Abstract
IN nicotinic acetylcholine receptors (nAChR), as well as glycine, GABAA (γ-aminobutyric acid), serotonin (5-HT3), and GluCl glut-amate receptors, a leucine residue at the approximate midpoint of the M2 transmembrane domain (the 9′ position1) is conserved across most known subunits2. Structural data for the nAChR suggest that the Leu 9′ residues occupy a ᤘkinkᤙ in each of the five M2 helices and point into the closed channel; in the opening step, the M2 helices rotate so that Leu 9′ side chains no longer occlude the conduction pathway3. Mutation of Leu 9′ to one of several other residues slows desensitization and increases sensitivity to agonist4á¤-6. We have exploited the α2βγδ stoichiometry of muscle nAChR to express receptors with ms* = 0 to 5 Leu 9′Ser mutated subunits. Strikingly, each Leu 9′Ser mutation shifts the dose-response relation for ACh to the left by ~10-fold; a nAChR with ms* = 4 is 104-fold more sensitive than the wild type. The results suggest that each of the five Leu 9′ residues participates independently and symmetrically in a key step in the structural transition between the closed and open states.
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Labarca, C., Nowak, M., Zhang, H. et al. Channel gating governed symmetrically by conserved leucine residues in the M2 domain of nicotinic receptors. Nature 376, 514–516 (1995). https://doi.org/10.1038/376514a0
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DOI: https://doi.org/10.1038/376514a0
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