RECEPTORS

INTRODUCTION
Generally speaking, there are two types of receptors – sensory (taste bud, rods and cones etc) and those
macromolecules which are specially related to physiology, biochemistry and pharmacology. Receptors which are
specifically related with physiology biochemistry especially pharmacology.
A receptor is any macromolecule or complex of macromolecules (proteins or peptide / DNA) which have a
minimum of two functional domains (ligand binding domain and effector domain).
A ligand is a substance which binds with a receptor at the ligand binding domain and lead to the production of
biological response. When the ligand binds to the receptor, it alters the structure of the receptor resulting in the
activation of the effector domain. Plasma proteins binds drug and other substances, but it does not have effector
domain, and no conformational change and therefore no specific biological response because no effector domain.
Ligand is substance which binds with a receptor and bring about conformational or functional change in the receptor
to produce some biological response. The ligand may be:
o Hormone
o Drug
o Neurotransmitter
o Toxins
o Other substances.
In response to binding, the receptor undergoes a conformational change (structural and functional change) it
undergoes a modification and result of that modification will be that the effector domain is activated or inactivated.
Receptors are broadly classified into the following groups based on their location:
o Cellular
o Membrane
o Intracellular
 Cytoplasm (steroid hormones)
 Nucleus (T3 and T4).
o extracellular

The ligands can access the receptor based on their molecular weight (size) charge and lipid solubility.

Cell surface (membrane):

 Large molecular weight
o Peptide hormones
 Insulin
 Growth Hormone
 Prolactin
 FSH
 LH
 TSH
 Highly polar (charged)
o Catecholamines
 Noradrenaline
 Adrenaline
 Dopamine
o Acetylcholine
o 5- HT
o Histamine
o Prostaglandin

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Intracellular

 Small molecular weight.

o T3 & T4
o Retinoids (Vitamin A).
 Lipid soluble
o All steroid hormones
 Testosterone
 Progesterone
 Oestrogen
 Aldosterone
 Glucocorticoid
 Vitamin D (cholecalciferol)

CELL MEMBRANE RECEPTORS

 7 pass / serpentine / G-protein coupled receptors.
 1 pass receptor (tyrosine kinase, insulin receptor)
 4 – 5 pass receptors / ion channel
 12 pass receptors

Transmembrane receptors take extracellular signal inside the cell and they bring about biological response inside the
cell.

7 PASS / SERPENTINE / G-PROTEIN COUPLED RECEPTOR

 Big family of receptors.

 Serpentine (snake-like)
 Passes in and out of the cell membrane 7 times
 Has two functional binding domains – ligand binding domain outside and the effector domain inside.
Extracellular domain is the ligand binding domain. When the ligand binds the receptor it activates the receptor, then
the intracellular part (effector domain) will start giving very unique signals to the cell.
Ligands for the 7-pass receptor include:
 Catecholamines

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  Acetylcholine
 Prostaglandins
 Histamine
 5 -Hydroxyl Tryptamine
 TSH

The 7-pass receptor is coupled to a unique type of protein – the trimetric primary protein found in the cell.

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The -subunit binds with a high energy compound (GTP) and the compound and the complex is highly energetic
and very active. Because the intracellular protein is binding with GDP or GTP, they are simply called G-protein
(serpentine receptor is a G-protein coupled receptor.

G-Proteins are unique type of intracellular proteins to which GTP or GDP binds. All the serpentine receptors work
through different types of G-Proteins – hence they are called G-protein coupled receptors.

ONE PASS RECEPTOR

One pass receptor has a unique effector domain – the domain is an enzyme, so the other name for the one pass
receptor is enzyme linked receptor.

Example of 1-pass receptors include:

 Tyrosine kinase
 Insulin
When insulin binds its 1-pass receptor, it attracts another 1-pass receptor resulting in a dimer; the intracellular
change is brought about by the dimer (insulin receptor dimerization).

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4 – 5 PASS RECEPTORS

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  May be 4 or 5 different peptide units eg ligand binding ion channels – nicotinic cholinergic receptors or
 Single peptide unit that is going in and out of the membrane.
 The effector unit is basically a canal or central pore which is opening and closing. When the ligand binds
the frequency of opening and closing of the canal changes and this brings about a biological change.
When Ach binds, it changes the frequency of opening and closing of the receptor canal. Upon ligand binding, some
ion channels undergo a conformational change that alters the flux or movement of the ions. Such receptors are called
ligand-gated or ligand operated ion channel.

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7-PASS / SERPENTINE / G-PROTEIN-COUPLED RECEPTOR
Examples of ligands that bind to the 7 – pass receptors include:
 Adrenergic receptors.
 Glucagon
 Muscarinic Ach receptors.
When adrenaline binds at the ligand binding domain, there is changes in intracellular cAMP levels.
 Ligand binding of catecholamine is the 1st messenger.
 Ultimate biological changes in cAMP is the 2nd messenger.

When the ligand binds at the ligand binding domain (amino acid end) extracellularly the carboxylic end (effector
domain) does not change the cAMP directly. In between there are many molecular signalling pathways going on.
When the ligand binds, there is a change (twist) at the effector domain resulting in its exposure. Binding of the
ligand result in a twist at the effector domain exposing it to the target protein (ie the next edition of protein that will
interact – ie the intracellular component become exposed to the signalling pathways. When the ligand binds it leads
to conformational changes in the transmembrane domain component in such a way that the intracellular component
becomes exposed to the signally pathways.

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The trimetric primary G-protein then binds to the intracellular effector domain – the G-protein binds GTP or GDP.
 Monomeric – 1 peptide
 Trimetric – 3 peptides (, , ).
The effector domain changes in such a way that the trimetric G-protein will bind there. 30 – 40 % of current drugs
act by modifying the action of the 7-pass receptors.

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12-PASS SERPENTINE RECEPTORS
 Single peptide chain
 Passes through the membrane 12 times.
 The 12 pass receptors are found at the presynaptic nerve endings of neurones which release monoamines
where they bring about their re-uptake into the presynaptic nerve endings.

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NUCLEAR HORMONE RECEPTORS:

Fig 1: Intracellular receptors

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Nuclear hormone receptors (NHRs) are located inside the cell. These receptors are found either in the cytoplasm
(type I) or the nucleus (Type II). Nuclear receptors are a family of ligand-regulated transcription factors that are
activated by:
 Steroid’s hormones (estrogen and progesterone)
 Lipid-soluble signals (retinoic acid, oxysterols)
 Thyroid hormones

MECHANISM OF ACTION OF NUCLEAR RECEPTOR.

Small lipophilic substances such as natural hormones diffuse through the cell membrane and bind to the nuclear
receptor located in the cytosol (type I) or nucleus (type II) of the cell. Binding causes a conformational change in the
receptor which, depending on the class of receptor, triggers a cascade of downstream events that direct the nuclear
receptor to DNA transcription regulation sites which result in up or down regulation of gene expression.

Fig 2: Mechanism of class I nuclear receptor action.

A class I nuclear receptor (NR), in the absence of a ligand, is located in the cytosol. Hormone binding to the NR triggers
dissociation of heat shock proteins (HSPs), dimerization, and translocation to the nucleus, where the NR binds to a specific
sequence of DNA known as a hormone response element (HRE). The nuclear receptor DNA complex in turn recruits other
proteins that are responsible for transcription of downstream DNA into mRNA, which is eventually translated into protein, which
results in a change in cell function.

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Fig 3: Mechanism of class II nuclear receptor action
A class II nuclear receptor (NR), regardless of ligand-binding status, is located in the nucleus bound to the DNA. For the purpose
of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence
of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of
coactivator protein, which, in turn, recruits additional proteins such as RNA polymerase that are responsible for transcription of
downstream DNA into RNA and eventually protein.

EXTRACELLULAR RECEPTORS

Example of extracellular receptor include:

 Coagulation factors.
 Antibodies
 Cytokines
 Complement C5a (activated).

COAGULATION FACTORS (ANTI-THROMBIN 3)

Coagulation factors are plasma proteins behaving like receptors. Anti-thrombin 3 are extracellular proteins which
inactivates some of the coagulation factors (eg active factor X). Anti-thrombin 3 behaves like receptor, it has
heparin binding domain and an effector domain. Some drugs bind with coagulation factors in such a way that their
action is either prolonged or reduced. When heparin binds at the ligand binding domain, it results in enhanced ability
of anti-thrombin 3 to inactivate coagulation factors.

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FORECES BETWEEN RECEPTOR AND LIGAND
 Van der Waal
 Hydrophobic interaction
 H+ bonds
 Ionic bond
 Covalent bond (strongest force)

Monoamines – amides derived from one amino acid

Amino acid amine
Tyrosine T3 and T4
Catecholamines [ Dopamine, Adrenaline, Noradrenaline]
Histidine Histamine
Tryptophan 5 -OH tryptamine

Monoamine Oxidase

Catechol ring

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Dopamine showing catechol ring, ethylene group (with beta carbon) and the amine group

Catecholamine catabolism involves the removal of the two OH group of the catechol ring by catechol – O- methyl
transferase (COMT). The OH group at the beta carbon is removed by monoamine oxidase inhibitors (MAOI).

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