Tocris Small Molecules for Stroke Research - Ion Channels

The regulation of intracellular and extracellular ion concentrations is necessary for maintaining the resting potential of neurons as well as initiating and propagating action potentials. Hypoxic conditions such as those induced by ischemic strokes promote neuronal death in part by disrupting the mechanisms that control intracellular ion levels. Under normal physiological conditions, ionic concentrations across the plasma membrane are tightly regulated, in part by ion channels.

Ion channels are integral membrane proteins that form pores in membranes through which ions flow. Ion channels are often composed of multiple subunits and are typically classified either by ion specificity or by the type of gating used to regulate them. Two main types of gated channels include those that are voltage-gated and those that are ligand-gated. Voltage-gated channels respond to changes in the electrical potential that exists across the plasma membrane (membrane potential). Similarly, ligand-gated channels respond to ligand binding to the extracellular domain of the channel.

Of particular interest to stroke research are NMDA receptors (NMDA R) which are both ligand- and voltage-gated. At the resting membrane potential, the pore of the NMDA receptor is blocked by magnesium ions thereby preventing ions from flowing into cells. Opening of the channel requires: 1) binding of glutamate, 2) binding of Glycine as a co-agonist, 3) membrane depolarization, and 4) the release of magnesium. When all four requirements are met, NMDA R are activated and the channel opens, allowing calcium and other ions to pass through. Under hypoxic conditions, NMDA R become over-activated leading to high intracellular calcium levels which induces neuronal death through a number of mechanisms including activation of enzymes that destroy cellular architecture. Tocris offers a range of small molecule agonists and antagonists to support ion channel research including ligand sets (e.g. Catalog # 1825) which offers five different NMDA receptor ligands.