TYPE OF RECEPTORS,THEIR STRUCTURE,MECHANISM.

1. RECEPTORS
PRESENTED BY:
HEENA PARVEEN,
ASST.PROFESSOR,
MRCP.

2. The protein targets for drug action on mammalian cells that
are described in this chapter can be broadly divided into:
• Receptors
• ion channels
• enzymes
• carrier molecules (transporters).
Receptors
Receptors are the sensing elements in the system of chemical
communications that coordinates the function of all the
different cells in the body, the chemical messengers being
the various hormones, transmitters and other mediators
Many therapeutically useful drugs act, either as agonists or
antagonists, on receptors for known endogenous
mediators.

3. Ion channels
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 the 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.

4. Examples of drugs that bind to accessory sites on the
channel protein and thereby affect channel gating
include:
vasodilator drugs of the dihydropyridine type ,which
inhibit the opening of L-type calcium channels .
• benzodiazepine tranquillisers These drugs bind to a
region of the GABA receptor-chloride channel complex
(a ligand-gated channel), this region being 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 tranquillity.
• Sulfonylureas used in treating diabetes, which act on
ATP-sensitive potassium channels of pancreatic β-cells
and thereby enhance insulin secretion.

5. Many drugs are targeted on enzymes .
Often, the drug molecule is a substrate analogue that acts as a
competitive inhibitor of the enzyme (e.g. captopril, acting on
angiotensin-converting enzyme);
In other cases, the binding is irreversible and non-competitive (e.g.
aspirin, acting on cyclo-oxygenase).
Drugs may also act as false substrates, where the drug molecule
undergoes chemical transformation to form an abnormal product
that subverts the normal metabolic pathway.
An example is the anticancer drug fluorouracil, which replaces uracil
as an intermediate in purine biosynthesis but cannot be converted
into thymidylate, thus blocking DNA synthesis and preventing cell
division .
It should also be mentioned that drugs may require enzymic
degradation to convert them from an inactive form, the prodrug ,
to an active form.
Drug toxicity often results from the enzymic conversion of the drug
molecule to a reactive metabolite.
.

6. RECEPTORS AGONISTS ANTAGONSITS
Nicotinic Ach receptor Ach Tubocurarine
Nicotine Bungarotoxin
Beta-Adrenoceptor Non-adrenaline Propanolol
Adrenaline
Isoprenaline
Histamine Histamine Mepyramie
Opiate Mophine Naloxone
Dopamine Dopamine Chlorpromazine
Oestrogen receptor Ethiylestradiol Tamoxifen

7. ION CHANNELS BLOCKERS MODULATORS
Voltage gated sodium
channels
Local Anaesthetics Veratridine
Renal tubule sodium
channels
Amiloride Aldosterone
Voltage gated calcium
channels
Divalent cations Dihydropyridines
ATP-Sensitive K+ channels ATP Sulphonylureas
GABA-gated chloride
channels
Picrotoxin BZD”s

8. The transport of ions and small organic molecules
across cell membranes generally requires a carrier
protein, because the permeating molecules are
often too polar (i.e. insufficiently lipid-soluble) to
penetrate lipid membranes on their own.
Those responsible for the transport of glucose and
amino acids into cells, the transport of ions and
many organic molecules by the renal tubule, the
transport of Na+ and Ca2+ out of cells, and the
uptake of neurotransmitter precursors (such as
choline) or of neurotransmitters themselves (such as
noradrenaline, 5-hydroxytryptamine [5-HT],
glutamate, and peptides) by nerve terminals. The
amine transporters belong to a well-defined
structural family, distinct from the corresponding
receptors.

10. Type 1: ligand-gated ion channels (also known as
ionotropic receptors).
These are membrane proteins with a similar
structure to other ion channels, and
incorporate a ligand-binding (receptor) site,
usually in the extracellular domain.
Typically, these are the receptors on which fast
neurotransmitters act.
Examples include the nicotinic acetylcholine
receptor (nAChR);
GABAA receptor ; and glutamate receptors of the
NMDA, AMPA and kainate types.

11. IONOTROPIC RECEPTORS

12. Type 2: G-protein-coupled receptors (GPCRs). These
are also known as metabotropic receptors or 7-
transmembrane-spanning (heptahelical) receptors.
They are membrane receptors that are coupled to
intracellular effector systems via a G-protein (see
below).
They constitute the largest family,and include
receptors for many hormones and slow
transmitters.
for example the muscarinic acetylcholine receptor
(mAChR, adrenergic receptors and chemokine
receptors .

15. Type 3: kinase-linked and related receptors. This is a
large and heterogeneous group of membrane receptors
responding mainly to protein mediators.
They comprise an extracellular ligand-binding domain
linked to an intracellular domain by a single
transmembrane helix. In many cases, the intracellular
domain is enzymic in nature (with protein kinase or
guanylyl cyclase activity).
Type 3 receptors include those for insulin and for various
cytokines and growth factors ; the receptor for atrial
natriuretic factor is the main example of the guanylyl
cyclase type.
The two kinds are very similar structurally, even though
their transduction mechanisms differ.

18. Type 4: nuclear receptors. These are receptors
that regulate gene transcription.
The term nuclear receptors is something of a
misnomer, because some are actually located
in the cytosol and migrate to the nuclear
compartment when a ligand is present.
They include receptors for steroid hormones,
thyroid hormone , and other agents such as
retinoic acid and vitamin D.

19. NUCLEAR RECEPTORS

22. 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 more
than 50 years ago on the basis of
electrophysiological studies on the mechanism of
membrane excitation.
Electrophysiology, particularly the voltage clamp
technique remains an essential tool for studying
the physiological and pharmacological properties of
ion channels.

23. Voltage Gated Sodium Channels

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