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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
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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
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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 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.
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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.
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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.
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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.
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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.
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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 voltagegated sodium channels (Fig. 3.19).
Ion channel pharmacology is likely to be a
fertile source of future new drugs (see Clare
et al., 2000).
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The gating and permeation of both voltagegated 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.
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
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.
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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
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Examples of this type of control include the
proliferation of various postsynaptic
receptors after denervation,
the upregulation of various G-proteincoupled and cytokine receptors in response
to inflammation
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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.
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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