Signal transduction within G-protein coupled receptors via an ion tunnel: a hypothesis.
Based on molecular modeling of the complexes between the mu-opioid receptor and its ligands, we present a hypothesis that accounts for several of the experimental data including the importance of conserved polar residues in rhodopsin-like G-protein-coupled receptors and the effect of Na+ on the binding of ligands to these receptors. We propose that agonists, but not antagonists, would displace Na+ from its initial binding site at the conserved D2.50 residue in the second transmembrane alpha-helical segment, H2. The displaced Na+ would pass through a "gate" of conserved hydrophobic residues and move along a tunnel-like interface (formed of H2, H3 and H7) enriched with several conserved hydrophilic residues including D3.49. Interaction of Na+ with D3.49 would result in the breaking of a salt-bridge between D3.49 and the conserved R3.50 residue thus exposing the latter for interaction with the G-protein.
Zhorov
B S
BS
Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
Ananthanarayanan
V S
VS
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D019204:GTP-Binding Proteins / Q000502:physiology*; D007477:Ions; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009020:Morphine / Q000819:agonists / Q000737:chemistry; D009292:Narcotic Antagonists; D051381:Rats; D017450:Receptors, Opioid, mu / Q000737:chemistry*; D012243:Rhodopsin / Q000737:chemistry; D015398:Signal Transduction / Q000502:physiology*; D012964:Sodium / Q000737:chemistry*; D013329:Structure-Activity Relationship
D007477:Ions; D008024:Ligands; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009020:Morphine; D012243:Rhodopsin; D012964:Sodium; D019204:GTP-Binding Proteins