Ionotropic GABA Receptors as Therapeutic Targets for Memory and Sleep Disorders

Abstract

Publisher Summary γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the brain. GABA produces neuronal inhibition by acting on two major types of receptors: ionotropic receptors that are ligand-gated ion channels (GABA A and GABA C receptors), and metabotropic receptors that are G-protein coupled receptors (GABA B receptors) that act via second messengers. This chapter focuses on ionotropic GABA A and GABA C receptors as therapeutic targets in particular for memory and sleep disorders. The ionotropic GABA A and GABA C receptors belong to the nicotinicoid superfamily of ligand-gated ion channels that includes nicotinic acetylcholine, strychnine-sensitive glycine and 5HT 3 receptors. Structurally, GABA A and GABA C receptors are similar to other members of the nicotinicoid superfamily of ligand-gated ion channels, consisting of five protein subunits arranged around a central pore that constitutes the actual ion channel. Agents acting on GABA A or GABA C receptors have widespread therapeutic potential including therapy of sleep and memory disorders. The discovery of selective ionotropic GABA receptor agents as modulators acting on the allosteric sites or as agonists, partial agonists or antagonists acting on the orthosteric, site is a major challenge in the continuing development of therapeutic agents acting on specific subtypes of GABA A or GABA C receptors.