Cell signaling
by Chemical messengers
Dr. Maha Sallam
Professor of Biohemistry
Objectives of studying hormones
1- Define signal transduction
2-Understand different classifications of hormones
3-Define hydrophilic and lipophilic hormones and
the difference between both groups.
4-Enumerate types of hormone receptors.
5- Study mechanism of action of lipophilic
hormones.
6- Study different second messengers of
hydrophilic hormones: cAMP,cGMP,Ca,IP3.
7- Study structure of insulin receptor & its
mechanism of action.
Signal transduction
This is the process by which exracellular signals
can be transduced (converted ) into intracellular
.chemical changes
:These signals ( chemical messengers) include
Hormones, neurotransmitters, growth factors,
light ..etc
Features of signal transduction
system
1.
2.
3.
4.
Specificity
Amplification
Desensitization & adaptation
Integration
Specificity-1
There is a molecular Complementarity
between the signal & Receptor
that are present only in certain cell
types.
Amplification-2
By Enzyme Cascades When an ENZ. With a
signal receptor is activated, it will activate
many molecules of a second ENZ. & so on.
Desensitization & adaptation-3
When a signal is present
continuously desensitization
. of receptor system results
Integration-4
The ability of the system to
receive multiple signals and
produce a response appropriate to
the needs of the cell.
:Endocrine System includes
Pituitary
gland
Thyroid gland
Parathyroid glands
Suprarenal gland ( cortex & medulla)
Testis & Ovaries
Islets of Langerhans of Pancreas.
(Insulin & glucagon)
Hypothalamous
Anterior lobe
Ovary
Pitutary
FSH,LH
Testis
Growth H
Posterior lobe
vasopressin
ACTH TSH
Oxytocin
Prolactin Suprarenal
gland
Mammary
gland
Thyroid
Mammary
gland
Some glands are out of control
of anterior pituitary
1.
The islets of Langerhans of pancrease
(Insulin & Glucagon controlled by glucose
level).
2.
Suprarenal medulla (Catecholamine
controlled by sympathetic nerves).
3.
Parathyroid gland ( by low calcium level).
4.
Parafollicular cells of thyroid gland( by
blood calcium level).
Classification of hormones
there are different types of
:classifications
Based on distance
of action
Based on chemical
structure
&Based on solubility
Mechanism of action
Based on distance
of action
AUTOCRINE
PARACRINE
ENDOCRINE
AUTOCRINE
Hormones that act on the cells that
secrete them e.g hypothalamic and
pituitary hormones and their effect
.on their own cells
PARACRINE
Hormone arises from one cell and acts at a
near celle.g prostaglandines act as local
hormones
Endocrine
Hormones secreted by endocrine glands,
transported in blood and act on distant target
organs
Based on chemical
structure
Based on solubility &
Mechanism of action
Lipophilic Hormones
ophilic Hormones
Hydrophilic H
Lipophilic H
Outside the cell
Cell membrane
Second messenger
That mediates Hormone action
Inside the cell
Hydrophilic Hormones
Lipophilic Hormones
These are :polypeptides,
proteins, glycoprotein's
and catecholamines
They are water soluble
can not cross cell
membrane
They do not need
transporter proteins
Short plasma half life
(minutes)
They are steroid
Hormones ,T3 ,T4 and
Calcitriol
They are lipid soluble
can cross cell membrane
Cell membrane receptors
Mediators ( second messanger)
: cAMP, cGMP, Calcium, PI3
They need transport
proteins
Long plasma half life
(hours or days)
Intracellular receptors
Hormone receptor complex
Cell signaling
Lecture 2
Hydrophilic H
Lipophilic H
Outside the cell
Cell membrane
Second messenger
That mediates Hormone action
Inside the cell
The cell membrane is formed of :-1
a-equalproportionsoflipid,proteinand
carbohydrates
b-amphipathiclipids,proteinsandsmall
amountofsugars
c-hydrophobicproteinsandsugars
d-amphipathiclipidsandsugars
Thereceptorofthelipophilic-2
hormoneispresentin
A-cellmembrane
B-mitochondria
C-nucleus
D-cytoplasm
E-endoplasmicreticulum
F-ribosomes
Thehydrophilichormone-3
needsa..foritsaction
A-cytoplasmicreceptor
B-transporterprotein
C-Nuclearreceptor
D-secondmessenger
Hormonal receptors
They are
Cell-associated recognition
molecules
can recognize & bind specific
hormones present at a very low
concentration in the
extra cellular fluid
Biological intercellular chemical effect
Agonists
Molecules
that bind the
receptors & induce all the
post-receptor events that lead
to a biological effect.
The hormone itself is agonist
Antagonists
Molecules that bind the
receptors & prevent binding
of the hormone, so block the
biologic effects of the
hormone
They can be used as drugs.
General structure of the receptor
Recognition domain
Coupling domain
Bind the hormone
Generates the signal
Any Receptor must have
Recognition domain:
Bind the Hormone.
coupling domain:
which transduce a specific
signal to the interior of the
cell giving the Hormone
response.
Hormonal receptors
Intracellular
receptors
Cell membrane
receptors
Intracellular Receptors are
:either
Cytoplasmic
As Steroid
hormones
Nuclear
As thyroid hormone
receptors
Cell Membrane receptors
Serpentine
R
R with
enzymatic
activity
R that activate
cytoplasmic
kinases
Ion channel
R
Ion channel receptor
Hormone receptor regulation
Down Regulation-1
1.
2.
3.
4.
5.
Decreasing receptor number
(Slow adaptation).
When target cell exposed continuously to
elevated levels of the hormone.
The cell can protect itself against
excessive hormonal stimulation.
E.g Insulin & Catecholamines
Receptor
mediated ENDOCYTOSIS.
Receptors
surface.
They
failed to recycle to cell
are delivered to lysosomes To be
degraded with the hormone.
Steroid receptors are down
regulated By Inhibiting
transcription of their Receptor
mRNA
Up regulation- 2
Increasing Receptor Synthesis.
(slow adaptation)
e.g Prolactin up regulates its
receptor in mammary gland.
Desensitization-3
This usually involves phosphorylation
of the receptor (Rapid adaptation)
Mechanism of action
of hormones
Lipophilic Hormones
1-Steroid hormones
Glucocorticoides (cortisol)
Mineralocorticoides (aldosterone)
Intracellular Receptors are
:either
Cytoplasmic
As Steroid
hormones
Nuclear
As thyroid hormone
receptors
HRE
Specific function
Thyroid hormones
Lecture 3
Hydrophilic Hormones
They have different second
:messenger
cAMP
cGMP
Calcium
and /or Phosphatidyl
inositol
Kinase or
Phosphatase
cAMP as a second messenger-1
Adenylate Cascade mechanism
Hormones acting by this method:
Glucagon, adrenergic catecholamines,
calcitonin, parathyroid hormone , FSH,
LH, ACTH, TSH
Serpentine Receptors
Serpentine Receptors
G- protein coupled adenyl cyclasecAMP
system
:This
system
is formed of
Hormone
Serpentine receptor
helical segments 7
.Adenyl Cyclase Enz
G Protein
a guanosine nucleotidebinding protein
G protein is formed of , and
Supportive units
Inhibitory or
Stimulatory
GTPase activity
On resting state
subunit is binding to GDP
PKA (Protein Kinase A)
cAMP dependant Protein kinase Enzyme
R
C
R
C
Phosphorylation of cellular proteins
at seine or threonine AA
.That stimulate or inhibit some enz
Effect of cAMP on transcription
PKA phosphorylates CREB (cAMP
Response Element Binding protein) to be
a potent transcription factor
This Hormonal action is terminat
by:
1-GTPase
activity of subunit that converts
GTP into GDP with re-association of the
three subunits to return to the resting state.
2- Phosphodiesterase that convert cAMP into
5-AMP.
3-Phosphatases
remove phosphate from
phosphorylated proteins and thus terminate
the hormonal action.
Medical Applications
Toxins disrupt G protein
Cholera toxins
are enzymes
catalyze ADP
ribosylation of
subunit of Gs
Of intestinal
cells
NAD
ADP- Ribose
Nicotinamide
Blocking GTPase activity
Continuous activation of Adenyl cyclase of intestinal cells
cAMP
Continuous secretion of CL- , HCO3 and water
Diarrhea & dehydration
Toxins disrupt G protein
Pertussis toxins secreted by Bordetella pertussis are
enzymes catalyze ADP ribosylation of subunit of Gi
ADP- Ribose
Preventing displacement of GDP by GTP and
blocking inhibition of adenyl cyclase by Gi
cAMP
Whooping cough symptoms
Lecture 4
cGMP as a second- 2
messenger
cGMP as a second messenger- 2
The receptor
itself has
: enzyme activity
Guanylate
cyclase activity
Activation of c GMP
dependant protein
kinase G
GTP
cGMP
Factors that depend on cGMP
as a second messenger
Atrial
natriuretic factor
ANF (Atriopeptin)
Nitric Oxide NO
There are two types of Guanyl cyclase
ANF
Nitric Oxide
cGMP as a second messenger
Guanylate
cyclase activity
Activation of c GMP
dependant protein
kinase G (PKG)
GTP
cGMP
Atrial natriuretic factor
ANF (Atriopeptin)
Atrial natriuretic Factor
cGMP
Blood volume
Renal excretion of Na and water &
induces vasodilatation decreasing
blood volume
Effect of atrial natriuretic factor
This peptide is produced in cardiac atrial
tissues. It binds to and activates the
membrane-bound form of guanylyl cyclase in
. the kidney ( cells of collecting ducts)
increase of cGMP
Natriuresis, diuresis, vasodilation, and
inhibition of aldosterone secretion decreasing
blood volume
Nitric Oxide
NO
endothelial cells
Nitric Oxide
synthase
NO
Smooth muscle cell
cGMP
Soluble guanyl
cyclase
Smooth muscle relaxation and vasodilatation
Medical Applications
Effect of NO
Nitro vasodilators as nitroglycerin are used to
treat Angina because they break down over
several hours producing a steady stream of NO
Increase cGMP by activating cytoplasmic guanylyl
cyclase
Activates cGMP-dependent protein kinase (PKG),
which in turn phosphorylates a number of smooth
muscle proteins with
.relaxation of smooth muscle and vasodilation
Calcium and /or Phosphatidyl-3
inositol as second messenger
Calcium and /or Phosphatidyl-3
inositol as second messenger
phosphatidylinositol- Ca
pathway
Examples of Hormones acting by this method
,1 adrenergic catecholamines*
,vasopressin *
oxytocin *
Types of phospholipases ( Enz. hydrolyse phospholipids)
Phosphatidylinositol 4,5 bisphosphate
PLC
IP3
DAG
Phospholipase C
Phosphatidylinositol 4.5 disphosphate
PLC
Role of Calcium as a second
messenger
Calcium release from its storage vesicles
:increasing its intracellular level 10000 times
: It affects target proteins by
Directly by activating certain enzymes e.g -1
phosphyrlase that hydrolyzes glycogen
Indirectly through calmodulin (regulatory -2
protein)
Ca is pumped inside Mitochonria And Endoplasmic
Reticulum by ATP dependant Ca/ATP ase pump
Cell
Calmodulin is one of
Ca2++- dependant proteins
++
Ca2
Ca binding induces conformational
changes in calmodulin
Activation of Ca
Kinase
/calmodulin-dependant
2++
Phosphorylation of of specific enzymes
Medical applications
Phorbol esters, synthetic compounds that
are potent activators of PKC. They
apparently mimic cellular diacylglycerol as
second messengers, but unlike naturally
occurring diacylglycerols they are not
rapidly metabolized. By continuously
activating PKC, these synthetic tumor
promoters interfere with the normal
regulation of cell growth and division causing
.cancer
Lecture 5
Second messenger is a - 4
Kinase or Phosphatase
1-The
receptor is a tyrosine
Kinase ( Growth factors, Insulin
etc ).
2-Receptor with no enzyme
activity but use cytoplasmic
tyrosine kinases ( Jak-STATs)
e.g Growth hormone)
The receptor is a tyrosine Kinase-1
.( Growth factors, Insulin etc )
1-Insulin receptor
heterotetramer glycoprotein
Extracellular 2
subunits that
bind to insulin
Intracellular B 2
subunits have
tyrosine kinase
activity and
autophosporylation
sites
Insulin
Insulin Receptor Substrate-1
Kinase
Protein Phosphorylation
(altering gene expression)
Phosphatase
Dephosphorylation
of certain regulatory enzymes
regulating metabolic pathways
Summary of metabolic effects of
insulin ( hypoglycemic hormone)
Insulin receptor activation activates
specific proteins, (e.g IRS-1) which
in turn activates a protein kinase
or a phosphatase cascade that
ends with the phosphorylation or
dephosphorylation of target
proteins in the cytosol and nucleus.
The result is specific metabolic
changes and altered gene
.expression
Receptor with no enzyme activity-2
but use cytoplasmic tyrosine kinases
( Jak-STATs) e.g Growth hormone,
prolactin, cytokines
Jak:acytoplasmictyrosinekinase(an
acronymforJanuskinase)
Janus(twoheadedgodoftheRoman)
STATs:signaltransducerandactivatorof
transcription.
RevisionQuestions
Insulin binding to subunit of its-1
:receptor will cause
a- ADP ribosylation of subunit
b- phosphorylation of tyrosine residues of
subunit
c- activation of GTPase activity of
subunit
d- dissociation of subunit from subunit
Cholera toxin-3
a-activatescholinergicreceptors
b-stimulatesadenylcyclase
c-inhibitsNa,K-ATPase
d-inhibitsvasopressinsecretion
cAMP dependant protein kinase:-4
a-isformedof2and2subunits
b-canbindto4calciumions
c-canphosphorylatemanyenzymes
d-isinhibitedbyphosphatase
A premature baby had difficulty in-5
breathing and cyanosis immediately
after birth. Which of the following
may be the defective substance in
that baby :
a-lysolecthicin
b-dipalmtoyllecithin
6-Steroid hormones act through
7- Inositol triphosphate acts as a
second messenger to :
a-stimulatecAMPdependantprotein
kinase
b-activateaphosphodiesterase
c-activatecyclo-oxygenase
Insulin actions include :-8
a-activationofcalmodulinprotein
b-covalentmodificationofmany
enzymesandalteringgene
expression
c-increaseintracellularcGMP
1-A patient infected with cholera had vomiting, diarrhea
and dehydration. Explain the biochemical mechanism
of diarrhea and dehydration.
2- Discuss mechanism of action of steroid hormones.
3- Give an account on G proteins.
4- Give short notes on protein kinase A
5- Explain the mechanism of intracellular calcium
release and its role as a second messenger.
6-Give short notes on c GMP as a second messenger.
7- Discuss structure of insulin receptor and mechanism
of action of insulin hormone.
Thank you
&
Good Luck
