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