MPL102T-Seminar

Presented by,
K ACHYUTH
[Link] 1st Year
Advanced Pharmacology-1
Department of Pharmacology
MSRUAS
What are RECEPTORS?

• Definition;
It is defined as a macromolecule or binding site located on the surface
or inside the effector cell that serves to recognize the signal molecule
or a drug and initiate the response to it.
• Itself has no other function.
• These are the proteins located on the cell or inside the cell
• It helps in transmitting the signals from outside the cell to the inside
the side.
• The word ‘receptor’ was given by Paul Ehrlich (1854- 1915).

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Terms used in Drug-Receptor interaction

• Affinity: Refers to the strength of the interaction between a drug and

its receptor.
• Efficacy: refers to the ability of a drug to produce a biological
response, such as opening or closing an ion channel, activating an
enzyme, or regulating gene expression.
• Agonist: a drug that binds to a receptor and activates it to produce a
biological response.
• Antagonist: a drug which prevents the action of an agonist on a
receptor from producing biological response.
• Inverse agonist : a drug which activates the receptors to produce a
effect in the opposite direction to that of the agonist. 3
Cont.…

• Partial agonist : a drug which activates a receptor to produce

submaximal effect but antagonizes the action of a full agonist.

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 Agonists
E=+1

Partial
Agonists

E= 0 Antagonists

Inverse
Agonists
E= -1
RECEPTOR FAMILIES
CLASSIFICATION OF RECEPTORS

[Link] RECEPTORS
a) Ligand gated ion channels (Ionotropic receptors).
b) G-Protein coupled receptors.
c) Enzyme linked receptors.
2. INTRACELLULAR RECEPTORS
a) Nuclear receptors

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G-PROTEIN COUPLED RECEPTORS:
• These receptors are comprised of single peptide that has seven
membrane spanning regions and hence they are called SEVEN-
TRANSMEMBRANE RECEPTORS.
• These comprises largest family of receptors.
• LOCATION : Localised on the cell membrane.
• TIMESCALE: Seconds.
• EFFECTOR: Enzymes and ion channels.
• COUPLING: G-PROTEIN
• EXAMPLE: Adrenergic receptors, Muscarinic Ach receptor, histaminic
receptors, opioid and cannabinoid receptors, 5-HT receptors etc
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• G proteins also known as guanine nucleotide-binding proteins,
are a family of proteins that act as molecular switches inside
cells.
• G-proteins activity is regulated by its ability to hydrolyze guanosine
triphosphate(GTP) to guanosine di-phosphate(GDP).
• When they are bound to GDP they are ‘OFF’ and when they are
bound to GTP they are ‘ON’
• When the GPCRs binds to a signal molecule, the receptor is
• activated and changes its shape.
• This in turn send signals to G-proteins which causes displacement of GDP by GTP
which in turn activates G-protein.
• Activation causes the α-subunit to dissociate from the β and γ subunits .
• The α-subunit may bind to effector enzymes like adenylate cyclase and
phospholipase C.
• The β and γ sub-units binds to the ion channel kinases
TYPES OF G-PROTEIN COUPLED
RECEPTORS:

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G-PROTEIN MEDIATED PATHWAYS

• SECONDARY MESSENGER SYSTEMS INVOLVED IN SIGNAL

TRANSDUCTION:
Adenylate cyclase c AMP mediated pathway.
Phospholipase mediated pathway.

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Adenylate cyclase cAMP mediated pathway

• Adenylate cyclase is a membrane bound enzyme.

• These are activated by Gs proteins and are inactivated by Gi proteins.
• It produces cAMP using ATP, which acts on the protein kinases (PKA).
• The catalytic subunits are activated and carry out transcription
process
• In contrast to cAMP, the cGMP serves as an intracellular second
messenger only in a limited number of tissues, such as vascular
smooth muscle, intestinal mucosal cell and kidney.

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 Phospholipase C: IP3-DAG pathway
• The activated GTP-carrying α subunit of Gq activates the phospholipase Cβ (PLcβ).
• It hydrolyses the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate
(PIP2 ) to generate the second messengers inositol 1,4,5-trisphosphate (IP3 ) and
diacylglycerol (DAG).
• The IP3 being water soluble diffuses to the cytosol and mobilizes Ca2+ from
endoplasmic reticular depots.
• The lipophilic DAG remains within the membrane, but recruits protein kinase C
(PKc) and activates it with the help of Ca2+.
• released Ca2+ acts as a highly versatile regulator acting through calmodulin
(CAM), PKc and other effectors—mediates/modulates smooth muscle,
contraction, glandular secretion, neuronal excitability, intracellular movements,
membrane function, metabolism, cell proliferation, etc 15
Ion channel receptor

• They are also known as ‘Ionotropic receptors’.

• LOCATION : Localised on the cell membrane.
• TIMESCALE: Milliseconds.
• EFFECTOR: ion channels.
• COUPLING: no coupling (direct acting)
• Ions include: Na+, K+, Ca2+, cl -
• EXAMPLE: Nicotinic Ach receptor, GABA receptors, Glutamate
receptors, Glycine receptors, 5-HT receptors.

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Cont.…

• They give response to a binding chemical substance which in turn

called as LIGAND.
• When the ligand binds to the ion channel the receptor shows
confirmational changes in the structure and hence opens the way for
the influx of the ions.
• Influx of ‘+’ve ion causes depolarization.
• The influx of ‘–’ve ion causes polarization , repolarization and
hyperpolarization

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Cont…

Signal molecule binds as a ligand at

a specific site on the receptor

Conformational changes open the

channel allowing ions to flow into
the cell

The change in ion concentration

within the cell triggers cellular
responses
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Enzyme linked receptors

• An enzyme-linked receptor, also known as a catalytic receptor.

• Examples of the enzymatic activity include : Receptor tyrosine kinase.
In few cases it can also be guanylyl cyclase.
• LOCATION : Localized on the cell membrane.
• TIMESCALE: Few minutes to few hours.
• EFFECTOR: Protein kinases.
• COUPLING: no coupling (direct acting).
• EXAMPLE: Insulin, Growth factors, cytokine, ANF(atrial-natriuretic
factor) receptors.
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STRUCTURE OF RECEPTOR
TYROSINE KINASE
• Receptors exist as individual polypeptides
• Each has an extracellular signal-binding site
• An intracellular tail with a number of tyrosine's
& a single α helix spanning the membrane.
• The signaling molecule binds to the receptor
on the outside of the cell and causes a
conformational change on the catalytic function
located on the receptor inside the cell

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NUCLEAR RECEPTORS:
• A class of proteins found within cells that are responsible for the regulation of
transcription in response to small lipophilic compounds.
• They have ability to directly bind to DNA and regulate the adjacent genes.
• Nuclear receptors play key roles in both embryonic development and adult
homeostasis.
• LOCATION : Intracellular.
• TIMESCALE: minutes to hours.
• EFFECTOR: Gene transcription.
• COUPLING: via DNA.
• EXAMPLE: Steroid hormone, Thyroid hormone, Retinoic acid and vitamin D
receptors
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STRUCTURE OF NUCLEAR RECEPTOR

1.(AB) N terminal regulator domain :

Contains the activation function 1 whose
action is independent of the presence of ligand.
2. (C)DNA binding domain(DBD):Highly
conserved
domain containing 2 zinc fingers that binds
to specific sequences of DNA called
hormone response elements(HRE)

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Cont.…
• (D) Hinge region : flexible domain that connects the DBD with the
LBD,it influences intracellular trafficking and subcellular distribution.
• (E)Ligand binding domain(LBD) : Moderately conserved in a sequence
and highly conserved in structure b/w various nuclear receptors.

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Functions of RECEPTORS

To propagate regulatory signals from outside to inside the effector

cell when the molecular species carrying the signal cannot itself
penetrate the cell membrane
To amplify the signal
To integrate various extracellular and intracellular regulatory signals
To adapt to short term and long term changes and to maintain
homeostasis.

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Summery

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PL102T-Seminar