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Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905

Correspondence to Steven M. Sine: sine{at}mayo.edu

Nicotinic acetylcholine receptors (AChRs) mediate rapid excitatory synaptic transmission throughout the peripheral and central nervous systems. They transduce binding of nerve-released ACh into opening of an intrinsic channel, yet the structural basis underlying transduction is not fully understood. Previous studies revealed a principal transduction pathway in which Arg 209 of the pre-M1 domain and Glu 45 of the β1–β2 loop functionally link the two regions, positioning Val 46 of the β1–β2 loop in a cavity formed by Pro 272 through Ser 269 of the M2–M3 loop. Here we investigate contributions of residues within and proximal to this pathway using single-channel kinetic analysis, site-directed mutagenesis, and thermodynamic mutant cycle analysis. We find that in contributing to channel gating, Val 46 and Val 132 of the signature Cys loop couple energetically to Pro 272. Furthermore, these residues are optimized in both their size and hydrophobicity to mediate rapid and efficient channel gating, suggesting naturally occurring substitutions at these positions enable a diverse range of gating rate constants among the Cys-loop receptor superfamily. The overall results indicate that Pro 272 functionally couples to flanking Val residues extending from the β1–β2 and Cys loops within the ACh binding to channel opening transduction pathway.

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				W. Y. Lee, C. R. Free, and S. M. Sine Binding to Gating Transduction in Nicotinic Receptors: Cys-Loop Energetically Couples to Pre-M1 and M2-M3 Regions J. Neurosci., March 11, 2009; 29(10): 3189 - 3199. [Abstract] [Full Text] [PDF]

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