chandra shekhar singh college of pharmacy U.P.

1. RECEPTOR
PHARMACOLOGY
Presented By:-
Uttam singh & Renoo
CsscP koilha, kaushambi

2. Receptor and its back ground
These are specific binding sites which are situated on the surface
or inside the effector cell, and specific agonist or bio molecule
bind it and initiates a characteristic response.

The term actually came in existence in order to explain drug
mechanism.
These are small region of a macromolecule which may an
enzyme, a membrane or a specific intracellular substance like
protein or a nucleic acid.

3. Biological response given by a drug is the
result of drug receptor interaction which alter
the function of that specific cellular component
and there by initiates the series of biochemical
and physiological changes that are collectively
recognized as biological response.

4. Binding of drugs to receptors involve various
types of forces such as-ionic,
hydrogen,vanderwalls and covalent binding.

The ability of a drug to bind to the receptor is
called as affinity, while the drug ability to elicit
its pharmacological response is termed as its
intrinsic activity or efficacy.

5. Receptor has ability to recognize a given molecule or
drug in three dimensional way and thus binding occurs
further which is responsible for biological response.

The receptor was coined by Langley in 1978 to define
the sites to which the drug combines and produces a
response thus receptor can be clearly defined target
molecule with which a drug molecule combines to
produce the effect.

6. Types of Receptors
1. Inotropic receptor or ligand gated ion channel
2. G-PCR (G-protein coupled receptor)
3. Intracellular receptor or cytoplasmic receptor or
nuclear receptor or steroidal receptor
4. Enzyme linked receptor

7. The first receptor family comprises ligand-gated ion
channels that are responsible for regulation of the flow
of ions across cell membranes.
The activity of these channels is regulated by the
binding of a ligand to the channel. Response to these
receptors is very rapid, having durations of a few
milliseconds.
The nicotinic receptor and the γ-amino butyric acid
(GABA) receptor are important examples of ligand-
gated receptors, the functions of which are modified by
numerous drugs.
Ionotropic Receptor

8. Stimulation of the nicotinic receptor by acetylcholine
results in sodium influx,
Generation of an action potential, and activation of
contraction in skeletal muscle. Benzodiazepines, on the
other hand, enhance the stimulation of the GABA
receptor by GABA, resulting in increased chloride
influx and hyperpolarization of the respective cell.

9. The single unit of pentameters are called as oligomers.
Example of cell surface receptors are- Na, K , Cl and
Ca ion.
Agonist binding open the channel and causes the
depolarization/ hyperpolarization/change in cytosolic
ionic composition----action potential generated-----
biological response.
In this receptor the involvement of 2nd messenger or
G-protein are absent.
Example-Ach ,local anesthetics, general anesthetics
etc.

10. Ligand binding
agonist
α α
β
δγ
Effector domain
Diagrammatic representation of receptor mediated operation of membrane ion channel.

11. In case of nicotinic cholinergic receptor. the molecule (8 nm in
diameter) is composed of 5 subunits (2α +β+ δ + γ) enclosing
a cylindrical ion channel. Normally the channel is closed (A).
When two molecules of acetylcholine bind to the two a
subunits (B). all subunits move apart opening the central pore
to 0 7 nm. enough to allow passage of partially hydrated Na"
ions Anions are blocked from passage through the channel by
positive charges lining it.
In other cases. K+, Ca2+ or Cl- ions move through the channel
depending on its ion selectivity

15. It is large family of receptors consists of G protein in
coupled receptors
Single subunit with 7 transmembrane spanning domains
(hepta-hilicle).
Ligand binds in cleft on external face.
These receptors are linked to a G-protein having 3subunits
(α,β,and γ)
Ligand binding activates G-protein
G protein activate various effectors.
Sometimes the effectors are the ion channels.
Also called as Metabotropic Receptors

16. GDPGTP
TM1
TM5
TM4
TM3
TM2
Asp -
NE +
N
C
β-adrenergic
receptor
TM7 TM6
Gs
protei
n
GDP
αs
i3
loop
TM1
TM5
TM4
TM3
TM2
N
TM7 TM6
Asp -
β
γ
ATP
cAMP
GDP
αs
β
γ
cAMP
cAMP
cAMP
Cytoplasm
Extracellular space

17.  The binding of an agonist to extracellular region of the receptors
which activates G-protein so that GTP hydrolyze in to GDP on the
α-subunit.
 All such receptors have a common pattern of structural organization.
 The G-protein float in the membrane with the exposed domain lying
in the cytosol and are heteromeric in composition (α,β,and γ
subunit) .
ACTION – EFFECT SEQUENCE :
Drug action transducer mechanism drug effect

18. There are three major effector pathways through which
GPCRs function.
1. Adenyl cyclase: cAMP pathway
2. Phospholipase C: IP3-DAG pathway
3. Channel regulation
Types of G-PCR

19. in
te
r
m
e
n
di
at
e
PKa
cAMP
Functional
proteins
Increase
interaction
with Ca ion
Phospholamban
Faster sequestration of Ca
ion in SR
FASTER RELAXATION
Ca ion
Induce troponin
Better excitation-contraction
coupling
Increase cardiac contraction
Gi
GDP
GTP
1. Adenyl cyclase: cAMP pathway

20. adrenaline (Adr) binds to β-adrenergic receptor (β-R) on the
cell surface inducing a conformational change which permits
interaction of the G-protein binding site with the stimulatory G-
protein (Gs).
The activated Gs now binds GTP (in place of GDP) causing its
active subunit to dissociate and inturn activate the enzyme
adenylyl cyclase (AC) located on the
Cytosolic side of the membrane: ATP is hydrolyzed to cAMP
which phosphorylates and thus activates cAMP dependent
Protein kinase (PKA). The PKA phosphorylates many
functional proteins including troponin and phospholamban, so
that
They interact with Ca ion ,respectively resulting in increased
force of contraction and faster relaxation.

21. Calcium is made available by entry from outside (direct
activation of myocardial membrane Ca ion channels by Gs and
through their phosphorylation by PKA) as well as from
intracellular stores.
One of the other proteins phosphorylated by cAMP is
phosphorylase kinase which then activates the enzyme
phosphorylase resulting in breakdown of glycogen to be utilized
as energy source for increased contractility.
Action of acetylcholine (ACh) on muscarinic M2 receptor (M2-
R), also located in the myocardial membrane, can activate an
inhibitory G-protein (Gi) which then opposes the activation of
AC by Gs.

22. HISTAMINE
G
q
IP3
P.kc
+
contractionMLCKCCPK
Other
effectors
CAM
+
+CAM
1. Phospholipase C: IP3-DAG pathway

23. The agonist, e.g. histamine binds to its H, receptor (H1 R) and activates
the G-protein Gq. which inturn activates membrane bound
phospholipase C (Plc) that hydrolyses phosphatidylinositol 4, 5-
bisphosphate (PIP2), a membrane bound phospholipid. The products
inositol 1 , 4, 5-trisphosphate (IP3) and diacylglycerol (DAG) act as
second messengers.
The primary action of IP3 is facilitation of Ca ion mobilization from
intracellular organellar pools, while DAG in conjunction with Ca ion
activates protein kinase C (PKc) which phosphorylates and alters the
activity of a number of functional and structural proteins. Cytosolic Ca
ion is a veritable messenger: combines with calmodulin (CAM) to
activate myosin light chain kinase (MLCK) inducing contraction, and
another important regulator calcium-calmodulin protein kinase (CCPK)
Several other effectors are regulated by Ca ion in a CAM dependent or
independent manner.

24. (c) Channel regulation
The activated G-proteins can also open or close ionic channels specific
for Ca++,K+or Na+, without the intervention of any second messenger
like cAMP or IP3, and bring about hyper polarization/ depolarization/
changes in intracellular Ca++.
 The Gs opens Ca2+ channels in myocardium and skeletal muscles,
while Gi and Go open K+ channels in heart and smooth muscle as well
as close neuronal Ca2+ channels.
Physiological responses like changes in inotropy, chronotropy,
transmitter release, neuronal activity and smooth muscle relaxation
follow.

25. Hormone
binding site
Peptide
hormone
membr
ane
E
C
F
I
C
F
t-Pr-K
Catalytic
site
Cytokine/hor
mone

26. Intrinsic tyrosine protein kinase receptor:
On binding the peptide hormone to the extracellular domains,
the monomeric receptors move laterally in the membrane and
form diamers. Dimerization activates tyrosine-protein kinase (t-
Pr-K) activity of the intracellular domains so that they
phosphorylate tyrosine (t) residues on each other as well as on
several SH2 domain substrate proteins (SH2-Pr).
The phosphorylated substrate proteins then perform
downstream signaling function.

27. JAK-STAT kinase binding receptor:
The intracellular domain of these receptors lacks intrinsic protein
kinase activity.
Signal molecule binding to the extracellular domain induces
receptor dimerization which activates the intracellular
domain to bind free moving JAK (Janus Kinase) molecules The
activated JAK phosphorylate tyrosine residues on the
receptor which then binds another protein STAT (signal
transducer and activator of transcription). Tyrosine residues
of STAT also get phosphorylated by JAK. The phosphorylated
STAT dimerize, dissociate from the receptor and move
to the nucleus to regulate transcription of target genes

28. Steroidal binding domain
protein
ribosome
Modification of cellular function

29. The glucocorticoid (G) penetrates the cell membrane and binds
to the glucocorticoid receptor (GR) protein that normally
resides in the cytoplasm in association with 3 other proteins
viz. heat shock protein 90 (HSP90), HSP70 and immunophilin
(I P).
The G R has a steroid binding domain near the carboxy
terminus and a mid region DNA binding domain having two
Zinc lingers' each made up of a loop of amino acids with
cheated zinc ion. Binding of the steroid to GR dissociates the
complexed proteins (HSP90, etc) removing their inhibitory
influence on it. A dimerization region that overlaps the steroid

30. binding domain is exposed, promoting dimerization of the
occupied receptor. The steroid bound receptor diamer
translocates to the nucleus and interacts with specific DNA
sequences called 'glucocorticoid responsive elements' (GREs)
with in the regulatory region of appropriate genes The expression
of these genes is consequently altered resulting in promotion (or
suppression) of their transcription.
The specific m RNA thus produced is directed to the ribosome
where the message is translated into a specific pattern of protein
synthesis, which inturn modifies cell function.

31. THANKS