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

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.