Heritable Mutations in the Glycine, GABAA/ and Nicotinic Acetylcholine Receptors Provide New Insights into The Ligand-Gated Ion Channel Receptor Superfamily

Abstract

Publisher Summary This chapter highlights new set of information that has become available with the identification of heritable disease-causing mutations in various ligand-gated ion channel (LGIC) receptor subunits. The chapter summarizes the collective state of the structural and functional knowledge of the LGIC receptor superfamily. Comparison of the sites of heritable mutations with existing knowledge of the structure and function of the ligand gated ion channel receptors predicts the likely consequences of some heritable mutations. Whereas others, particularly the mutations that cause hyperekplexia in the glycine receptor, have defined new receptor domains involved in the process of signal transduction. The significance of these findings is that they provide a means of developing a unified model of the mechanism of action of the ligand-gated ion channel receptors. Excitatory signals are mediated by neurotransmitters such as acetylcholine, whereas inhibitory signals are mediated by glycine or γ-aminobutyric acid (GABA). The identification of naturally occurring heritable mutations in the various members of the LGIC receptor superfamily has provided a new set of targets for structure-function analysis. Mutations in subunits of the glycine receptor lead to a variety of startle syndromes in man and mouse. Mutations in subunits of the nicotinic acetylcholine receptor cause several forms of congenital myasthenia gravis and a rare form of epilepsy, whereas GABA A receptor subunit mutations result in insecticide resistance and alcohol sensitivity.