6.12 - Ion Channels

Abstract

The transport of ions across biological membranes, via ion channels, is a critical event that regulates signal transduction, ionic homeostasis, and other cellular physiological and biochemical processes like the osmotic health of cells, providing nutritional requirements, and maintaining electrogenic gradients. Ion channels are integral pore-forming membrane proteins that are activated by changes in membrane voltage or by binding of specific ligands. Specific binding sites on ion channels are also modulatory targets for a variety of toxic compounds, which affect ion channel function resulting in deleterious toxicological effects. Several toxins that target one specific subtype of ion channels have been isolated from a variety of plants, invertebrates, and vertebrates. Voltage-gated sodium channels are ubiquitously expressed in several cell types. The classification of toxins is based on toxin-specific binding sites. Sodium channel physiology and toxicology have been extensively researched, and the major types of toxins that modulate these channels include tetrodotoxin, saxitoxin, scorpion toxins, spider toxins, sea anemone toxins, and pyrethroids. The potassium channels show great variation in terms of their genetic diversity and channel properties. The major toxins that modulate potassium channels include scorpion toxins and dendrotoxins. The voltage-gated calcium channels are classified based upon their voltage threshold for activation and channel properties and are affected by toxins such as ω-conotoxins, ω-agatoxins, huwenotoxins, and glycerotoxin. Chloride channels are inhibited by Georgia anion toxin and are different from the ligand-gated γ-aminobutyric acid (GABA) and glycine receptors. GABA receptors are well characterized in terms of toxicology and are prominent targets of certain insecticides. The ionotropic glutamate receptors are one class of ligand-gated receptors that are affected by heavy metal ions and toxins, both synthetic and natural. The other major types of receptors include acetylcholine receptors and serotonin receptors; the former are targets of peptide toxins from venoms and the latter are targets of abused drugs of plant origin. The ion channel toxins, especially the ones with high binding affinities, have served as valuable tools for elucidating the structure and function of various ion channels. In addition, the knowledge of ion channel modulations by toxins serves as a basis for the future development of effective therapies. This chapter provides an updated systematic review of ion channel toxicology, particularly of the voltage-gated ion channels.