A comparison of glycine- and ivermectin-mediated conformational changes in the glycine receptor ligand-binding domain

Int J Biochem Cell Biol. 2012 Feb;44(2):335-40. doi: 10.1016/j.biocel.2011.11.005. Epub 2011 Nov 11.


Glycine receptor chloride channels are Cys-loop receptor proteins that isomerize between a low affinity closed state and a high affinity ion-conducting state. There is currently much interest in understanding the mechanisms that link affinity changes with conductance changes. This essentially involves an agonist binding in the glycine receptor ligand-binding site initiating local conformational changes that propagate in a wave towards the channel gate. However, it has proved difficult to convincingly distinguish those agonist-induced domain movements that are critical for triggering activation from those that are simply local deformations to accommodate ligands in the site. We employed voltage-clamp fluorometry to compare conformational changes in the ligand-binding site in response to activation by glycine, which binds locally, and ivermectin, which binds in the transmembrane domain. We reasoned that ivermectin-mediated activation should initiate a conformational wave that propagates from the pore-lining domain towards the ligand-binding domain, eliciting conformational changes in those extracellular domains that are allosterically linked to the gate. We found that ivermectin indeed elicited conformational changes in ligand-binding domain loops C, D and F. This implies that conformational changes in these domains are important for activation. This result also provides a mechanism to explain how ivermectin potentiates glycine-induced channel activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fluorometry
  • Glycine / metabolism
  • Glycine / pharmacology*
  • Ivermectin / pharmacology*
  • Ligands
  • Patch-Clamp Techniques
  • Protein Structure, Tertiary / drug effects
  • Rats
  • Receptors, Glycine / chemistry*
  • Xenopus laevis / metabolism


  • Ligands
  • Receptors, Glycine
  • Ivermectin
  • Glycine