this seminar mainly gives the information about hormonal receptor.

1. By,
Sanket J. Gandhi
M. PHARM (Ist SEM)
Department of Pharmacology
R.C. Patel Institute Of Pharmaceutical education and Research
HORMONAL RECEPTORS

2. Index
Introduction to Hormone 3,4
Slide No.
Hormonal receptor 5,6
Cell surface receptor
7-
16
Nuclear receptor 17-
29
Cell surface receptor
description
30-
43
Nuclear receptor description
44-
51
Recent advances
52,
53
References 54,
55 2

3. INTRODUCTION TO HORMONE
 A Hormone is any member of a class of signaling molecules produced by glands in
multicellular organisms that are transported by the circulatory system to target distant
organs to regulate physiology and behaviour.
 Hormones effects on the body:
 Stimulation or inhibition of growth
 Sexual arousal
 Induction or suppression of apoptosis and to control puberty and menopause
 Activation or inhibition of the immune system 3
Norman, Anthony W., and Gerald Litwack. Hormones. Academic Press, 1997.

4.  Regulation of metabolism
 Control of the reproductive cycle
Hormones exert their actions as:
 1.Endocrine action
 2.Paracrine action
 3.Autocrine action
INTRODUCTION TO HORMONE
4
Norman, Anthony W., and Gerald Litwack. Hormones. Academic Press, 1997.

5.  Hormone receptors have two mandatory characteristics:
 The receptor must identify a unique binding site within the hormone.
 The receptor must be able to transmit the signal caused by
binding with the hormone into a cellular response.
HORMONAL RECEPTORS
5
Norman, Anthony W., and Gerald Litwack. Hormones. Academic Press, 1997.

6. Hormonal receptors
Intercellular(nuclear) receptors
steroidal hormone
receptors:
1)Glucocorticoid H. R.
2)Mineralocorticoid H. R.
3)Androgen H. R.
4)Estrogen H. R.
5)Progesteron H. R.
Thyroid
hormone
(T3and T4)
receptor
Cell surface(plasma membrane)
receptors
Examples:
1)FSH and LH R.
2)Insulin H. R.
3)Growth H. R.
4)Oxytosin and ADH R.
5)Catecholamines H. R.
Etc.
CLASSIFICATION OF HORMONAL
RECEPTORS
6
Giguère, Vincent, et al. "Identification of a new class of
steroid hormone receptors." (1988): 91-94.

7.  Structure of Cell Surface Receptors:
 Cell surface receptors are integral
membrane proteins, have regions
that contribute to three basic domains:
 Extracellular domains:
 Transmembrane domains:
 Cytoplasmic or intracellular domains:
CELL SURFACE RECEPTORS
7
Deller, Marc C., and E. Yvonne Jones. "Cell surface receptors." Current opinion in
structural biology 10.2 (2000): 213-219.

8.  Cell surface receptors hormones can show theirs action
via 2 different pathways by activating various sec. messengers
systems which are,
1) G-Protein couple receptor(GPCR) pathway.
1. cAMP sec.messenger
2. calcium or phosphoinositide sec.messenger
2) Tyrosine kinase receptor pathway.
MECHANISMS OF CELL SURFACE RECEPTORS
8
Deller, Marc C., and E. Yvonne Jones. "Cell surface receptors." Current opinion in
structural biology 10.2 (2000): 213-219.

9. 1)GPCR PATHWAY
1.CAMP SEC.MESSENGER ACTIVATION
9

10.  Epinephrine and Norepinephrine
 Glucagon
 Luteinizing hormone, Follicle stimulating hormone
 Thyroid-stimulating hormone,Calcitonin,Parathyroid hormone
 Antidiuretic hormone
EXAMPLES OF HORMONES ACT THROUGH SUCH PATHWAY
10

11. 1)GPCR PATHWAY
2.CALCIUM OR PHOSPHOINOSITIDE SEC.MESSENGER
11

12.  Epinephrine and norepinephrine
 Angiotensin II
 Antidiuretic hormone
 Gonadotropin releasing hormone
 Thyroid-releasing hormone
EXAMPLES OF HORMONES ACT THROUGH SUCH PATHWAY
12

13. Protein Tyrosine kinase
 Protein tyrosine kinases (PTKs) are a large family of enzymes that
play critical roles in signal transduction. Through transferring
γ-phosphate group from ATP to protein substrates, PTKs
regulate functions of these substrates.
Dimerization
 A dimer is a macromolecular complex formed by two, usually
non-covalently bound, macromolecules such as proteins or
nucleic acids. It is a quaternary structure of a protein.
 When two monomers get attached to each chemically and form
dimer then its called dimerization.
2.TYROSINE KINASE PATHWAY
13
Schlessinger, Joseph. "Cell signaling by receptor tyrosine kinases." Cell 103.2 (2000): 211-
225.

14. 2.TYROSINE KINASE PATHWAY
14

15. Dimerization activates the kinase activity and leads to
autophosphorylation, creating sites for interactions with
specific effectors.
Ras
 A key component of the RTK cascade is Ras
 Ras is small, monomeric G protein with very low
GTPase
activity.
Grb2
 SH2 protein that binds to phosphorylated RTKs
 It has three domains, one binds the RTK, the other
Binds Sos
Sos
 It is a Ras-GEF. When recruited to the membrane it
activates Raf
Raf
 Ras-GTP recruits Raf, which becomes activated as a
protein kinase and initiates the MAP kinase cascade 15

16.  Insulin
 Growth hormone
 Prolactin
 Oxytocin
 Erythropoietin
 Several growth factors
EXAMPLES OF HORMONES ACT THROUGH SUCH PATHWAY
16

17.  Nuclear receptors are intracellular proteins expressed in the
nucleus of a cell.
 Nuclear receptors are a family of ligand-regulated transcription
factors that are activated by steroid hormones, such as estrogen
and progesterone, and various other lipid-soluble signals,
including retinoic acid, and thyroid hormone.
 Nuclear receptors (NRs) are proteins that share considerable
amino acid sequence similarity in two highly conserved domains.
 DNA binding (DBD) and the ligand binding domains (LBD).
NUCLEAR RECEPTORS
17
Freedman, Leonard P. "Increasing the complexity of coactivation in nuclear receptor
signaling." Cell 97.1 (1999): 5-8.

18. NUCLEAR RECEPTORS
Nuclear receptor
super family
Class 1 steroid receptor
family
1.Estrogen receptor
2.Androgen receptor
3.Progesteron
receptor
4.Minerelocortocoid
receptor
5.Glucocorticoid
receptor
1.Thyroid receptor
2.Retinoicacid
receptor
3.VitamineD
receptor
4.Peroxisome
proliferator activated
receptor
Class 2 receptor family
Class 3 receptor family
Orphans type of
receptors
1.Farnesoicx
receptor
2.Liver x receptor
18
Mangelsdorf, David J., et al. "The nuclear receptor superfamily: the second
decade." Cell 83.6 (1995): 835-839.

19.  Basic components related to nuclear receptor:
 Zinc fingers:
 Zinc fingers have one or more zinc atoms gripped
by a combination of four amino acids, either cysteine
or histidine. a protein can grab a zinc ion and fold tightly
around it. a short chain of 20-30 amino acids is enough
to create a solid, stable structure.
 Many zinc fingers play essential roles in DNA recognition
and essential role in the development of blood cells.
NUCLEAR RECEPTORS
19
Nolte, Robert T., et al. "Differing roles for zinc fingers in DNA recognition: structure of a six-
finger transcription factor IIIA complex." Proceedings of the National Academy of
Sciences 95.6 (1998): 2938-2943.

20.  Heat shock proteins (HSP):
 Are a family of proteins that are produced by cells in response
to exposure to stressful conditions such as infection,
inflammation, exercise, exposure of the cell to toxins (ethanol
arsenic, tracemetals and ultraviolet light), starvation, hypoxia.
 Heat-shock proteins are named according to their molecular
weight. For example, Hsp60, Hsp70 and Hsp90 (Chaperones).
 Heat Shock Proteins bind to denatured proteins to prevent
aggregation.
NUCLEAR RECEPTORS
20
Freedman, Leonard P. Molecular biology of steroid and nuclear hormone receptors.
Springer Science & Business Media, 1998.

21.  Coactivator and Corepressor: Transcription coregulators that
activate gene transcription are referred to as coactivators while those
that repress are known as corepressors. The mechanism of action of
transcription coregulators is to modify chromatin structure and thereby
make the associated DNA more or less accessible to transcription.
NUCLEAR RECEPTORS
21
Petkovic, Martin, et al. "A human retinoic acid receptor which belongs to the family of
nuclear receptors." Nature 330.6147 (1987): 444-450

22.  A hormone response element (HRE) is a short sequence
of DNA within the promoter of a gene that is able to bind a
specific hormone receptor complex and therefore regulate transcription.
HRE responds to steroid hormones, as the activated steroid receptor is
the transcription factor binding HRE.
NUCLEAR RECEPTORS
sequence of DNA
Actual mechanism
22
Umesono, Kazuhiko, et al. "Direct repeats as selective response elements for the thyroid
hormone, retinoic acid, and vitamin D 3 receptors." Cell 65.7 (1991): 1255-1266.

23. NUCLEAR RECEPTORS
A/B region
C region
D region
E region
F region 23
Moras, Dino, and Hinrich Gronemeyer. "The nuclear receptor ligand-binding domain:
structure and function." Current opinion in cell biology 10.3 (1998): 384-391.

24. NUCLEAR RECEPTORS
 DNA-binding domain (DBD):
 Highly conserved domain
containing two zinc fingers
that binds to specific sequences
of DNA called hormone
response elements (HRE).
Zinc atoms
Double strained DNA
DNA-binding domain dimer
24

25. NUCLEAR RECEPTORS
 Ligand binding domain (LBD):
 The structure of the LBD is referred to as
an alpha helical sandwich fold in which
three anti parallel alpha helices are
flanked by two alpha helices on one side
and three on the other. The ligand binding
cavity is within the interior of the LBD and
just below three anti parallel alpha helical
sandwich "filling“.
Crystallographic structure of the ligand binding
domain of the human RORγ (rainbow colored, N-
terminus = blue, C-terminus = red) complexed with
25-hydroxycholesterol (space-filling model (carbon =
white, oxygen = red) and the NCOA2 coactivator
(magneta). 25

26. MECHANISMS OF NUCLEAR RECEPTORS
1)MECHANISM OF CLASS I NUCLEAR RECEPTOR ACTION
26

27.  Steroid hormone receptors:
 Glucocorticoid Receptor
 Mineralocorticoid Receptor
 Androgen Receptor
 Estrogen Receptor
 Progesterone Receptor
EXAMPLES OF HORMONES ACT THROUGH SUCH MECHANISM
27

28. MECHANISMS OF NUCLEAR RECEPTORS
2)MECHANISM OF CLASS II NUCLEAR RECEPTOR ACTION
28

29.  Retinoic acid receptor
 Retinoid X receptor
 Thyroid hormone receptor
EXAMPLES OF HORMONES ACT THROUGH SUCH MECHANISM
29

30.  Steroid hormone receptors:
 Glucocorticoid Receptor
 Androgen Receptor
 Estrogen Receptor
 Progesterone Receptor
 Thyroid hormone receptor:
NUCLEAR RECEPTORS DESCRIPTION
30

31.  History of glucocorticoid receptor:
 Glucocorticoid receptor (GR) drug discovery was initiated by adrenal
gland extracts.
 In 1948 sufficient quantities of cortisone could be purified and
its effects in inflammatory disease could be tested. Finally, total
syntheses of cortisone were independently achieved by R.B.Woodward.
GLUCOCORTICOID RECEPTOR
31
Rousseau, Guy G., John D. Baxter, and Gordon M. Tomkins. "Glucocorticoid receptors:
relations between steroid binding and biological effects." Journal of molecular biology 67.1
(1972): 99-115.

32. Agonist Antagonist
Cortisol Mifepristone
Corticosterone Org 34850
Aldosterone RU-486
GLUCOCORTICOID RECEPTOR
 The GR is expressed in a wide variety of lymphoid
cells, including T and B cells, and macrophages.
32

33.  Role of Glucocorticoid Receptor In Disease Condition :
 Inflammatory and immune disease
 Asthma therapy
 Allergic Reaction
 Myasthenia Gravis
 Infective Disease
 Hypercalcaemia
GLUCOCORTICOID RECEPTOR
33

34.  Androgens act via the AR and play an important role in the development
and differentiation of the male sexual organ.
 It is also important in maintaining skeletal muscle mass and strength, BMD,
hematopoiesis.
 The two natural occurring androgens are testosterone (T) and the
more potent 5α-dihydrotestosterone (DHT).
ANDROGEN RECEPTOR
34
Drews, Jürgen. "Drug discovery: a historical perspective." Science 287.5460 (2000): 1960-
1964.

35.  Role of Androgen Receptor In Disease Condition
 Hypogonadism
 Anaemia
 Osteoporosis
ANDROGEN RECEPTOR
Agonist Antagonist
Synthetic progestin Flutamide
Dihydrotestosterone Spironolactone
Testosterone Danazol
35

36.  History of estrogen receptor:
 Estrone was isolated in 1929 as the first natural estrogenic
hormone independently by the chemists E. A. Doisy and A. Butenand
from the urine of pregnant women
 In 1938, H. H. Inhoffen achieved for the first time the synthesis of
estradiol from cholesterol.
 The first synthesis of ethinyl-estradiol,which has an improved
oral bioavailability, was published in 1938 by H. H. Inhoffen and
W. Hohlweg.
ESTROGEN RECEPTOR
36
Drews, Jürgen. "Drug discovery: a historical perspective." Science 287.5460 (2000): 191964.

37.  Both ERs are widely expressed, although ERα is more abundant in
breast, endometrial, ovarian, and hypothalamus tissues, whereas
ERβ is more abundant in brain, bone, endothelial, heart, intestine,
kidney, lung, and prostate tissues.
ESTROGEN RECEPTOR
Agonist Antagonist
Estradiol Tamoxifen
Estrone Doloxifen
Estriol Toremifen
Clomiphene Raloxifene
37

38. 38

39.  History of progesterone receptor:
 The observation that progesterone prevented ovulation was taken
up by Haberlandt who was able to demonstrate that it could be
used for fertility control.
 In 1955, Gregory Pincus demonstrated that large doses of orally
Administered progesterone inhibited ovulation in women.
 Inhoffen had discovered in 1938 that 17a-ethynyl-testosterone was
a weakly active progestin when administered orally.
PROGESTERONE RECEPTOR
39
Drews, Jürgen. "Drug discovery: a historical perspective." Science 287.5460 (2000): 1960-
1964.

40.  The PR is involved in diverse functions in female reproduction
 Progesterone is mainly produced in the corpus luteum, placenta
 The PR is expressed in the uterus, ovary.
 Role of Progesterone Receptor In Disease Condition:
 Contraception
 Hormone Replacement Therapy
 Breast Cancer
 Endometrial Hyperplasia
PROGESTERONE RECEPTOR
40

41.  The thyroid hormones (THs) triiodothyronine (T3) and thyroxine (T4)
bind to and activate the nuclear thyroid receptors TRα and TRβ.
 Studies dating back to the 19th century showed that transplantation
of sheep thyroid gland tissue could rapidly improve the state of a
patient suffering from hypothyroidism.
 Differential binding activity of THα and THβ could be shown among various
tissues, with high binding in the liver, kidney, pituitary gland, heart, and
brain.
THYROID HORMONE RECEPTOR
41
Shibata, Hirotaka, et al. "Role of co-activators and co-repressors in the mechanism of
steroid/thyroid receptor action." Recent Progress in Hormone Research 52 (1996): 141-64

42.  Actions of Thyroid Hormone Receptor
 Growth and Development
 Calorigenic Effects
 Cardiovascular Effects
 Metabolic Effects
 Thyroid Hypofunction
 Thyroid Hyperfunction
THYROID HORMONE RECEPTOR
42

43.  Disorders of the thyroid gland
 Hyperthyroidism—excess of thyroid hormone production.
 Hypothyroidism—deficiency of thyroid Hormone production.
 Goitre formation.
 Adenoma (benign growths) of the thyroid.
 Carcinoma of the thyroid.
THYROID HORMONE RECEPTOR
43
Shibata, Hirotaka, et al. "Role of co-activators and co-repressors in the mechanism of
steroid/thyroid receptor action." Recent Progress in Hormone Research 52 (1996): 141-64.

44.  Growth hormone receptor
 Insulin receptor
 Vasopressin receptor
CELL SURFACE RECEPTORS DESCRIPTION
44

45.  Growth hormone was identified in the 1920s as a growth promoting Factor.
 By mid to late 1980s scientists were able to produce this 191-residue
protein hormone in bacteria using recombinant DNA technology.
 Growth hormone is a protein hormone of about 190 amino acids that
is synthesized and secreted by cells called somatotrophs in the
anterior pituitary.
GROWTH HORMONE RECEPTOR
45

46. GROWTH HORMONE RECEPTOR
 When two receptors are brought together,
interaction between the portions inside the cell
triggers several enzymatic reactions and signaling
processes that stimulate growth.
 Thus formation of this receptor dimer is crucial
for growth hormone function.
46

47.  To regulate normal growth and development of body.
 Metabolic Effects
 Protein metabolism:
 Fat metabolism:
 Carbohydrate metabolism:
 Role of Growth hormone in Disease States.
 Gigantism
 Acromegaly
GROWTH HORMONE RECEPTOR
47

48. INSULIN RECEPTOR
Insulin receptor visualised by electron microscope in frozen
hydrated state(top) and its illustration(bottom)
Structure of Insulin receptor
48

49. INSULIN RECEPTOR
49

50. VASOPRESSIN RECEPTOR
Distribution and signaling pathway of vasopressin receptor.
RECEPTOR SIGNALING PATHWAY LOCATION
V1(V1A) G protein
couple/phosphatidylinositol
calcium
Vascular smooth muscle, platelet,
Hepatocytes and myometrium.
V2 Adenylyl cyclase/cAMP Basolateral membrane of
collecting duct and vascular
smooth muscle cell.
V3(V1B) G protein
couple/phosphatidylinositol
calcium
Anterior pituitary gland.
50
Jagadeesh, J. S., Muthiah, N. S., & Muniappan, M. (2014). Vasopressin Receptors and
Drugs: A Brief Perspective. Global Journal of Pharmacology,8(1), 80-83.

51.  Functions of vasopressin receptor
 Vasoconstriction
 Myocardial hypertrophy
 Platelet aggregation
 Glycogenolysis
 Uterine contraction
 Insertion of AQP-2 water channels into apical membrane
 Releases ACTH, prolactin, endorphins
VASOPRESSIN RECEPTOR
51

52. 1)The concentration of the estrogen binding protein in the rat uterus has
been studied in three stages of uterine development. A 3- to 4-fold
increase in concentration of estrogen binding protein occurs between
days one and ten after birth.
After estrogen is injected, the receptor concentration in the cytoplasm
goes into a three-stage cycle.
(1) Initially, there is a loss of binding protein, followed by
(2) a stage sensitive to inhibitors of protein and RNA synthesis, and
(3) a replenishment period that is not affected by the inhibitors
RECENT ADVANCES
52
Gorski, J., M. Sarff, and J. Clark. "The regulation of uterine concentration of estrogen
binding protein." (1971).

53. 2)Bisphosphonates (BPs) have become the standard therapy for breast
cancer patients with bone metastasis. It is now clear that the
bisphosphonates reduce both the symptoms and complications of bone
involvement
The administered bisphosphonates (BPs) differed according to the
periods of treatment, compliance, tolerability and insurance strategy.
The types of bisphosphonate used were zoledronate or pamidronate.
These drugs were given at three or four week intervals.
RECENT ADVANCES
53
Park, In H., et al. "Potential antitumor effects of nitrogen-containing bisphosphonate in
hormone receptor negative breast cancer patients with bone metastases." BMC cancer 9.1
(2009): 154.

54.  Norman, Anthony W., and Gerald Litwack. Hormones. Academic Press, 1997
 Giguère, Vincent, et al. "Identification of a new class of steroid hormone receptors." (1988): 91-94.
 Deller, Marc C., and E. Yvonne Jones. "Cell surface receptors." Current opinion in structural biology 10.2 (2000):
213-219.
 Schlessinger, Joseph. "Cell signaling by receptor tyrosine kinases." Cell 103.2 (2000): 211-225.
 Freedman, Leonard P. "Increasing the complexity of coactivation in nuclear receptor signaling." Cell 97.1 (1999): 5-8.
 Mangelsdorf, David J., et al. "The nuclear receptor superfamily: the second decade." Cell 83.6 (1995): 835-839.
 Nolte, Robert T., et al. "Differing roles for zinc fingers in DNA recognition: structure of a six -finger transcription
factor IIIA complex." Proceedings of the National Academy of Sciences 95.6 (1998): 2938-2943.
 Petkovic, Martin, et al. "A human retinoic acid receptor which belongs to the family of nuclear
receptors." Nature 330.6147 (1987): 444-450
 Umesono, Kazuhiko, et al. "Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and
vitamin D 3 receptors." Cell 65.7 (1991): 1255-1266.
 Moras, Dino, and Hinrich Gronemeyer. "The nuclear receptor ligand-binding domain: structure and function." Current
opinion in cell biology 10.3 (1998): 384-391.
 Rousseau, Guy G., John D. Baxter, and Gordon M. Tomkins. "Glucocorticoid receptors: relations between steroid
binding and biological effects." Journal of molecular biology 67.1
 Drews, Jürgen. "Drug discovery: a historical perspective." Science 287.5460 (2000): 1960-1964.
 Shibata, Hirotaka, et al. "Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor
action." Recent Progress in Hormone Research 52 (1996): 141-64
REFRENCES
54

55.  Jagadeesh, J. S., Muthiah, N. S., & Muniappan, M. (2014). Vasopressin Receptors and Drugs: A Brief
Perspective. Global Journal of Pharmacology,8(1), 80-83
 Gorski, J., M. Sarff, and J. Clark. "The regulation of uterine concentration of estrogen binding protein." (1971).
 Park, In H., et al. "Potential antitumor effects of nitrogen -containing bisphosphonate in hormone receptor negative
breast cancer patients with bone metastases." BMC cancer 9.1 (2009): 154.
REFRENCES
55