC05284G

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