this is prepared from various receptor seminars.i kindly thank them.

1. Presented by
DR. MAHENDRANATH Y
1ST YEAR PG STUDENT
DEPT OF PHARMACOLOGY
RECEPTORS
113-08-2018

2. CONTENTS
2
Introduction – receptor
Drug – receptor interactions
Ligand gated ion channel receptors
G – protein coupled receptors
Kinase liked receptors
Nuclear receptors
Comparison of receptor types
Conclusion
References
2
13-08-2018

3. HISTORY
• JOHN LANGLEY:- (1878)
• CALLED RECEPTORS AS RECEPTIVE SUBSTANCES
• OBSERVED ANTAGONISM BETWEEN PILOCARPINE AND
ATRPOINE
3
PAUL EHRLICH:- (1906)
COINED THE TERM RECEPTORS
CORPORA NON AGUNT NISI FIXATA
DRUG TARGETS=MAGIC BULLETS13-08-2018

4. DEFINITION
Receptor:
• Macromolecular component of the cell that interact
with a drug (ligand) and initiates the chain of biochemical
events leading to the drug’s observed effects.
(Ligands: Endogenous ligands: Neurotransmitters,
hormones, etc.; Exogenous ligands: Drugs, xenobiotics)
• Most of drug receptors are proteins
• Receptors are present on cell surface (majority),
cytoplasm and nucleus.
• Responsible for selectivity and specificity of drug action.
413-08-2018

5. k1
k2
Drug
Effect
Drug-Receptor
Complex
Ligand-binding
domain
Effector domain
Receptor
Drug(Ligand)  Receptorinteraction
Langley (1878)
5
EffectD+R DR
k1
k2
13-08-2018

6. 613-08-2018

7. AFFINITY
7
AFFINITY:isthe ability of adrugto bindwith the
receptor andform adrug-receptorcomplex.it
doesn'tguarantee response.
13-08-2018

8. EFFICACY
8
EFFICACY/INTRINSIC ACTIVITY:whichmeansthe
ability of a drug-receptorto trigger the
pharmacologicalresponse.
13-08-2018

9. Receptor “agonist”
9
 Any drug that binds to a receptor and stimulates
the functional activities
 e.g.: adrenaline at muscarinic receptors
Receptor
Effect
Epinephrine
Cell
13-08-2018

10. • Partial agonist :These drug have full affinity to
receptor but with low intrinsic activity (IA=0 to 1).
• These are only partly as effective as agonist
Ex: Pindolol at beta adrenergic receptors
1013-08-2018

11. • Inverse agonist: These have full affinity
towards the receptor but intrinsic activity is
zero to -1 i.e., produces effect is just
opposite to that of agonist.
agonist forEx:- ß-Carboline is inverse
Benzodiazepines receptors.
1113-08-2018

12. Receptor antagonist
12
epinephrine
 Any drug which can influence a receptor and
produce no response
 e.g.: propranolol (a beta blocker)
propranolol


Competitive Antagonist: both the drug and its antagonist compete for the same site of the receptor
Non-competitive Antagonist: the drug and its antagonist do not compete for the same site
13-08-2018

13. RECEPTOR CLASSIFICATION
13
1. Inotropic.
2. Metabotropic.
3. Ligand regulated trans
membrane.
1. Nuclear receptors .
Cell surface Intracellular
13-08-2018

14. TRANSMEMBRANE
GLYCOPROTEIN PORES
that open and close in aregulated
manner and allow passage ofions
through it.
14
1413-08-2018

15. change in the voltage
across the membrane
(voltage-gated channels)
the binding of a ligand
(ligand-gated
channels)
Confirmational Changes
15
15
13-08-2018

16. TRANSMEMBRANE ION
CHANNEL that are activated
by changes in electrical
membrane potential.
16
1613-08-2018

17.  Voltage Gated ion channels are made of three basic
parts:
1) The transmembrane pore
2) Voltage sensor
3) Selectivity filter
 Contains different
subunits:
α subunit and other auxillary
Subunits.
17
1713-08-2018

18. 14
1813-08-2018

19. FEATURES – ION CHANNELS
19
 Protein molecules form water filled Pores that span
the membrane.

 Switch between open and closed states.

Rate and Direction of movement depends on
electro chemical gradient of the ions
9
13-08-2018

20. 2013-08-2018

21. 16
2113-08-2018

22. ION CHANNELS
22
 Due to the concentration changes of different ions the
following effects are seen.
 Increase in Na+and Ca+levels- excitatory
 Decrease in Na+and Ca+levels- inhibitory
 Increase in K+levels – inhibitory
 Decrease in K+levels – excitatory
  Increase in Cl- levels – inhibitory
 Decrease in Cl- levels- excitatory 15
13-08-2018

23. ION CHANNELS - IMPORTANCE
23
 Generation , propagation of nerve impulse.
 Synaptic transmission of neurons.
 Muscle contraction.
 Salt balance.
 Hormone release.
.
13-08-2018

24. TRANSMEMBRANE PROTEIN which
open to allow ions suchas Na+, K+,
Ca2+, or Cl−to pass through the
membrane in response to the
binding of a chemical messenger (i.e.
a ligand).
They are all receptors.
2413-08-2018

25.  Also called ionotropic receptors.
25

 Involved mainly in fast synaptic transmission.
 Eg: nAchR, GABAA,and glutamate receptors of the NMDA.
13-08-2018

26. Ligand binding
site
2613-08-2018

27. 2713-08-2018

28. 26
BASIC
MECHANIS
M OF
ACTION:
2813-08-2018

29. (2) Nicotinic receptor:
(1)
2913-08-2018

30. (3) Ionotropic glutamate receptor:
3013-08-2018

31. 30
(4) G protein activated potassium channel:
3113-08-2018

32. LIGAND GATED ION CHANNELS
ION CHANNELS AGONIST ANTAGONIST
Nicotinic receptor Acetycholine D-tubocurarine,
suxamethonium
GABAAgated chloride
channel
Muscimol
(BZD, barbiturates-
positive modulators)
Bicuculline
(flumazenil-negative
modulator)
ATP sensitive potassium
channel
Diazoxide, nicorandil Sulfonylurease
Glutamate NMDA
receptor
Glutamate Phencyclidine,
memantine, ketamine
Glutamate AMPA receptor AMPA, glutamate
(Piracetam –positive
modulators)
Kyenurenic acid
Glutamate kainate
receptor
Glutamate
Glycine receptor Glycine Strychnine 3213-08-2018

33. Sulfonyurease activity on ATP sensitive K+ channel:
3313-08-2018

34.  Metabotropic or 7-transmembrane-spanning
(heptahelical) receptors.
34

 coupled to intracellular effector systems via a G-protein.
 mAChRs, adrenoceptors, dopamine, 5-HT, opiate, peptide,
purinoceptors
17
13-08-2018

35. GPCR- Basic structure
35
CYTOSOL
EXTRACELLULAR
Extracellular loops
Intracellular loops
Plasma
membrane
13-08-2018

36. GPCR
3613-08-2018

37. FAMILIES OF GPCR
37
3 Families:-
  A– Rhodopsin Family
Eg. Amine NT, purines , cannabinoids
 B - Secretin/Glucagon receptor family
Eg. Peptide hormones.
  C - Metabotropic Glutamate receptor/calcium sensor family.
Eg. GABAB, Glutamate.
19
13-08-2018

38. G-PROTEIN SUBTYPES
38
G-PROTEIN RECEPTOR FOR
GS Beta adrenergic amines,
glucagon histamine,
serotonin
Gi1, Gi2, Gi3 Alpha2 adrenergic amines,
mAchR, opioid,
serotonin
SIGNALLING
PATHWAY
Adenylyl cyclase
CAMP
•Excitatory effects
adenylyl cyclase
CAMP
Cardiac K+ channel
open- heart
rate
Golf Olfactory epithelium Adenylyl cyclase –
CAMP
21
13-08-2018

39. G-PROTEIN
39
RECEPTOR FOR SIGNALLING PATHWAY
GO NT ,Opioid
cannabinoid
Gq mAchR, serotonin
5HT1C
Not clear
PLC
IP3 , DAG
Cytoplasmic Ca
Gt1 , Gt2 Rhodopsin and colour
opsins in retinal rod
and cone cells
cGMP
phosphodiesterase-
cGMP
22
13-08-2018

40. 4013-08-2018

41. SECONDARY MESSENGER SYSTEMS INVOLVED IN SIGNAL
TRANSDUCTION
41
 The adenylyl cyclase / Camp system

The Phospholipase C / inositol phosphate system
 The Ion channels
 The Rho A /Rho kinasesystem 23
13-08-2018

42. 4213-08-2018

43. E Cam E*
Gq PLC PIP2
DAG
S
Agonist
Activation
IP3
PKC
ATP ADP
Product
Cam Ca+2
Water soluble
release
Response
Phospholipase-C system
Hydrolysis
Hydrolysis
PLC= Phospholipase-C PIP2 =Phosphotiydl inositol 4,5 di phosphate
IP3 =Inositol tri phosphate DAG = Diacylglycerol
E= Ezyme PKC = Phosphokinase -C
4313-08-2018

44. PHOSPHOLIPASE C-INOSITOL SYSTEM
44
  Phospholipase C : Cleaves membrane phospholipids- phosphoinositides.
 PLC beta– cleaves phosphatidylinositol(4,5)bis Phosphate PIP2 - into
DAG and IP3
3.
 DAG and IP3- Secondary messenegers – elicit cellular responses.
25
13-08-2018

45. GPCR ACTIVATIONEFFECTS
4513-08-2018

46. ION CHANNELS
46
GPCR- directly control ion channel-without secondary messenger
Eg. mAchR in heart – activate K+channel.
13-08-2018

47. Abnormal G protein signalling can occur due to:
a) Bacterial toxins. Eg. Cholera and Pertussis toxin.
b) Gene mutations:
1. Gain of function mutation: can lead to development of Congenital
Nightblindness (rhodopsin), Familial Precocious puberty (LH),
Familial Hypocalcemia (Ca2+ sensing), etc.
2. Loss of function mutation: can lead to development of Retinitis
Pigmentosa (rhodopsin), DiabetesInsipidus (V2), Hypocalciuric
Hypercalcemia (Ca2+ sensing), etc.
c) GPCR Misfoldings: can lead to diseases like Nephrogenic DI (V2R),
Hypogonadotrophic Hypogonadism (GnRHR),etc.
GOODMAN, GILMAN, L.BRUTON: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS; 12TH
EDITION, NEW YORK: MCGRAW HILL
ABNORMAL GPCR
4713-08-2018

48.  Involved in growth, proliferation, differentiation or survival-called growth
factors.
48
 Mediate actions of protein mediators- GF, cytokines , harmones - insulin
and leptin.
 Slow – require the expression of new genes.
 Single membrane spanning helix - extracellular ligand binding domain
- intracellular domain.
13-08-2018

49. Structure of Kinases linked receptors
49
Y
Y
Y
Y
Y
Y
Extracellular domain
Binds to the ligand (growth factor)
Trans membrane domain
Intracellular domain
Endogenous kinases bind
and get phosphorlated
28
13-08-2018

50. Kinase cascadeGene
transcription
RECEPTORS@VPC
30
5013-08-2018

51. TYPES
51
 receptor Tyrosine kinases
Eg. EGF , NGF , insulin receptor
 Serine/ Threonine kinases
 Eg. Transforming growth factor
 Cytokine receptors
Eg. Cytokines , CSF
 Guanylyl cyclase receptors
Eg. ATRIAL NATRIURETIC PEPTIDE
29
13-08-2018

52. RAS/RAF/MAP:- TYROSINE KINASE
5213-08-2018

53. JAK/STAT PATHWAY:-
5313-08-2018

54. Important pathways activated :
• 1. The Ras/Raf/mitogen- activated protein
(MAP)
-activated by tyrosine kinases.
- important in cell division, growth.
• 2. The Jak/Stat pathway:-
• - activated by cytokines.
• - controls synthesis and release of
inflammatory mediators.
5413-08-2018

55.  Ligand activated transcription factors.
55
 Present in soluble form – either in cytoplasm or nucleus – freely diffusable.
 Transduce signals by- modifying gene transcription.
 Eg: steroid hormones, glucocorticoids, vit D.
 Play vital role in endocrine signaling and metabolic regulation.
32
13-08-2018

56. 5613-08-2018

57. response elements
-Binds with corepressor
coactivator ptns
AF1
Zn fingers;hor
AF2
5713-08-2018

58. Mechanism of action
58
H.P RANG, J.M. RITTER, R.J. FLOWER, G.HENDERSON: RANG & DALE’S PHARMACOLOGY; 8TH
13-08-2018

59. NUCLEAR RECEPTOR CLASS 2
59H.P RANG, J.M. RITTER, R.J. FLOWER, G.HENDERSON: RANG & DALE’S PHARMACOLOGY;
8TH EDITION. CHINA: ELSEVIER;
13-08-2018

60. .
60
H.P RANG, J.M. RITTER, R.J. FLOWER, G.HENDERSON: RANG & DALE’S PHARMACOLOGY; 8TH
Clinical Significance:
1. NRs are very important drug targets, being responsible
for the biological effects of
approximately 10–15% of all prescription drugs.
2. NRs also regulate expression of many drug
metabolising enzymes and transporters.
3. Many illnesses are associated with malfunctioning of
the NR system, including inflammation, cancer,
diabetes, cardiovascular disease, obesity and
reproductive disorders.
13-08-2018

61. Class I Hybrid
class
Class II
Present in
cytoplasm
Mainly
endocrine
Present in nucleus
•Associated with
heat shock
proteins.
•Form homodimers •Form
•Mainly endocrine; hetero
dimers with
RXR
•Form hetero
dimers with RXR
•Mainly lipids
•Associated with
co-repressor
proteins.
High affinity
binding
Low affinity
binding
GR, MR, ER, PR,AR TR, VDR,
RAR
PPAR, LXR, FXR,
RXR
6113-08-2018

62. Regulation of receptors
Desensitization / down-regulation (Decreased number or
functioning of receptors)
 Results from continued stimulation of cells with agonists
(chronic use of receptor agonists).
 As a result, subsequent exposure to the same
concentration of drug is diminished.
E.g.: Decreased response to the repeated use of
selective β2 -adrenergic agonists (bronchodilators)
6213-08-2018

63. Regulation of receptors
Supersensitivity / Up-regulation
 Results from chronic reduction of receptor stimulation
(chronic use of antagonists)
 If the antagonist is withdrawn abruptly after chronic
administration, the elevated number of receptors can
produce an exaggerated response to normal
concentrations of agonists.
e.g.. Rebound hypertension after sudden withdrawal of
β-adrenergic receptor blockers.
6313-08-2018

64. 6413-08-2018

65. Characteristics of receptor families
65
Ligand
gated
G-protein
coupled
Enzymatic Nuclear
Location Membrane Membrane Membrane Intracellular
Effector Ion channel Ion Channel
or enzyme
Enzyme Gene
coupling Direct G-protein Direct Via DNA
Example Nicotinic Muscarinic Insulin Steroid ,
hormone
63
13-08-2018

66.  TO PROPAGATE REGULATORY SIGNALS FROM OUTSIDE TO
INSIDE OF THE CELL.
 TO INTERAGATE VARIOUS EXTRACELLULAR &
INTRACELLULAR REGULATORY SIGNALS.
 TO AMPLIFY THE SIGNAL.
 TO ADAPT TO SHORT TERM & LONG TERM CHANGES IN
REGULATING AND MAINTAINING HOMEOSTASIS.
 THE RECEPTOR CONCEPT HAS IMPORTANT PRACTICAL
CONSEQUENCES IN DEVELOPMENT OF DRUGS AND FOR
ARRIVING AT THERAPEUTIC DECISIONS IN CLINICAL PRACTICE.
FUNCTIONS OF
RECEPTORS
6613-08-2018

67. CON CLU SION
67
 Extensive research done on Receptor pharmacology -lead to discovery of
new drug targets for treatment of several diseases.
Still requires discovery of new receptor types and the mechanisms of many
orphan receptors that can result in effective treatment of many diseases.
Requires development of receptor crystallization etc.
Much to be discovered about the nuclear receptors.
34
13-08-2018

68. REFERENCES
68
Rang , Dale, Ritter ,Flower :Rang and Dale’s,
pharmacology;6th edition, Churchill Livingstone;2008,
9-52.
 BertramG. Katzung , Basic and clinical pharmacology;
10thedition ; 2006 , 197-209
KD Tripati , essentials of medical pharmacology ; 6th
edition; 2008, 40-52.
RICHARD’s LIPPINCOTT’s illustrated reviews of
PHARMACOLOGY , 4thedition , Page no 25 – 34.
36
13-08-2018

69. 6913-08-2018