2. Mechanism of Hormone
Action
Each hormone exerts a characteristic
effects on the target organ by acting on
the cells of the organ
But same chemical category of hormone
have similar mechanisms of action
Involves
a. Location of cellular receptor proteins
b. Events occurring in the target cells after
the hormone has combined w/ its
receptor protein
3. Mechanism of Hormone
Action
Hormones are delivered by blood to
every cell in the body
But! Only target cells are able to respond to
these hormones.
Target cells must have specific receptor
proteins that is SPECIFIC
Hormonesbind with a high affinity and
low capacity
4. Location of Hormone’s
Receptor Protein
Depends on the chemical nature of hormone
Lipid-soluble hormone receptor are located
within the target cells
Because they can pass through cell membrane
and enter target cell
Water-soluble hormone receptor are located
outside the target cells
Because they can’t pass through cell
membrane
Therefore they need the activation of 2nd
messengers within the cell for hormone action
5. Lipid-soluble Hormone Action
Hormones includes thyroid and steroid
hormones + nitric acid
Attached to plasma carrier proteins then
dissociate to pass thru lipid component of
plasma membrane to enter cell where
the receptor proteins are located
6. Lipid-soluble Hormone Action
Receptorare called “nuclear hormone
receptors”
Because they func. w/in the nucleus to
activate genetic transcription (production
of mRNA)
Thus func. as transcription factors
Has two regions or domains
a. ligand-binding domain/hormone-binding
domain
b. DNA-binding domain
7. Nuclear Hormone Receptors
With two families:
a. Steroid family
b. Thyroid Hormone family – includes
receptors for active form of Vit. D
and for retinoic acid that play
important roles in the regulation of
cell function and organ physiology
Receptors for unknown hormone
ligands are called “orphan receptors”
8. Mechanism of Steroid
Hormone Action
1. Hormone-receptor binding(in cytoplasm)
2. Translocation to nucleus
3. DNA-binding domain binds to specific
hormone-response element of DNA
• Hormone response element of DNA have
two half-sites, each 6 nucleotide bases
long, separated by 3-nucleotide spacer
segment.
9. Mechanism of Steroid
Hormone Action
Onesteroid receptor binds to one half-site
and another to the other half-site
Thus called “dimerization”
“Monodimer” due to same receptor unit
binds to the DNA hormone-response
element
12. Mechanism of Thyroid
Hormone Action
Major hormone secreted is thyroxine or
tetraiodothyrinine(T4)
Small amount of triiodothyronine (T3)
Travels through blood and attached to
carrier proteins primarily “thyroxine-binding
globulin” or TBG which has higher affinity to
T4 than T3
13. Mechanism of Thyroid
Hormone Action
Approximately 99.96% of thyroxine in the
blood is attached to carrier proteins in the
plasma
• The rest are free
Only thyroxine and T3 can enter target cells
Protein bound thyroxine serves as reservoir of
the hormone in the blood
Once free thyroxine enter cytoplasm, it is
enzymatically converted to T3
• T3 is the one active in cytoplasm
14. Mechanism of Thyroid
Hormone Action
Inactive receptor proteins for T3 are
located in the nucleus
Incapable of binding to DNA and
stimulate transcription unless bind with T3
T3 enters cell from plasma or may be
produced in the cell by converting T4
Needs a binding protein to enter nucleus
15. Mechanism of Thyroid
Hormone Action
Difference to steriod:
Binds with non-specific binding protein in
the cytoplasm
nuclear receptor is heterodimer(diff.
receptor proteins attached to the half-sites)
16.
17.
18. Water-soluble Hormone Action
Includes catecholamines (epi and
norepinephrine), polypeptides and
glycoproteins
Cannot pass through lipid barrier of target cell
Some may enter through “pinocytosis” but
mostly acts on the outer surface of the target
cell and therefore can be mediated by other
molecules
Uses 2nd messenger to exert their effects
19. Second-messenger Systems
A. Adenylate Cyclase-Cyclic AMP (cAMP)
Second Messenger System
B. Phospholipase C-Ca2+ Second-
Messenger System
C. Tyrosine Kinase Second-Messenger
System
20. Adenylate Cyclase-Cyclic
AMP
(cAMP) Second Messenger
System
For activation of adenylate cyclase
First known and understood “second
messenger”
Responsible for b-adrenergic effects of
epi and norepinephrine
21. Cyclic Adenosine
Monophosphate
Hormone(water-soluble) binds to receptor
protein results to dissociation of subunit
from the G-protein
G-protein subunits moves thru membrane
to bind and activates adenylate cyclase
as catalyst
ATP cAMP + Ppi
Intracellular concentration of this
increases
22. Cyclic Adenosine
Monophosphate
Activates protein kinase
Inactivated form:
Catalytic subunit and inhibitory subunit
Becomes active once cAMP binds to
inhibitory and dissociate from catalytic
subunit
insummary, the hormone causes an
increase in protein kinase enzyme activity
within its target cells
23. Cyclic Adenosine
Monophosphate
Activeprotein kinase catalyzes
phosphorylation of diff. proteins in the cell
causing some enzymes to be activated
and others to be inactivated
cAMP must be rapidly inactivated by
phosphosdiesterase to function effectively
24.
25. Phospholipase C-Ca2+
Second Messenger System
Ca pumps in the plasma membrane and
endoplasmic reticulum keeps Ca
concentration very low in the cytoplasm
The steep concentration gradient for Ca that
results allows various stimuli to evoke a rapid
diffusion of Ca into the cytoplasm that serves
as a signal in diff. control systems
The entry of the Ca thru voltage-regulated Ca
channels in the plasma membrane serves as
a signal for the release of neurotransmitters
26. Phospholipase C-Ca2+
Second Messenger System
When epinephrine stimulates target
organ, it must first bind to andrenergic
receptor proteins in the membrane
2 types of adrenergic receptors:
a. Alpha
b. Beta
Alpha adrenergic receptors by
epinephrine activates the target cell via
the Ca second-messenger system
27. Phospholipase C-Ca2+
Second Messenger System
G-proteinintermediate enables binding of
epinephrine to alpha-adrenergic receptor
and the binding activates phospholipase
C
• Substrate is split by an active enzyme into
inositol triphosphate (IP3) and
diacylglycerol (DAG) that both acts as
second messengers but IP3 is better
understood
28. Phospholipase C-Ca2+
Second Messenger System
IP3leaves the plasma membrane and
diffuses thru the cytoplasm to the
endoplasmic reticulum
• Membrane of ER has receptor for IP3 so the
message of hormone is carried by IP3 from
cytoplasm to ER
Thebinding of IP3 to receptor causes specific
Ca channels to open.
29.
30. Phospholipase C-Ca2+
Second Messenger System
Results to rapid and transient rise of
cytoplasmic Ca concentration
Ca that enters the cytoplasm binds to a
protein called “calmodulin”
Activated calmodulin then activates
other specific protein kinase enzymes that
modify actions of other enzymes in the
cell
31. Tyrosine Kinase
Second-Messenger System
Insulin promotes glucose and amino acid
transport and stimulates glycogen, fat
and protein synthesis
Primary target organs are liver, skeletal
muscles and adipose tissue
Insulin’s mechanism of action is same with
growth factors’
32. Insulin Mechanism of Action
“Tyrosine kinase” is the enzyme that serves as
receptor protein for insulin and GF
Specifically adds phosphate groups to amino
acid tyrosine with in the protein
With two units(dimer) when binds to insulin
forming active tyrosine kinase enzyme
Each unit have ligand-binding site and an
enzymatic site
Ligand binding site-outside site that binds with
insulin
Enzymatic site-part that spans the plasma
membrane
33. Insulin Mechanism of Action
Enzymatic site activates only after binding
of insulin to ligand-binding site and causes
dimerization of the receptor
One unit then phosphorylates the other
- “autophosphorylation”
Signaling molecules are proteins
phosphorylated by the activated tyrosine
kinase receptor
Activates second messenger systems
34. Insulin Mechanism of Action
The complex reactions enables the insulin
to regulate the metabolism of its target
cells.
Example:
• binding of insulin to its receptor indirectly
causes the activation of “glycogen
synthetase”
Enzyme in liver and skeletal muscles that
catalyzes the production of glycogen
