An open-channel blocker interacts with adjacent turns of α-helices in the nicotinic acetylcholine receptor

• Published in: Neuron (Cambridge, Mass.) Vol. 4; no. 1; pp. 87 - 95
• Main Authors: Charnet, Pierre, Labarca, Cesar, Leonard, Reid J., Vogelaar, Nancy J., Czyzyk, Linda, Gouin, Annie, Davidson, Norman, Lester, Henry A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 1990
• Subjects: Amino Acid Sequence; Amino Acids - metabolism; Animals; Electrophysiology; Ion Channels - metabolism; Kinetics; Lidocaine - analogs & derivatives; Lidocaine - metabolism; Lidocaine - pharmacology; Mice; Molecular Sequence Data; Mutation; Oocytes; Protein Conformation; Receptors, Nicotinic - drug effects
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/0896-6273(90)90445-L

The binding site for an open-channel blocker, QX-222, at mouse muscle nicotinic acetylcholine receptors was probed using site-directed mutagenesis, oocyte expression, and elect rophysiologicaI analysis. The proposed cytoplasmic end of the M2 transmembrane helix is termed position 1′. At position 10′ (αS252, βT263, γA261, δA266), Ala residues yield stronger and longer binding of QX-222 than Ser or Thr residues. These effects are opposite and roughly equal (30%–50% per mutation) to previously reported effects at position 6′. The polar end of an anesthetic molecule seems to bind to the position 6′ OH groups, which provide a water-like region; the nonpolar moiety is near position 10′ and binds more strongly in a nonpolar environment. Interactions with adjacent OH-rich turns of an amphiphilic helix may explain the widespread blocking effects of local anesthetics at the conduction pore of ion channels.