ION CHANNELS AS DRUG TARGETS & CONTROL OF RECEPTOR EXPRESSION

Some ion channels (known as ligand-gated ion channels or ionotropic receptors) incorporate a receptor and open only when the receptor is occupied by an agonist; Others are gated by different mechanisms, voltage-gated ion channels being particularly important In general, drugs can affect ion channel function by interacting either with the receptor site of ligand-gated channels or with other parts of the channel molecule.

The interaction can be indirect, involving a G-protein and other intermediaries, or Direct, where a drug itself binds to the channel protein and alters its function In the simplest case, exemplified by the action of local anaesthetics on the voltage-gated sodium channel, the drug molecule plugs the channel physically blocking ion permeation.

E.g. of drugs that bind to accessory sites on the channel protein and thereby affect channel gating include: Vasodilator drugs of dihydropyridine type; these inhibit the opening of the L-type calcium channels Benzodiazepine tranquillizers: these bind to a region of the gamma-aminobutyric acid (GABA) receptor/chloride channel complex (a ligand-gated channel; that is distinct from the GABA-binding site;

most benzodiazepines facilitate the opening of the channel by the inhibitory neurotransmitter GABA, but some inverse agonists are known that have the opposite effect, causing anxiety rather than tranquility Sulfonylureas: these are used in treating diabetes mellitus and act on ATP-sensitive potassium channels of pancreatic beta-cells and thereby enhance insulin secretion

We have discussed ligand-gated ion channels as one of the four main types of drug receptors. There are many other types of ion channel that represent important drug targets, even though they are not generally classified as ‘receptors’ since they are not immediate targets of fast transmitters.

Ion channels consist of protein molecules designed to form water-filled pores that span the membrane, and they can switch between open and closed states. The rate and direction of ion movement through the pore is governed by the electrochemical gradient for the ion in question, which is a function of its concentration on either side of the membrane, and of the membrane potential.

Ion channels are characterized by: Their selectivity for particular ion species, which depends on the size of the pore and the nature of its lining Their gating properties (i.e. the mechanisms that controls the transition between open and closed states of the channel) Their molecular architecture

SELECTIVITY Channels are generally either cation or anion selective. Cation-selective channels may be selective for Na+, Ca2+ or K+ or may be non selective and permeable to all three. Anion channels are mainly permeable to Cl-, though other types also occur.

GATING Voltage-gated channels: Most of these channels open when the membrane is depolarised. They form a very important group because they underly the mechanism of membrane excitability Most important channels in this group Selective sodium, potassium or calcium channels

Commonly, the channel opening (activation) induced by membrane depolarization is short-lasting, even if the depolarization is maintained. This is because, with some channels, the initial activation of the channels is followed by a slower process of inactivation. Revise on: The role of voltage-gated channels in the generation of action potentials and in controlling other cell functions

Ligand-gated channels: Are activated by binding of a chemical ligand to a site on the channel molecule. Fast neurotransmitters, such as glutamate, acetylcholine, GABA and ATP act in this way, binding to sites on the outside of the membrane. Some ligand-gated channels in the plasma membrane respond to intracellular, rather than extra cellular, signals, the most important being:

Ca2+ activated potassium channels, which occur in most cells and open, thus hyperpolarizing the cell, when intracellular Ca2+ levels increases ATP-sensitive potassium channels, which open when the intracellular ATP concentration falls because the cell is short of nutrients; these channels which are distinct from those mediating the excitatory effects of extra cellular ATP, occur in many nerve and muscle cells, and also in insulin-secreting cells, where they are part of the mechanism linking insulin secretion to blood glucose concentration

The vanilloid receptor, for which the binding site for capsaicin resides on the cytoplasmic part of the molecule

Calcium release channels: These channels are present on the ER or SR, rather than the plasma membrane. The main ones, inositol triphosphate (IP3) and ryanodine receptors are a special class of ligand-gated calcium channels that controls the release of calcium from intracellular stores

‘Store operated’ Ca2+ channels (SOCs) : When the intracellular Ca2+ stores are depleted, channels in the plasma membrane open to allow Ca2+ entry. the mechanism by which this linkage occurs is poorly understood but these SOCs are important in the mechanism of action of many GPCRs that elicit Ca2+ release. The opening of SOCs allows intracellular Ca2+ to remain elevated even when the stores are running low, and they also provide a route through which the stores can be replenished.

CONTROL OF RECEPTOR EXPRESSION Receptor proteins are synthesized by the cells that express them, and the level of expression is itself controlled, via pathways, by receptor mediated events. Receptors are themselves subject to regulation Short-term regulation of receptor function generally occurs through desensitisation Long-term regulation occurs through an increase or decrease of receptor expression

Control of receptor expression.... Examples of long-term receptor regulation Proliferation of various postsynaptic receptors after denervation Up-regulation of various G-protein-coupled and cytokine receptors in response to inflammation Induction of growth factor receptors by certain tumuor viruses

Control of receptor expression.... Adaptive responses following long-term drug treatment are very common, particularly with drugs that act on the CNS. They may take the form of a very slow onset of the therapeutic effects e.g with antidepressant drugs or the development of drug dependence

Receptors and disease Increasing understanding of receptor function in molecular terms has revealed a number of diseases directly linked to receptor malfunction The principle mechanisms are: Autoantibodies directed against receptor proteins Mutations in genes encoding receptors and proteins involved in signal transduction

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