Download ION CHANNELS AS DRUG TARGETS

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.
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• 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 voltagegated sodium channel, the drug molecule
plugs the channel physically blocking ion
permeation.
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• 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 ligandgated channel; that is distinct from the GABAbinding site;
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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
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• 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.
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• 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.
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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
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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.
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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
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• 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
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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:
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1. Ca2+ activated potassium channels, which occur
in most cells and open, thus hyperpolarizing the
cell, when intracellular Ca2+ levels increases
2. 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
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3. The vanilloid receptor, for which the
binding site for capsaicin resides on the
cytoplasmic part of the molecule
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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
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‘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.
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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
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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
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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
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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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READ THOUROUGHLY ON ION
CHANNELS!
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