Receptors are macromolecules that bind ligands like drugs and initiate a cellular response. There are several types of receptors including G-protein coupled receptors (GPCRs), ligand gated ion channels, kinase-linked receptors, and nuclear receptors. GPCRs are the largest family and signal through G proteins to regulate effectors like adenylyl cyclase. Ligand gated ion channels directly open or close ion channels. Kinase receptors have enzymatic activity and regulate transcription. Nuclear receptors directly bind DNA to regulate gene expression. Receptors play a key role in many physiological and pharmacological processes.

1. RECEPTORS AND ITS
FAMILIES
SUBMITTED BY
P.ASWIN
M.PHARM I YEAR I SEM
DEPARTMENT OF PHARMACOLOGY 1

2. WHAT IS RECEPTOR
The largest number of drugs do not bind directly to the
effectors, like enzymes, channels, transporters, structural
proteins, template biomolecules, etc. But act through
specific regulatory macromolecules which control the
above listed effectors. These regulatory macromolecules
or the sites on them which bind and interact with the drug
are called ‘receptors’.
 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/drug and initiate the
response to it, but itself has no other function.
2

3. INTRODUCTION
Drug action: It is the initial combination of the drug with
its receptor resulting in a conformational change in the
latter (in case of agonists), or prevention of conformational
change through exclusion of the agonist (in case of
antagonists).
Drug effect: It is the ultimate change in biological
function brought about as a consequence of drug action,
through a series of intermediate steps (transducer). 3

4. FUNCTION OF RECEPTOR
Receptors subserve two essential functions, viz,
recognition of the specific ligand molecule and
transduction of the signal into a response.
Accordingly, the receptor molecule has a ligand binding
domain (spatially and energetically suitable for binding the
specific ligand) and an effector domain which undergoes a
functional conformational change.
4

5. DEFINITIONS
 Ligand :(Latin: ligare—to bind) Any molecule which
attaches selectively to particular receptors or sites. The
term only indicates affinity or ability to bind without
regard to functional change: agonists and competitive
antagonists are both ligands of the same receptor.
 Agonist: An agent which activates a receptor to produce
an effect similar to that of the physiological signal
molecule. Agonists have both affinity and maximal
intrinsic activity. e.g. adrenaline, histamine, morphine.5

6. CONT…
Inverse agonist: An agent which activates a receptor to
produce an effect in the opposite direction to that of the
agonist. chlorpheniramine (on H1 histamine receptor).
Antagonist: An agent which prevents the action of an
agonist on a receptor or the subsequent response, but does
not have any effect of its own. . Competitive antagonists have
affinity but no intrinsic activity , e.g. propranolol, atropine,
chlorpheniramine,naloxone
Partial agonist: An agent which activates a receptor to
produce submaximal effect but antagonizes the action of a
full agonist. e.g. pentazocine (on μ opioid receptor).
6

7. GRAPH
7

8. TYPES OF RECEPTORS
The transducer mechanisms classifies receptors into 4 major
categories:
 G-Protein Coupled Receptors (GPCRs)
 Ligand Gated Ion channel receptor
 Kinase-linked and related receptors
 Receptors regulating gene expression ( Transcription
factors, Nuclearfactors
8

9. 1.GPCRS
 The first GPCR to be fully characterised was the β
adrenoreceptor, which was cloned in 1986.
 The GPCR molecule has 7 α-helical membrane
spanning hydrophobic amino acid (AA) segments
which run into 3 extracellular and 3 intracellular
loops. They are called seven-transmembrane
receptors because they pass through the cell
membrane seven times
 Two binding sites: agonist binding and G-protein
coupling.
 The third intracellular loop interacts with the G
protein. 9

10. GPCR
10

11. G-PROTEINS
These comprise a family of membrane-resident
proteins whose function is to recognize activated
GPCRs and pass on the message to the effector systems
that generate a cellular response.
They are called G proteins because of their interaction with
the guanine nucleotides, GTPand GDP.
G proteins consist of three subunits: α, β and γ.
Guanine nucleotides bind to the α subunit, which has
enzymatic (GTPase) activity, catalyzing the conversion of
GTP to GDP.
The β and γ subunits remain together as a βγ complex.
11

12.  In the basal state of the receptor-heterotrimer complex, the
α subunit contains bound GDPand the α-GDP:βγ complex
is bound to the unliganded receptor.
The G protein family is comprised of 23 α subunits, 7 β
subunits, and 12 γ subunits. 12

13. A number of G-proteins distinguished by their α subunits
have been described. The important ones with their action
on the effectorare:
1. Gs- Adenylyl cyclase activation, Ca+ channel opening.
2. Gi- Adenylyl cyclase inhibition, K+ channel opening.
3. Go- Ca+ channel inhibiton.
4. Gq- Phospholipase C activation.
13

14. MECHANISM OF ACTION
 When an agonist binds to a GPCR, there is a
conformational change in thereceptor.
 This causes the α subunit to exchange its bound GDP for
GTP.
 Binding of GTP activates the α subunit and causes it to
release both the βγ dimer andthe receptor.
 Both the GTP bound α subunit and the βγ heterodimer
become active signalingmolecules.
14

15. 15

16. 16

17. EFFECTOR PATHWAYS
The main targets for G proteins, through which GPCR control
different aspects of cellfunction are:
Adenylyl cyclase, the enzyme responsible for cAMP
formation.
Phospholipase C, the enzyme responsible for inositol
triphosphate and diacylglycerol(DAG) formation.
Ion channels, particularly calcium and potassium
channels.
17

18. 18
Adenylyl cyclase/cAMP pathway:
Activation of
AC
Intracellular
accumulation of
second messenger
cAMP
Activates Protein
Kinase (PKA)
Phosphorylates and alters the
function of many enzymes, ion
channels, transporters, transcription
factors and structural proteins
Increased contractility/
impulse generation,
relaxation, glycogenolysis,
lipolysis, secretion of
hormones, etc.

19. PHOSPHOLIPASE C : IP3-DAG
PATHWAY:
19
Activation of
phospholipase C
Hydrolyses the membrane
PIP2 to generate IP3 and
DAG
IP3 diffuses to cytosol and
mobilizes calcium from ER
whereas, DAG stays in the
membrane and recruits and
activates PKc.
The activated PKc
phosphorylates many
intracellular proteins and
mediated various physiological
responses

20.  Activation of phospholipase Cβ (PLcβ) by the activated GTP
carrying α subunit of Gq 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+. The activated PKc phosphorylates many
intracellular proteins (depending on the type of effector cell)
and mediates various physiological responses.
20

21. ION CHANNELS
 Another major function of G protein-coupled receptors
is to control ion channelfunction directly.
 These do not involve second messengers such as cAMP or
inositolphosphates.
Examples:
 In Cardiac muscles, mAChRs enhance K+ permeability.
 In neurons, inhibitory drugs such as opioid analgesics
reduce excitability by opening certain K+ channels or by
inhibiting voltage-activated Ca2+ channels and thus
reducing neurotransmitter release.
21

22. 2.LIGAND-GATED IONCHANNELS
Also known as Ionotropic receptors.
These are the receptors on which fast neurotransmittersact.
These mediate fast synaptic transmission, on a millisecond
time scale, in the nervous system and at the somatic
neuromuscular junction.
Typical example of this is Nicotinic Acetylcholine receptor at
NMjunction.
Other examples include GABAA , 5HT3 receptors, Glycine
receptors, IP3 receptors, Ionotropic Glutamate receptors,
etc.
22

23. These are integral membrane proteins that contain a
pore which allows the regulated flow of selected ions
across the plasma membrane.
Ion flux is passive and driven by the electrochemical
gradient for the permeant ions.
These channels are open, or gated, by the binding of a
neurotransmitter to an orthosteric site(s) that triggers a
conformational change that results in the conductingstate.
Modulation of gating can occur by the binding of
endogenous, or exogenous, modulatorsto allosteric sites.
23

24. The nicotinic acetylcholine receptor consists of a
pentameric assembly of four subunits, termed α, β, γ
and δ, each of molecular weight 40–58 kDa.
The pentameric structure (2α, β, γ, δ) possesses two
acetylcholine binding sites, each lying at the
interface between one of the two α subunits and its
neighbour.
Both must bind acetylcholine molecules in order for the
receptor to be activated.
Each subunit contains four membrane-spanning α-
helices, insertedinto the membrane.
24

25. NICOTINIC RECEPTOR
25

26. Mechanism ofAction:
The five helices that form the pore are sharplykinked
inwards halfway through the membrane, forming a
constriction.
When two acetylcholine molecules bind to the binding
sites, a conformational change occurs in the extracellular
part of the receptor.
This twists the α subunits, causing the kinked helical
segments to swivel out of the way, thus opening the
channel.
26

27. GABAA RECEPTOR
27

28. KINASE-LINKED AND RELATED
RECEPTORS
Diverse group of physiological membrane receptors.
They have extracellular ligand binding domains and an
intrinsic enzymatic activity on the cytoplasmic surface
of the cell.
Most are activated by a wide variety of protein
mediators, including growth factors and cytokines,
hormones such as insulin and leptin.
Here, the effects are exerted mainly at the level of
gene transcription.
28

29. The main types are as follows:
 Receptor tyrosine kinases (RTKs)
 Cytokine receptors ( JAK-STATReceptor)
 Receptor serine/threonine kinases
29

30. RECEPTOR TYROSINE KINASES
(RTKS):
These molecules consist of single polypeptide chains.
Have large, cysteine-rich extracellular domains.
Have short transmembrane domains.
The intracellular region containing one (or in some cases
two) protein tyrosine kinase domains.
Examples include receptors for hormones such as insulin,
for multiple growth factors.
30

31. INSULIN RECEPTOR
31

32. Cytokine receptors ( JAK-STATReceptor):
• These receptors signal to the nucleus by a more direct
manner than the receptortyrosine kinases.
• These receptors have no intrinsic enzymatic activity.
• The intracellular domain binds a separate, intracellular
tyrosine kinase termed a Januskinase (JAK).
• JAKs phosphorylate other proteins termed signal
transducers and activators oftranscription (STATs).
• Examples include receptors for cytokines such as γ-
interferon, hormones like growth hormone and
prolactin.
32

33. CYTOKINE RECEPTOR
33

34. Receptor serine/threonine kinases:
 This smaller class is similar in structure to RTKs.
 However, they phosphorylate serine and/or threonine
residues rather thantyrosine.
 The activated receptor on ligand binding, phosphorylates
a gene regulatory protein termeda Smad.
 The main example is the receptor for transforming
growth factor (TGF-β).
34

35. TGF SIGNALING
35

36. RECEPTORS REGULATING GENE
EXPRESSION
 Also called as Nuclear Receptors (NR).
 NRs can directly interact with DNA, so called ligand
activated transcriptionfactors.
 The core domain of the receptor is highly conserved and
consists of the structure responsible for DNA recognition
and binding.
 These transduce signals by modifying gene transcription.
 Examples are receptors for steroid hormones,
glucocorticoids, mineralocorticoids, thyroid hormone,
Vit D, etc. 36

37. NR RECEPTOR
37

38. Clinical Significance:
 NRs are very important drug targets, being responsible for
the biological effects of approximately 10–15% of all
prescription drugs.
 NRs also regulate expression of many drug metabolizing
enzymes and transporters.
 Many illnesses are associated with malfunctioning of the
NR system, including inflammation, cancer, diabetes,
cardiovascular disease, obesity and reproductive
disorders.
38

39. 39

40. REFERENCE
 Goodman, Gilman, L.Bruton: The Pharmacological Basis of
THERAPEUTICS; 12th Edition. New York: McGraw Hill Medical; 2011.
 H.P Rang, J.M. Ritter, R.J. Flower, G.Henderson: RANG & DALE’S
Pharmacology; 8th Edition. China: Elsevier; 2016.
 K.D Tripathi: Essentials of Medical Pharmacology; 7th Edition. New
Delhi: Jaypee Brothers;2013.
 IUPHAR/BPS. Guide to Pharmacology. www.guidetopharmacology.org/
 Nishimura A. et. al.(2010) Structural basis for the specific inhibition of
heterotrimeric Gq protein by a small molecule. Proc Natl Acad Sci;
107(31): 13666–13671.
40

41.  Gomes I et al. (2016). Identification of GPR83 as the receptor for the
neuroendocrine peptide PEN.Sci. Signal. 9(425): ra43.
 Huang XP, Karpiak J, Kroeze WK et al. (2015). Allosteric ligands for
the pharmacologically dark receptors GPR68 and GPR65 Nature
527: 477-83.
 Olmos-Alonso A, Schetters ST, Sri S et al. (2016). Pharmacological
targeting of CSF1R inhibits microglial proliferation and prevents
the progression of Alzheimer's-like pathology Brain : epub jan8.
 Schmidt HR, Zheng S, Gurpinar E et al. (2016). Crystal structure of
the human σ1 receptor. Nature 532(7600):527-530.
 Wayne D Bowen, et al. Sigma receptors: recent advances and new
clinical potentials. Pharmaceutica Acta Helvetiae, Vol 74, Issues 2–
3, 2000: 211–218.
41

42. 42
THANK
YOU