Glycine receptors: lessons on topology and structural effects of the lipid bilayer

The members of the superfamily of nicotinicoid receptors, sometimes referred to as the ligand-gated ion channel superfamily (LGICS), are essential mediators in the propagation of electrical signals between cells at neuronal and neuromuscular synapses. Given the significant sequence and proposed topological similarities between family members, the structural architecture of any one of these neuroreceptors is believed to be archetypic for the family of ligand-gated channels. We have focused our biophysical studies on the glycine receptor (GlyR) since homomeric expression of just the alpha1 chain of the receptor is sufficient to reconstitute native-like activity when expressed in heterologous cells, and we have successfully overexpressed and purified relatively large quantities of this receptor. Our CD data suggests that the historical four transmembrane helix topology model for nicotinicoid receptors may be erroneous. Proteolytic studies as well as chemical modification studies coupled with mass spectroscopy (MS) have provided additional evidence that this model may be inappropriate. While we suggest a novel topological model for the superfamily of nicotinicoid receptors, the absence of high resolution data for the transmembrane regions of these ion channels precludes further refinement of this model. In addition, we observe structural changes in the recombinant alpha1 GlyR as a function of bilayer composition, suggesting that these receptors may be dynamically modulated by cellular control over the properties of the plasma membrane.