Competition between Li+ and Na+ in sodium transporters and receptors: Which Na+ -Binding sites are "therapeutic" Li+ targets?

Chemical Science
Todor DudevCarmay Lim

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 disorde...Continue Reading

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Citations

Sep 26, 2019·Pharmacological Reviews·Barbara ZarzyckaVsevolod Katritch
Jan 21, 2019·The Journal of Chemical Physics·Jean Jules Fifen, Noam Agmon
Dec 28, 2019·Angewandte Chemie·Esteban Suárez-PicadoFélix Freire
Aug 25, 2020·The Journal of General Physiology·Jiali WangChristof Grewer
Jan 8, 2020·Metallomics : Integrated Biometal Science·Todor DudevObis Castaño
Jan 17, 2020·Journal of Molecular Biology·Benjamin C McIlwainRandy B Stockbridge
Nov 10, 2018·Inorganic Chemistry·Todor DudevCarmay Lim
Sep 27, 2019·Accounts of Chemical Research·Todor DudevCarmay Lim
Nov 21, 2020·Inorganic Chemistry·Nikoleta KirchevaTodor Dudev
Sep 14, 2021·The Journal of Physical Chemistry. B·Todor DudevCarmay Lim

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Methods Mentioned

BETA
NMR
X-ray

Software Mentioned

MEAD ( Macroscopic Electrostatics with Atomic Detail )
Gaussian
HBPLUS Hydrogen Bond Calculator
CHARMM
MOLMOL

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