Sodium is a negative allosteric regulator of the

The functional properties of G protein-coupled receptors (GPCRs) are intimately associated with the different components in their cellular environment. Among them, sodium ions have been proposed to play a substan-tial role as endogenous allosteric modulators of GPCR-mediated signaling. However, this sodium effect and the underlying mechanisms are still unclear for most GPCRs. Here, we identified sodium as a negative allo-steric modulator of the ghrelin receptor GHSR (growth hormone secretagogue receptor). Combining 23Na-nuclear magnetic resonance (NMR), molecular dynamics, and mutagenesis, we provide evidence that, in GHSR, sodium binds to the allosteric site conserved in class A GPCRs. We further leveraged spectroscopic and functional assays to show that sodium binding shifts the conformational equilibrium toward the GHSR-inactive ensemble, thereby decreasing basal and agonist-induced receptor-catalyzed G protein activation. All together, these data point to sodium as an allosteric modulator of GHSR, making this ion an integral component of the ghrelin signaling machinery.

Automated summary

Sodium ions act as endogenous allosteric modulators of G protein-coupled receptors (GPCRs) in a negative regulatory manner. Studies on the ghrelin receptor GHSR reveal that sodium binds to a conserved allosteric site in GPCRs, leading to decreased receptor-catalyzed G protein activation. These findings highlight the importance of sodium as an integral component of the ghrelin signaling machinery.