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The Journal of Neuroscience, April 15, 2001, 21(8):2589-2599

The Surface Accessibility of the Glycine Receptor M2-M3 Loop Is Increased in the Channel Open State

Joseph W. Lynch1, Nian-Lin Reena Han1, Justine Haddrill1, Kerrie D. Pierce2, and Peter R. Schofield2

1 Department of Physiology and Pharmacology, University of Queensland, Brisbane, QLD, 4072, Australia, and 2 Neurobiology Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, 2010, Australia

Mutations in the extracellular M2-M3 loop of the glycine receptor (GlyR) alpha 1 subunit have been shown previously to affect channel gating. In this study, the substituted cysteine accessibility method was used to investigate whether a structural rearrangement of the M2-M3 loop accompanies GlyR activation. All residues from R271C to V277C were covalently modified by both positively charged methanethiosulfonate ethyltrimethylammonium (MTSET) and negatively charged methanethiosulfonate ethylsulfonate (MTSES), implying that these residues form an irregular surface loop. The MTSET modification rate of all residues from R271C to K276C was faster in the glycine-bound state than in the unliganded state. MTSES modification of A272C, L274C, and V277C was also faster in the glycine-bound state. These results demonstrate that the surface accessibility of the M2-M3 loop is increased as the channel transitions from the closed to the open state, implying that either the loop itself or an overlying domain moves during channel activation.

Key words: ligand-gated ion channel; glycine receptor alpha 1 subunit; substituted cysteine accessibility method (SCAM); methanethiosulfonate ethyltrimethylammonium (MTSET); methanethiosulfonate ethylsulfonate (MTSES); hyperekplexia

Copyright © 2001 Society for Neuroscience  0270-6474/01/2182589-11$05.00/0


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