Allosteric sodium in class A GPCR signaling

• A sodium ion binding site is found in high-resolution structures of class A GPCRs.
• This allosteric site in the middle of the 7TM domain is highly conserved in class A GPCRs.
• Specific binding of Na+ explains its biochemical and functional effects on GPCRs.
• Collapse of the pocket and Na+ relocation are involved in class A GPCR signaling.

Despite their functional and structural diversity, G-protein-coupled receptors (GPCRs) share a common mechanism of signal transduction via conformational changes in the seven-transmembrane (7TM) helical domain. New major insights into this mechanism come from the recent crystallographic discoveries of a partially hydrated sodium ion that is specifically bound in the middle of the 7TM bundle of multiple class A GPCRs. This review discusses the remarkable structural conservation and distinct features of the Na+ pocket in this most populous GPCR class, as well as the conformational collapse of the pocket upon receptor activation. New insights help to explain allosteric effects of sodium on GPCR agonist binding and activation, and sodium's role as a potential co-factor in class A GPCR function.