" ً‫ وأﻧْتَ ﺗَﺟْ ﻌَ ُل اﻟﺣَ زْ نَ إذَ ا ﺷِ ﺋْتَ ﺳَ ْﮭﻼ‬،ً‫"اﻟﻠﱠ ُﮭ ﱠم ﻻ ﺳَ ْﮭ َل إِﻻﱠ ﻣﺎ ﺟَ ﻌَ ْﻠ َﺗ ُﮫ ﺳَ ْﮭﻼ‬

Biochemistry Team 437

General Mechanisms of The
Action of Hormones

Color index:
Doctors slides
Doctor’s notes
Extra information
Highlights Endocrine block
Objectives:
By the end of this lecture, students should be able to:
● Acquire the knowledge for general consequence of hormone-receptor interaction
● Understand different mechanisms of action of hormones.
● Recognize the biomedical importance due to disturbance in the normal mechanisms of
hormonal action

Overview:

2
Outline:

● Background —
● Factors determining the response of a target cell to a hormone —
● Hormone-receptor interaction —
● General features of hormone classes —
● Classification of hormones by mechanism of action —
● Biomedical importance

3
 Background

● Multicellular organisms depend in their survival on their adaptation¹ to a constantly

changing environment
● Intercellular communication is necessary for this adaptation to take place
● Human body synthesizes many hormones that can act specifically on different
cells of the body
● More than one hormone can affect a given cell type
● Hormones can exert many different effects in one cell or in different cells²
● A target³ is any cell in which the hormone (ligand) binds to its receptor to start the action

Some Terms:
1: response of the target cell - Stimulus : environmental change
2: e.g. insulin has different effects in muscles and hepatocytes - Hormone / ligand : signal
3: Target cell: cell that has the specific receptor for the hormone - Receptor: Recognise the signal, present on the cell surface or
inside the cell

4
- 1,2,3 are hormone related
- 4,5 are receptor relate

5- The number, relative activity, and state

of occupancy of the specific receptors³

Factors determining the

1- The rate of synthesis &
secretion of the hormone¹
response of a target cell to a 4- Post-receptor factors⁴
hormone

2- The conversion of inactive form 3- The rate of hormone clearance

of the hormone to its active form² from plasma (half-life & excretion)

1: It’s controlled by 3 factors

- Stimulant that increase its synthesis
- The healthy of gland to produce hormone
- The presence of precursor that makes hormone
2: e.g: insulin is first secreted ase preproinsulin → proinsulin → insulin “active” If it remain in inactive form it will be worthless
3: Either the receptor is present or absent or free or occupied by drugs
4: examples are: second messengers, gene transcription machinery. 5
 “Change in the environment”
which gives rise to different hormones

Based on how the hormone is going to act

it is classified into 2 groups

- Lipid soluble, can enter the cell membrane - Peptide / protein in nature
- Do Not require a second messenger , has intracellular receptor - Hydrophilic , Can't cross the plasma membrane
- Steroids + thyroid hormones - Require second messenger, has an extracellular receptor

hormone/ receptor
2nd messenger
In this case the complex binding at target cells
itself is the signal Leads to the generation of a signal In this case the hormone is
the first messenger

6
 Important! General Features of Hormone Classes
Group I Group II

Steroids Polypeptides
Thyroid Hs (T3 & T4) Glycoproteins
Types
Calcitriol (vitamin D) , retinoids (retinoic acid Catecholamines (fight and flight hormones e.g.
form of vitamin A) epinephrine & norepinephrine)

Solubility Lipophilic Hydrophilic

Transport proteins Yes (maily albumin) No

Plasma half-life Long (hours – days) Short (minutes)

Receptor Intracellular inside cell “cytosolic or nuclear” Plasma membrane (on the plasma membrane)

cAMP, cGMP, Ca2+, metabolites of

2nd messengers(indirect):
Mediator Receptor-hormone complex (direct)
complex phosphoinositols, tyrosine kinase cascades

7
Classification of Hormones by Mechanism of Action

All the examples of the mechanisms are

important ! (in this slide and others)

I. Hormones that bind to intracellular receptors

(Steroid-Thyroid superfamily):

● Steroid hormones
● Thyroid Hormones (T3 & T4)
● Calcitriol (active form of vitamin D, 1,25[OH]2-D3)
● Retinoic acid

8
 Mechanism of Action of Steroid-Thyroid Hormones

Team 436 Explanation

● Steroid Hormones:
○ Glucocorticoids
○ Mineralocorticoids Steroid hormone is
bound to albumin in the
○ Sex hormones: plasma → it crosses the
● Male sex hormones: Androgens cell membrane where it
will bind to its inactive
● Female sex hormones:Estrogens & Progestins
receptor (steroid
hormone receptor
● Thyroid Hormones (T3 & T4) complex) → when the
complex crosses to the
● Calcitriol (1,25[OH]2-D3) nucleus it binds to
Hormone Response
● Retinoic acid (vitamin A) Element (HRE) which is
present in the enhancer
region and it affects the
promoter region to
change the transcription
and protein synthesis of
the gene.
9
Classification of Hormones by Mechanism of Action

You have to memorize all the mechanisms and know

which hormone acts by which second messenger.

II. Hormones that bind to cell surface receptors

A. The second messenger is cAMP

● Catecholamines (α2- Adrenergic)

● Catecholamines (b- Adrenergic)
● Ant. Pituitary: ACTH, FSH, LH & TSH
● ADH (Renal V2-receptor 1) Antidiuretic Hormone
● Calcitonin & PTH (work to maintain the calcium levels)
● Glucagon

Be mindful:
- Α2 and b Adrenergic catecholamines have cAMP as their 2nd messenger, whereas α1 has
calcium and IP3
- There are two types of ADH receptors: - V2: renal, cAMP
- V1: extra renal, calcium and IP3 10
 Cascade for Formation of cAMP by cell-surface Hormones

- Hormones which will act by cAMP or cGMP are G protein coupled receptors
- Our unoccupied receptor is coupled to a trimeric G protein “3 subunits, alpha beta and gamma” & bound to a GDP (inactive) → when the hormone
binds to the receptor it causes a conformational change in the receptor → the alpha subunit detaches from the beta & gamma and GDP is replaced by
GTP → activates the adenylyl cyclase → produces cAMP from ATP
- There are many types of G protein like G s which is stimulatory and G i which is inhibitory
1. Ligand (hormone) binds to receptor which will react with Gs and activate G protein
2. The active form of G protein is G a (alfa) subunit
3. This active form will activate adenylyl cyclase and this activation will convert ATP to CAMP
11
Important!
Actions of cAMP
1
- Adenylyl cyclase produced cAMP which activate protein kinase A
- Guanylyl cyclase produced cGMP which activate protein kinase G
Not Protein
Kinase C! cAMP activates protein kinase A. follow the image :
1) Protein kinase A has 2 regulatory subunits and 2 catalytic subunits. The
regulatory subunits cover the active sites of the catalytic subunits, and
the enzyme cannot do any catalysis
2
2) To make this enzyme active, you have to remove the regulatory subunit
which can be done by cAMP.
3
3) Active catalytic subunits bind to protein substrates and phosphorylate
them (add phosphate group).
4
4) Phosphorylated proteins are translated to intracellular effect.
5 5) Protein phosphatase is the enzyme that stops the intracellular effect if
we don’t need it anymore by dephosphorylating the proteins

12
 Abortion of Hormonal Stimulus

1. Release of hormone from its receptor (unbound receptor)

2. Dephosphorylation of protein substrate by phosphatase
3. Degradation of cAMP into AMP by phosphodiesterase
4. Inactivation of protein kinase A by a decrease of cAMP¹
5. Hydrolysis of GTP into GDP2
6. Binding of α-subunit to βγ-subunits
7. Inactivation of adenylyl cyclase

-Phosphorylation of protein kinase A occurs on the hydroxyl groups of Serine, Threonine

residues in a protein
1- protein kinase A is cAMP dependant
2: can be done by the alpha subunit itself
13
 Classification of Hormones by Mechanism of Action
II. Hormones that bind to cell surface receptors Atrial Natriuretic Peptide (ANP)
B. The second messenger is cGMP

● Atrial natriuretic peptide (ANP)

● Nitric oxide

- ANP is released in response to stretching of the cardiac muscle due

to volume overload
- It functions to reduce the rate of synthesis of collagen → decreases
fibrosis
Pathway:
- ANP binds to NPR receptor → GC protein activation → conversion of
GTP to cGMP
- cGMP activates protein kinase G which phosphorylate SMAD3
- Normally, non phosphorylated SMAD3 binds to SMAD4 and
upregulate collagen synthesis and fibrosis. But when it is
phosphorylated, it can't bind to SMAD4 so collagen synthesis and
fibrosis rate goes down. Difference between cAMP & cGMP pathways:
- Guanylate cyclase (GC) instead of Adenylyl cyclase
- No α-β subunits (GC binds directly to receptors)
14
 Differences between cAMP and cGMP

cAMP cGMP

G protein is not bound to the receptor G protein is bound to receptor

Adenylyl cyclase Guanylate cyclase (GC)

Adenylyl cyclase is not attached to the Guanylate cyclase is attached to the

receptor receptor

α-β subunits are present No α-β subunits

ِATP is converted to cAMP GTP is converted to cGMP

15
 Classification of Hormones by Mechanism of Action
II. Hormones that bind to cell surface receptors
C. The second messenger is calcium or phosphatidylinositol (or both)

● Acetylcholine* (muscarinic)
● Catecholamines (α1- Adrenergic)
● Angiotensin II
● ADH (vasopressin): Extra-renal V1-receptor

Diacylgly
Calcium/Phosphatidylinositol System cerol
(DAG) Phospholipase C

Phosphatidylinositol bisphosphate “PIP2” is a

Inositol
membrane phospholipid that can be phosphorylated
“by phospholipase C* into IP3 “inositol trisphosphate” Trisphosphate
- Pathway is in the next slide (IP3)
16
Don’t skip the picture!

G protein coupled

17
 Classification of Hormones by Mechanism of Action
II. Hormones that bind to cell surface receptors Don’t skip the pictures!
D. The second messenger is a tyrosine kinase cascade
- Kinase: responsible for phosphorylating proteins
- Tyrosine kinase: phosphorylates tyrosine
● GH & Prolactin
● Insulin
● Erythropoietin

Mechanism of Insulin action

- Two α𝜷 dimers “subunits” make the - When insulin binds to the receptor, it activates the receptor by causing conformational changes the
tetramer receptor brings the two subuints together “dimerization”
- Alpha is outside the cell membrane - The activated beta subunit has 2 kinase activities:
“where insulin binds” - Autophosphorylation of tyrosine within the beta subunit
- Beta has an intramembranous and intra - phosphorylation of the target proteins, mainly IRS “insulin receptor substrates”, which in
cytosolic part turn phosphorylates other proteins leading to the action of insulin “next slide” 18
Biologic Effects of Insulin Biomedical Importance

● Excessive (e.g.,hyperthyroidism, Cushing)

● Deficient (e.g., hypothyroidism, Addison)
● Inappropriate secretion (e.g., syndrome of
inappropriate secretion of ADH “SIADH”*)
of hormones are major causes of diseases
● Pharmacological treatment of these
diseases depends on replacement of
deficient hormone (hypo-) or use of drugs
All happen due to:
that interfere with the mechanism of action
of the hormones (hyper- or inappropriate)

*Mainly causes increase in ADH secretion, which leads to

excessive water retention that is perceived as hyponatremia.

19
Take Home Messages
● Hormones are involved in responses to a stimulus, using a variety of signaling mechanisms
to facilitate cellular adaptive responses.
● Group I hormones are lipophilic, while group II are hydrophilic. Other differences exist
between both groups.
● Hormones can be classified according to their mechanism of action (specific examples of
each category were discussed)
● Biomedically, studying hormones’ actions in details helps to:
● Understand consequences of abnormal hormone release-related diseases (excessive,
deficient or inappropriate)
● Design therapeutic approach for such diseases.

20
Summary

General Features of Hormone Classes

Group I Group II

Steroids Polypeptides
Types Thyroid Hs (T3 & T4) Glycoproteins
Calcitriol, retinoids Catecholamines

Solubility Lipophilic Hydrophilic

Transport proteins Yes No

Plasma half-life Long (hours – days) Short (minutes)

Receptor Intracellular Plasma membrane

cAMP, cGMP, Ca2+, metabolites of

Mediator Receptor-hormone complex complex phosphoinositols, tyrosine
kinase cascades

21
Summary
Classification of Hormones by Mechanism of Action

Types Subtypes Examples Mechanism Other

Steroid hormones
1-steroid hormone cross the plasma membrane into the cytosol
Thyroid Hormones (T3 & T4) 2-In the cytosol it binds to a specific cytosolic or nuclear receptor and forms
I. Hormones
receptor ligand complex
that bind to (Steroid-Thyroid
Calcitriol (1,25[OH]2-D3) 3-the complex goes inside the nucleus and binds to HRE (hormone response -
intracellular superfamily):
element) which is a specific regulatory DNA sequences
receptors
4-this is causes increase of the transcription so the rate of the protein
Retinoic acid synthesize increases as well

Catecholamines (α2- Adrenergic). 1-Binding of ligand “Hormone” causes a conformational change in the Actions of cAMP :
Catecholamines (b- Adrenergic). receptor
2-Replacement of of the GDP of the G protein(S) “α subunit” with GTP.
A. The second
Ant. Pituitary: ACTH, FSH, LH & TSH. 3-GTP-bound form of the alpha subunit dissociates from the beta and
messenger is cAMP
gamma subunits and move to adenylyl cyclase “AC” and activate it.
ADH (Renal V2-receptor). 4-ATP will be converted to cAMP which will activate protein kinase A
II. Hormones Adenylyl cyclase =
that bind to cell cAMP
Calcitonin & PTH.
surface
receptors Glucagon.

B. The second Atrial natriuretic peptide (ANP). 1- ANP binds to it’s receptor which is associated with the enzyme guanylate
messenger is cGMP cyclase(GC)
Guanylate cyclase = Nitric oxide (NO). 2- GC converts GTP into cGMP
cGMP 3- The cGMP activate the enzyme protein kinase G
22
Summary

Classification of Hormones by Mechanism of Action

Types Subtypes Examples Mechanism Other

Acetylcholine 1- Hormone binds to G-protein coupled receptor.

(muscarinic). 2- Receptor Interacts with G protein(q) Which releases GDP and binds with
C. The second
GTP.
messenger is calcium
Catecholamines 3. 𝛼 subunit dissociates from βγ- subunits, and activates Phospholipase C.
or phosphatidylinositol
(α1-Adrenergic). 4. Phospholipase cleaves phosphatidylinositol 4,5-bisphosphate to DAG and
(or both) -
IP3
Angiotensin II. 5. IP3 binds to a specific receptor on RER causing release of Ca.
Phospholipase C = IP3
6. Calcium and DAG synergistically activate protein kinase C .
ADH (vasopressin): 7. Protein kinase C catalyzes protein phosphorylation.
II. Hormones
ExtrarenalV1-receptor.
that bind to cell
surface
receptors GH & Prolactin. Insulin receptor is a dimer that consists of 2 identical units. Biologic Effects of Insulin
1-Insulin binding activates receptor tyrosine kinase of Beta Subunit.
Insulin. 2-phosphorylation of tyrosine. Increase Decrease
D. The second 3-receptor tyrosine kinase phosphorylates other proteins like IRS.
messenger is a tyrosine Erythropoietin. 4-IRS activates other proteins and lead to the biological action.
kinase cascade 1- Glucose up take 1-Gluconeogenesis.
2- Glycogen 2-Glycogenolysis.
synthesis 3- 3-Lipolysis.
Protein synthesis
4- Fat synthesis

23
24
MCQs:
1- Which of the followings are considered as 3- Glycogenolysis is decreased by?
hydrophilic hormone? A. Glucagon
A. Estrogen B. Insulin
B. Aldosterone C. Epinephrine
C. Epinephrine D. cAMP

2- When ADH binds to its extra renal V1 receptor, 4- Which one of the following hormones uses
its second messenger will be? tyrosine kinase cascade as a second messenger?
A. Ca/Phosphatidylinositol A. Prolactin
B. cAMP B. ADH 4-A
C. cGMP C. Acetylcholine 3-B
D. Tyrosine kinase D. Glutaminase 2-A
1-C

25
‫‪Girls team‬‬ ‫‪Boys team‬‬ ‫‪Team leaders‬‬

‫رﯾﻧﺎد اﻟﻐرﯾﺑﻲ‬ ‫●‬ ‫طﺎرق اﻟﻌﻣﯾم‬ ‫●‬ ‫رھﺎم اﻟﺣﻠﺑﻲ‬ ‫●‬

‫اﻟﻌﻧود اﻟﻣﻧﺻور‬ ‫●‬ ‫ﻣﺣﻣد اﻟﺻوﯾﻎ‬ ‫●‬ ‫ﻣﻌﺎذ اﻟﺣﻣود‬ ‫●‬
‫اروى اﻟﺟﮭﻧﻲ‬ ‫●‬ ‫ﻧﺎﯾف اﻟﻣطﯾري‬ ‫●‬
‫ﺳﻠطﺎن اﻟﻧﺎﺻر‬ ‫●‬
‫ﺻﺎﻟﺢ اﻟوﻛﯾل‬ ‫●‬
‫ﻧواف اﻟﻠوﯾﻣﻲ‬ ‫●‬
‫ﻋﺑداﻟﻣﻠك اﻟﺷرھﺎن‬ ‫●‬

‫‪@biochemistry437‬‬

‫ﺷﻛر ﺧﺎص ﻟﻐﯾداء اﻟﺳﻧد‬ ‫‪[email protected]‬‬