Principal pathway coupling agonist binding to channel gating in nicotinic receptors

• Published in: Nature 2005-11, Vol.438 (7065), p.243-247
• Main Authors: Sine, Steven M, Lee, Won Yong
• Format: Article
• Language: English
• Subjects: Allosteric Regulation - drug effects; Aminoacid receptors (glycine, glutamate, gaba); Animals; Binding sites; Biological and medical sciences; Cell receptors; Cell structures and functions; Chondrichthyes; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Ion Channel Gating - drug effects; Kinetics; letter; Marine; Models, Molecular; Molecular and cellular biology; Molecular biology; multidisciplinary; Mutation - genetics; Nervous system; Neurotransmitters; Nicotinic Agonists - metabolism; Nicotinic Agonists - pharmacology; Protein Structure, Tertiary - drug effects; Protein Subunits - chemistry; Protein Subunits - genetics; Protein Subunits - metabolism; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - genetics; Receptors, Nicotinic - metabolism; Residues; Science; Science (multidisciplinary); Torpedo
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature04156

Synaptic receptors respond to neurotransmitters by opening an intrinsic ion channel in the final step in synaptic transmission. How binding of the neurotransmitter is conveyed over the long distance to the channel remains a central question in neurobiology. Here we delineate a principal pathway that links neurotransmitter binding to channel gating by using a structural model of the Torpedo acetylcholine receptor at 4-Å resolution, recordings of currents through single receptor channels and determinations of energetic coupling between pairs of residues. We show that a pair of invariant arginine and glutamate residues in each receptor α-subunit electrostatically links peripheral and inner β-sheets from the binding domain and positions them to engage with the channel. The key glutamate and flanking valine residues energetically couple to conserved proline and serine residues emerging from the top of the channel-forming α-helix, suggesting that this is the point at which the binding domain triggers opening of the channel. The series of interresidue couplings identified here constitutes a primary allosteric pathway that links neurotransmitter binding to channel gating.