Ion Channels – Ligand Gated

Abstract

Ligand gated ion channels (LGIC) constitute an important class of plasma membrane proteins recognized as critical for mediating cell-cell communication and cellular excitability. Classically, LGIC have been divided into three families based upon molecular biology and protein structure criteria: (i) “cys-loop” LGIC which include nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA) A and C receptors, 5-hydroxytryptamine-3 (5HT3) receptors and glycine receptors (ii) glutamate receptors of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA)-sensitive classes and (iii) ATP-sensitive P2X receptors. Adopting a more liberal definition, we consider two additional LGIC: (iv) members of the transient receptor potential (TRP) family that respond to endogenous or exogenous extracellular signals and (v) acid-sensitive ion channels (ASIC). These LGIC are known to mediate neurotransmitter/ligand responses in central and peripheral nervous systems, in skeletal and smooth muscle, and in the endocrine system. Additionally, some of these LGIC appear to function in non-excitable cells (e.g. glia, endothelial cells and T-cells). Among these LGIC, therapeutic examples are best known among GABAA, 5HT3, nicotinic acetylcholine, and NMDA-sensitive glutamate receptors. Direct ligands (agonists and antagonists) have been a principal focus, but benzodiazepines exemplify the potential scope of LGIC modulators and, accordingly, development of other LGIC modulator therapeutics continues to be an interesting challenge. In this chapter, each section presents a broad overview of the LGIC structure, physiology, pharmacology, and examples of key ligands and therapeutics. Recent review articles that will direct the reader to more in-depth coverage are cited at the beginning of each section, and original research literature is cited for points of particular interest.