1 research outputs found
Mechanistic Insights into the Allosteric Modulation of Opioid Receptors by Sodium Ions
The idea of sodium ions altering
G-protein-coupled receptor (GPCR)
ligand binding and signaling was first suggested for opioid receptors
(ORs) in the 1970s and subsequently extended to other GPCRs. Recently
published ultra-high-resolution crystal structures of GPCRs, including
that of the δ-OR subtype, have started to shed light on the
mechanism underlying sodium control in GPCR signaling by revealing
details of the sodium binding site. Whether sodium accesses different
receptor subtypes from the extra- or intracellular sides, following
similar or different pathways, is still an open question. Earlier
experiments in brain homogenates suggested a differential sodium regulation
of ligand binding to the three major OR subtypes, in spite of their
high degree of sequence similarity. Intrigued by this possibility,
we explored the dynamic nature of sodium binding to δ-OR, μ-OR,
and κ-OR by means of microsecond-scale, all-atom molecular dynamics
(MD) simulations. Rapid sodium permeation was observed exclusively
from the extracellular milieu, and following similar binding pathways
in all three ligand-free OR systems, notwithstanding extra densities
of sodium observed near nonconserved residues of κ-OR and δ-OR,
but not in μ-OR. We speculate that these differences may be
responsible for the differential increase in antagonist binding affinity
of μ-OR by sodium resulting from specific ligand binding experiments
in transfected cells. On the other hand, sodium reduced the level
of binding of subtype-specific agonists to all OR subtypes. Additional
biased and unbiased MD simulations were conducted using the δ-OR
ultra-high-resolution crystal structure as a model system to provide
a mechanistic explanation for this experimental observation