Homology modeling of the transmembrane domain of the GABAA receptor

Abstract

The permeability of ion channels for ions and substances that bind inside the pore depends on the cross-sectional area of the pore. We have constructed models of the closed, open, and desensitized α1β2γ2 GABAA receptor on the basis of known structures of both prokaryotic and eukaryotic ligand-gated channels. We employed Monte Carlo energy minimization to optimize the model structures. We have found significant pore constrictions, whose diameter depends on the functional state of the receptor in the cytoplasmic, middle, and extracellular parts of the pore-forming M2 segments. It is known that the constrictions in the middle (the 9' ring of residues) and cytoplasmic (the 2' ring of residues) parts of the M2 helices form the activation and desensitization gates of the GABAA receptor. Our computations predict that the constriction in the extracellular part of the M2 helices (the 20' ring of residues) may also serve as a gate in the GABAA receptor, whose physiological role is still unclear. Our results imply that the structures of a number of prokaryotic and eukaryotic ligand-gated channels that have been found in bacteria and lower organisms can be used for homology modeling of the pore region of the human GABAA receptor.