Class A GPCRs use the membrane potential to increase their sensitivity and selectivity

The human genome contains about 700 genes of G protein-coupled receptors (GPCRs) of class A; these seven-helical membrane proteins are the targets of almost half of all known drugs. In the middle of the helix bundle, crystal structures revealed a highly conserved sodium-binding site, which is connected with the extracellular side by a water-filled tunnel. Sodium ions are observed in GPCRs crystallized in their inactive conformations, but not in GPCRs that were trapped in agonist-bound active conformations. The escape route of the sodium ion upon the inactive-to-active transition and its very direction, either into the cytoplasm or back outside the cell, hitherto remained obscure. We modeled sodium-binding GPCRs as electrogenic carriers of sodium ions. In this model the sodium gradient over the cell membrane would increase the sensitivity of GPCRs if their activation is thermodynamically coupled to the translocation of the sodium ion into the cytoplasm, while decreasing it if the sodium ion retreats into the extracellular space upon receptor activation. The model quantitatively describes the available data on both activation and suppression of distinct GPCRs by membrane voltage. The model also predicts selective amplification of the signal from (endogenous) agonists if only they, but not their (partial) analogs, could induce sodium translocation. Comparative structure and sequence analyses of sodium-binding GPCRs indicate a key role for the conserved leucine residue in the second transmembrane helix (Leu2.46) in coupling sodium translocation to receptor activation. Hence, class A GPCRs appear to utilize the energy of the transmembrane sodium potential to increase their sensitivity and selectivity.