1. Mechanism of
Hormone
Action

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

10. Ligand-binding
Dimerization of receptors domain
Steroid DNA-binding
hormone domain
Half-sites
DNA
Genetic transcription
Hormone-response element RNA

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)

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

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.

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