Maleeva G. Modulation of function and expression of glycine receptors in different cell systems

Thesis is dedicated to the study of expression and modulation of inhibitory ligand-gated glycine receptors. The research was performed using methods of electrophysiology and immunohistochemistry, as well as techniques of cultivation of hippocampal slices, CHO-cells and neurons generated from human fibroblasts. We have found that oxygen-glucose deprivation causes a decrease of the number of glycine receptors expressed on the surface of pyramidal neurons of CA1 zone of hippocampus. Our results stress the importance of a search for new modulators of glycine receptors function. We have identified two new modulators of glycine receptors - ginkgolic and niflumic acids. We have shown that ginkgolic acid is a subunit-specific positive modulator of alpha1-glycine receptors and detected the amino acids responsible for their interaction. Niflumic acid is a voltage sensitive inhibitor of glycine receptors with higher affinity to alpha2 and alpha3 subunits than to alpha1. Mutation G254A in alpha1 receptors increases their sensitivity to niflumic acid. Our data evidences for the pore-blocking mechanism of niflumic acid action. We also have investigated ligand-gated and voltage-gated channels of the neurons generated from human fibroblasts and found that this cell type expresses on its surface glycine receptors and can be used as a model to study their functioning.