ION CHANNELS AS DRUG TARGETS & CONTROL OF RECEPTOR EXPRESSION

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

Ion Channels Ions are unable to penetrate the lipid bilayer of the cell membrane, and can get across only with the help of membrane-spanning proteins in the form of channels or transporters. The concept of ion channels was developed in the 1950s on the basis of electrophysiological studies on the mechanism of membrane excitation

Ion Channels (2) Ion channels consist of protein molecules designed to form water-filled pores that span the membrane, and 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 (3) Ion channels are characterised by: their selectivity for particular ion species, determined by the size of the pore and the nature of its lining their gating properties (i.e. the nature of the stimulus that controls the transition between open and closed states of the channel) their molecular architecture.

ION SELECTIVITY Channels are generally either cation selective or anion selective. The main cation-selective channels are selective for Na+, Ca2+ or K+, or non-selective and permeable to all three. Anion channels are mainly permeable to Cl-, although other types also occur.

VOLTAGE-GATED CHANNELS These channels open when the cell membrane is depolarised. They form a very important group because they underlie the mechanism of membrane excitability The most important channels in this group are selective sodium, potassium or calcium channels. Commonly, the channel opening (activation) induced by membrane depolarisation is short lasting, even if the depolarisation is maintained. This is because, with some channels, the initial activation of the channels is followed by a slower process of inactivation.

LIGAND-GATED CHANNELS These (see above) 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. The vanilloid receptor TRPV1 mediates the pain-producing effect of capsaicin on sensory nerves (as well as responding to low pH and heat.

LIGAND-GATED CHANNELS (2) Some ligand-gated channels in the plasma membrane respond to intracellular rather than extracellular signals, the most important being the following: Calcium-activated potassium channels, which occur in most cells and open, thus hyperpolarising the cell, when [Ca2+]i increases. ATP-sensitive potassium channels, which open when the intracellular ATP concentration falls because the cell is short of nutrients. These channels, which are quite distinct from those mediating the excitatory effects of extracellular ATP, occur in many nerve and muscle cells, and also in insulin-secreting cells (see Ch. 30), where they are part of the mechanism linking insulin secretion to blood glucose concentration.

PHARMACOLOGY OF ION CHANNELS Many drugs and physiological mediators described in this book exert their effects by altering the behaviour of ion channels. Here we outline the general mechanisms as exemplified by the pharmacology of voltage- gated sodium channels (Fig. 3.19). Ion channel pharmacology is likely to be a fertile source of future new drugs (see Clare et al., 2000).

Modulation of Ion Channels The gating and permeation of both voltage- gated and ligand-gated ion channels is modulated by many factors, including the following. Ligands that bind directly to various sites on the channel protein. These include many neurotransmitters, and also a variety of drugs and toxins that act in different ways, for example by blocking the channel or by affecting the gating process, thereby either facilitating or inhibiting the opening of the channel.

Modulation of Ion Channels (2) Mediators and drugs that act indirectly, mainly by activation of GPCRs. The latter produce their effects mainly by affecting the state of phosphorylation of individual amino acids located on the intracellular region of the channel protein. This modulation involves the production of second messengers that activate protein kinases. The opening of the channel may be facilitated or inhibited, depending on which residues are phosphorylated. Drugs such as β-adrenoceptor agonists affect calcium and potassium channel function in this way, producing a wide variety of cellular effects

Modulation of Ion Channels (3) Intracellular signals, particularly Ca2+ and nucleotides such as ATP and GTP Many ion channels possess binding sites for these intracellular mediators. Increased [Ca2+]i opens certain types of potassium channels, and inactivates voltage-gated calcium channels. [Ca2+]i is itself affected by the function of ion channels and GPCRs. Drugs of the sulfonylurea class act selectively on ATP-gated potassium channels.

CONTROL OF RECEPTOR EXPRESSION Receptor proteins are synthesised by the cells that express them, and the level of expression is itself controlled 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 (2) Examples of this type of control include the proliferation of various postsynaptic receptors after denervation, the upregulation of various G-protein- coupled and cytokine receptors in response to inflammation

CONTROL OF RECEPTOR EXPRESSION (3) Long-term drug treatment invariably induces adaptive responses, which, particularly with drugs that act on the central nervous system, are often the basis for therapeutic efficacy. They may take the form of a very slow onset of the therapeutic effect (e.g. with antidepressant drugs;, or the development of drug dependence.

CONTROL OF RECEPTOR EXPRESSION (4) It is likely that changes in receptor expression, secondary to the immediate action of the drug, are involved in delayed effects of this sort-a kind of 'secondary pharmacology' whose importance is only now becoming clearer. The same principles apply to drug targets other than receptors (ion channels, enzymes, transporters, etc.) where adaptive changes in expression and function follow long-term drug administration, resulting, for example, in resistance to certain anticancer drugs