Assignment no : 02

NAME : MALIK AYAZ ALI

Enrollment : 4-11/2020/031

Subject : Pharmacology

Date : 18-january-2020

Receptors:
Receptors are chemical structures, composed of protein, that receive and transduce signals that may be
integrated into biological systems. These signals are typically[nb 1] chemical messengers which bind to a
receptor and cause some form of cellular/tissue response, e.g. a change in the electrical activity of a cell.
There are three main ways the action of the receptor can be classified: relay of signal, amplification, or
integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and
integration allows the signal to be incorporated into another biochemical pathway.

Structure

The structures of receptors are very diverse and include the following major categories, among others:

Type 1:

Ligand-gated ion channels (ionotropic receptors) – These receptors are typically the targets of fast
neurotransmitters such as acetylcholine (nicotinic) and GABA; activation of these receptors results in
changes in ion movement across a membrane. They have a heteromeric structure in that each subunit
consists of the extracellular ligand-binding domain and a transmembrane domain which includes four
transmembrane alpha helices. The ligand-binding cavities are located at the interface between the
subunits.

Type 2:

G protein-coupled receptors (metabotropic receptors) – This is the largest family of receptors and
includes the receptors for several hormones and slow transmitters e.g. dopamine, metabotropic
glutamate. They are composed of seven transmembrane alpha helices. The loops connecting the alpha
helices form extracellular and intracellular domains. The binding-site for larger peptide ligands is usually
located in the extracellular domain whereas the binding site for smaller non-peptide ligands is often
located between the seven alpha helices and one extracellular loop. The aforementioned receptors are
coupled to different intracellular effector systems via G proteins.

Type 3:

Kinase-linked and related receptors , they are composed of an extracellular domain containing the
ligand binding site and an intracellular domain, often with enzymatic-function, linked by a single
transmembrane alpha helix. The insulin receptor is an example.

Type 4:

Nuclear receptors – While they are called nuclear receptors, they are actually located in the cytoplasm
and migrate to the nucleus after binding with their ligands. They are composed of a C-terminal ligand-
binding region, a core DNA-binding domain (DBD) and an N-terminal domain that contains the
AF1(activation function 1) region. The core region has two zinc fingers that are responsible for
recognizing the DNA sequences specific to this receptor. The N terminus interacts with other cellular
transcription factors in a ligand-independent manner; and, depending on these interactions, it can
modify the binding/activity of the receptor. Steroid and thyroid-hormone receptors are examples of
such receptors.

Membrane receptors may be isolated from cell membranes by complex extraction procedures using
solvents, detergents, and/or affinity purification.

The structures and actions of receptors may be studied by using biophysical methods such as X-ray
crystallography, NMR, circular dichroism, and dual polarisation interferometry. Computer simulations of
the dynamic behavior of receptors have been used to gain understanding of their mechanisms of action.

Binding and activation

Ligand binding is an equilibrium process. Ligands bind to receptors and dissociate from them according
to the law of mass action in the following equation, for a ligand L and receptor, R. The brackets around
chemical species denote their concentrations.

One measure of how well a molecule fits a receptor is its binding affinity, which is inversely related to
the dissociation constant Kd. A good fit corresponds with high affinity and low Kd. The final biological
response (e.g. second messenger cascade, muscle-contraction), is only achieved after a significant
number of receptors are activated.

Affinity is a measure of the tendency of a ligand to bind to its receptor. Efficacy is the measure of the
bound ligand to activate its receptor.
Agonists versus antagonists

Efficacy spectrum of receptor ligands.

Not every ligand that binds to a receptor also activates that receptor. The following classes of ligands
exist:

agonists are able to activate the receptor and result in a strong biological response. The natural
endogenous ligand with the greatest efficacy for a given receptor is by definition a full agonist (100%
efficacy).

Partial agonists do not activate receptors with maximal efficacy, even with maximal binding, causing
partial responses compared to those of full agonists (efficacy between 0 and 100%).

Antagonists bind to receptors but do not activate them. This results in a receptor blockade, inhibiting
the binding of agonists and inverse agonists. Receptor antagonists can be competitive (or reversible),
and compete with the agonist for the receptor, or they can be irreversible antagonists that form
covalent bonds (or extremely high affinity non-covalent bonds) with the receptor and completely block
it. The proton pump inhibitor omeprazole is an example of an irreversible antagonist. The effects of
irreversible antagonism can only be reversed by synthesis of new receptors.

Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity (negative
efficacy).

Allosteric modulators: They do not bind to the agonist-binding site of the receptor but instead on
specific allosteric binding sites, through which they modify the effect of the agonist. For example,
benzodiazepines (BZDs) bind to the BZD site on the GABAA receptor and potentiate the effect of
endogenous GABA.

Note that the idea of receptor agonism and antagonism only refers to the interaction between receptors
and ligands and not to their biological effects.

Constitutive activity

A receptor which is capable of producing a biological response in the absence of a bound ligand is said to
display "constitutive activity". The constitutive activity of a receptor may be blocked by an inverse
agonist. The anti-obesity drugs rimonabant and taranabant are inverse agonists at the cannabinoid CB1
receptor and though they produced significant weight loss, both were withdrawn owing to a high
incidence of depression and anxiety, which are believed to relate to the inhibition of the constitutive
activity of the cannabinoid receptor.
The GABAA receptor has constitutive activity and conducts some basal current in the absence of an
agonist. This allows beta carboline to act as an inverse agonist and reduce the current below basal
levels.

Mutations in receptors that result in increased constitutive activity underlie some inherited diseases,
such as precocious puberty (due to mutations in luteinizing hormone receptors) and hyperthyroidism
(due to mutations in thyroid-stimulating hormone receptors).

Receptor ligands can be distinguished on the basis of their potential to initiate a biological response
following receptor binding:

• Agonists bind to a receptor protein to produce a conformational change, which is necessary to initiate
a signal that is coupled to a biological response. As the free ligand concentration increases, so does the
proportion of receptors occupied, and hence the biological effect. When all of the receptors are
occupied the maximum biological effect is achieved. It has been observed in many receptor systems that
full agonists can elicit the maximum effect without occupying all available receptors, suggesting the
concept of ‘spare receptors’. This apparent excess of receptors allows full responses to occur at lower
ligand concentrations than would otherwise be required.

• Antagonists bind to a receptor but do not produce the conformational change that initiates an
intracellular signal. Occupation of the receptor by a competitive antagonist prevents binding of other
ligand and so 'antagonizes' the biological response to the agonist. The inhibition that antagonists
produce can be overcome by increasing the dose of the agonist. Some antagonists interfere with the
response to the agonist in other ways than receptor competition and are known as non-competitive
antagonists. Simply increasing the dose of the agonist cannot overcome their effects and so the
maximum response to the agonist (its 'efficacy') is reduced.

• Partial agonists are able to activate a receptor but cannot produce a maximal signaling effect
equivalent to that of a full agonist even when all available receptors are occupied. When mixed with full
agonists, partial agonists block receptor sites that could potentially be occupied by the full agonist,
which reduces the overall response (i.e. they seem to antagonize the effect of the full agonist). Partial
agonists have some advantages as therapeutic agents. Although they are unable to achieve the same
maximum effect as the full agonist, they are less likely to produce receptor-mediated adverse effects at
the top of their dose–response curve (e.g. the partial opioid receptor agonist buprenorphine does not
cause as much respiratory depression as morphine when it is used as an analgesic).
• Inverse agonists produce the opposite effect to the full agonist when they bind to a receptor. For
inverse agonists to be identified, the relevant endogenous receptor must show some degree of coupling
to a biological response even in the absence of ligand binding (i.e. constitutive activity). Many receptors
possess constitutive activity.

Receptors are typically glycoproteins located in cell membranes that specifically recognize and bind to
ligands. These are smaller molecules (including drugs) that are capable of 'ligating' themselves to the
receptor protein. This binding initiates a conformational change in the receptor protein leading to a
series of biochemical reactions inside the cell (‘signal transduction’), often involving the generation of
‘secondary messengers’ that is eventually translated into a biological response (e.g. muscle contraction,
hormone secretion). Although the ligands of interest to prescribers are exogenous compounds (i.e.
drugs), receptors in human tissues have evolved to bind endogenous ligands such as neurotransmitters,
hormones, and growth factors. Formation of the drug-receptor complex is usually reversible and the
proportion of receptors occupied (and thus the response) is directly related to the concentration of the
drug. Reversibility enables biological responses to be modulated and means that similar ligands may
compete for access to the receptor. The term 'receptor' is usually restricted to describing proteins
whose only function is to bind a ligand, but it is sometimes used more widely in pharmacology to include
other kinds of drug target such as voltage-sensitive ion channels, enzymes and transporter proteins.

Internal receptors, also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of
the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma
membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of
mRNA synthesis. Recall that mRNA carries genetic information from the DNA in a cell’s nucleus out to
the ribosome, where the protein is assembled. When the ligand binds to the internal receptor, a change
in shape is triggered that exposes a DNA-binding site on the receptor protein. The ligand-receptor
complex moves into the nucleus, then binds to specific regions of the DNA and promotes the production
of mRNA from specific genes (Figure 2). Internal receptors can directly influence gene expression (how
much of a specific protein is produced from a gene) without having to pass the signal on to other
receptors or messengers.

This illustration shows a hydrophobic signaling molecule that diffuses across the plasma membrane and
binds an intracellular receptor in the cytoplasm. The intracellular receptor-signaling molecule complex
then travels to the nucleus and binds DNA.

Hydrophobic signaling molecules typically diffuse across the plasma membrane and interact with
intracellular receptors in the cytoplasm. Many intracellular receptors are transcription factors that
interact with DNA in the nucleus and regulate gene expression.

CELL-SURFACE RECEPTORS
Cell-surface receptors, also known as transmembrane receptors, are proteins that are found attached to
the cell membrane. These receptors bind to external ligand molecules (ligands that do not travel across
the cell membrane). This type of receptor spans the plasma membrane and performs signal
transduction, in which an extracellular signal is converted into an intercellular signal. Ligands that
interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors
are also called cell-specific proteins or markers because they are specific to individual cell types.

Each cell-surface receptor has three main components: an external ligand-binding domain, a
hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The size and extent
of each of these domains vary widely, depending on the type of receptor.

Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are three
general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors,
and enzyme-linked receptors.

Ion channel-linked receptors

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows
specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive
membrane-spanning region. When a ligand binds to the extracellular region of the channel, there is a
conformational change in the proteins structure that allows ions such as sodium, calcium, magnesium,
and hydrogen to pass through .

This illustration shows a gated ion channel that is closed in the absence of a signaling molecule. When a
signaling molecule binds, a pore in the middle of the channel opens, allowing ions to enter the cell.

Figure 4 Gated ion channels form a pore through the plasma membrane that opens when the signaling
molecule binds. The open pore then allows ions to flow into or out of the cell.

G-protein-coupled receptors

G-protein-coupled receptors bind a ligand and activate a membrane protein called a G-protein. The
activated G-protein then interacts with either an ion channel or an enzyme in the membrane . Before
the ligand binds, the inactive G-protein can bind to a site on a specific receptor. Once the G-protein
binds to the receptor, the G-protein changes shape, becomes active, and splits into two different
subunits. One or both of these subunits may be able to activate other proteins as a result.
This illustration shows the activation pathway for a heterotrimeric G-protein, which has three subunits:
alpha beta, and gamma, all associated with the inside of the plasma membrane. When a signaling
molecule binds to a G-protein-coupled receptor in the plasma membrane, a GDP molecule associated
with the alpha subunit is exchanged for GTP. The alpha subunit dissociates from the beta and gamma
subunits and triggers a cellular response. Hydrolysis of GTP to GDP terminates the signal.

When a signaling molecule binds to a G-protein-coupled receptor in the plasma membrane, a GDP
molecule associated with the G-protein is exchanged for GTP. The subunits come apart from each other,
and a cellular response is triggered either by one or both of the subunits. Hydrolysis of GTP to GDP
terminates the signal.

Enzyme-linked receptors

Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with
an enzyme. In some cases, the intracellular domain of the receptor itself is an enzyme. Other enzyme-
linked receptors have a small intracellular domain that interacts directly with an enzyme. When a ligand
binds to the extracellular domain, a signal is transferred through the membrane, activating the enzyme.
Activation of the enzyme sets off a chain of events within the cell that eventually leads to a response.

How Viruses Recognize a Host

Unlike living cells, many viruses do not have a plasma membrane or any of the structures necessary to
sustain life. Some viruses are simply composed of an inert protein shell containing DNA or RNA. To
reproduce, viruses must invade a living cell, which serves as a host, and then take over the hosts cellular
apparatus. But how does a virus recognize its host?

Viruses often bind to cell-surface receptors on the host cell. For example, the virus that causes human
influenza (flu) binds specifically to receptors on membranes of cells of the respiratory system. Chemical
differences in the cell-surface receptors among hosts mean that a virus that infects a specific species (for
example, humans) cannot infect another species (for example, chickens).

However, viruses have very small amounts of DNA or RNA compared to humans, and, as a result, viral
reproduction can occur rapidly. Viral reproduction invariably produces errors that can lead to changes in
newly produced viruses; these changes mean that the viral proteins that interact with cell-surface
receptors may evolve in such a way that they can bind to receptors in a new host. Such changes happen
randomly and quite often in the reproductive cycle of a virus, but the changes only matter if a virus with
new binding properties comes into contact with a suitable host. In the case of influenza, this situation
can occur in settings where animals and people are in close contact, such as poultry and swine farms
(Sigalov, 2010). Once a virus jumps to a new host, it can spread quickly. Scientists watch newly
appearing viruses (called emerging viruses) closely in the hope that such monitoring can reduce the
likelihood of global viral epidemics.

REFERENCES

Text adapted from: OpenStax, Biology. OpenStax CNX. October 13, 2017.
https://cnx.org/contents/GFy_h8cu@10.118:H4oMpCSi@8/Signaling-Molecules-and-Cellul#footnote1