title: Principal pathway coupling agonist binding to channel gating in nicotinic receptors.
abstract: 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-A 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 alpha-subunit electrostatically links peripheral and inner beta-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 alpha-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.
authors.affiliation: Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Won Yong
authors.initials: WY
authors.lastname: Lee
authors.forename: Steven M
authors.initials: SM
authors.lastname: Sine
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D018722:Nicotinic Agonists / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000187:drug effects; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014101:Torpedo
chemical_list: D018722:Nicotinic Agonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic