Ion Channels: A physiological function for polyamines?

It is now recognized that polyvalent organic cations, such as polyamines, can act as endogenous modifiers of ion-channel gating, properties which were previously assumed to be entirely intrinsic to the channel proteins. All cells possess myriad different ion channels, which span their plasma membranes. These proteins are usually made up of four or five subunits, which together form an ion-permeable pore and a selectivity filter. A conforma-tional change in the protein is associated with a gating process, which 'opens' the pore, allowing permeant ions to flow down their electrochemical gradient, thus generating an electrical current. This current changes the voltage across the membrane, and in doing so modifies the gating of other ion channels. These channels may be broadly divided into two groups: voltage-gated channels, such as Na+ and Ca 2 + channels, which incorporate an integral voltage-sensor; and ligand-gated channels, such as nicotinic-acetylcholine and glutamate receptors, in which the conformational change is triggered by binding of a ligand to a receptor. It is the integration of currents through a variety of channels which sets the resting potential of a cell, generates action potentials, triggers exocytosis and mediates synaptic transmission. Over the last decade or so, the patch-clamp technique has permitted direct measurement of the currents generated by the opening and closing of single channels in small membrane patches, or of the summed currents in large patches or whole cells. Parallel developments in molecular biology have led to the cloning and sequenc-ing of genes encoding a wide range of channel proteins. The combined use of mutant channel proteins, generated by in vitro manipulation of their cloned genes, with patch-clamp recording has proved to be a powerful way of examining the intrinsic molecular determinants f channel gating (providing, for example, the evidence on which the ball-and-chain model for inactivation of the Shaker K + channel is based [1]). Not all of the gating properties of an ion channel need be integral to the channel structure-other molecules may be able to modify the gating, for example by entering and blocking the open pore. Such open-channel blocks are usually characterized by their voltage-dependence. As the blocking molecule is usually charged, its movement into the pore towards the blocking site will be influenced by the membrane potential. For example, an internal positively charged ion, such as Mg 2 +, will be attracted into the membrane field by depolarization, and repelled by hyperpolarization (an external …