Translocation Mechanism of Allosteric Sodium Ions in β-Adrenoceptor.

The allosteric modulation of G-protein-coupled receptors (GPCRs) by sodium ions has received significant attention as the crystal structures of several receptors show the binding of sodium ions (Na) at the conserved D. Theoretical studies have shown that extracellular Na would enter the allosteric D via the orthosteric site. However, it remains unclear how the bound allosteric Na would leave the GPCRs. In this study, we performed molecular dynamics (MD) simulations to illustrate the energy barriers of Na transfer through the transmembrane helix bundle of βAR. In contrast to the postulations from other GPCRs, the translocation of this allosteric Na into the intracellular side is found to be significantly difficult. Hence, the translocation direction could be receptor-specific.