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Human Health and Disease
Lecture 3
The series of steps involved in signal transduction pathway
2
General elements of GPCRs
Most abundant class of receptors
 Found in organisms from yeast to man
1. A receptor with 7 membrane-spanning
domains
2. A coupled trimeric G protein
3. A membrane bound effector protein
4. Feedback regulation and desensitization of
the signalling pathway
5. A 2nd messenger present in many GPCRs.
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Second messengers are molecules that
relay signals from receptors on the cell
surface to target molecules inside the cell, in
the cytoplasm or nucleus.
 These components of GPCRs can be mixed
and matched to achieve an astonishing
number of different pathways
 GPCR pathways usually have short term
effects in the cells
 Allow the cells to respond rapidly to a
variety of signals like environmental stimuli
(light) or hormonal stimuli (epinephrine)
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General features
 GPCRs have same orientation in the
membrane , 7 transmembrane alphahelical regions, 4 extra cellular segments,
4 cytosolic segments
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G Protein
•Guanine nucleotide-binding
proteins, family of proteins involved in
transmitting chemical signals originating
from outside a cell into the inside of the
cell.
•G proteins function as molecular
switches. Their activity is regulated by
their ability to bind to and
hydrolyze guanosine triphosphate (GTP)
to guanosine diphosphate (GDP).
•When they bind GTP, they are 'on', and,
when they bind GDP, they are 'off'.
•G proteins belong to the larger group
of enzymes called GTPases.
Gβ§
Involvement of G- Protein in Cell
Signaling
Opening of ion channels
What do we know about ion
channels?
‘’Ion channels are responsible for the transmembrane flux of ions that
lead to the generation of action potentials. There is a stunning array of
different types of channels that can be activated by different stimuli.
Biophysical studies have begun to reveal the fundamental mechanisms
responsible for the selectivity of a channel for one ion over another.
And, both physicians and scientists are learning much about the role
of ion channels in normal physiology from the discovery of human
mutations. Nevertheless, the functions of many ion channels remain
unknown, and their structure-function relationships are still undefined.
Despite being very small structures, ion channels have large functions;
they control the beating of a heart, the perception of sound or sight,
or storage of a memory. Ultimately, these biological processes depend
not on a single ion channel, but on all the ion channels in a cell and
tissue network functioning in a coordinated manner. How this
happens will continue to capture our imagination and attention for
decades to come.’’
http://www.nature.com/scitable/topicpage/ion-channels-and-excitablecells-14406097
Signal amplification occurs in many
signaling pathways
Receptors are low abundance proteins
 The binding of few signaling molecules to available
receptors require production of tens of
thousands or even millions of second messenger
or activated enzyme molecules per cell.
 Substantial signal amplification must occur in
order for a hormone signal to induce a significant
cellular response.
 For example, a single epinephrine-GPCR complex
causes conversion of up to 100 inactive Gαs
molecules to the active form before
epinephrine dissociate from the receptor.

•Binding of a single epinephrine molecule to the receptor induces synthesis
of a large number of cAMP molecules, first level of amplification.
•2 molecules of cAMP activate 1 molecule of protein kinase A.
•Each activated PKA phosphorylates and activates multiple product
molecules, second level of activation.
How does the signaling terminate?
The Gα-GTP state is short-lived because the
bound GTP is hydrolyzed to GDP in minutes.
 The GPCR signal-transduction system
contains a built-in feedback mechanism that
ensures the effector protein becomes
activated only for a few seconds or minutes
following receptor activation.
 Gα the switches back to Gα-GDP state
blocking any further activation of effector
proteins.
 The resulting Gα-GDP reassociates with Gβγ
and the complex becomes ready to interact
with an activated receptor to stop the
process.

Acetylcholine induces different
responses in different target cells
Cardiac Cycle
LA: Left Atrium
RA: Right Atrium
LV: Left ventricle
RV: Right Ventricle
Ao: Aorta
SVC: Superior vena cana
IVC: Inferior vena cava
PA: Pulmonary Artry
1. Atrial
Systole
2. Ventricle
Diastole
3. Ventricle
Systole
Diastole represents the period of time when the ventricles
are relaxed (not contracting).
Systole represents the time during which the left and right
ventricles contract and eject blood into the aorta and
pulmonary artery, respectively.
http://www.cvphysiology.com/Heart%20Disease/HD002.htm
Action Potential of Heart Muscles
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An action potential is the transient, rapid rise and fall of the membrane
voltage.
The voltage difference across the cell membrane is about -70mV at rest, and there
is a greater concentration of Na outside the cell than inside.
So, when the cell reaches a certain threshold potential, the Na channels open, and
Na rushes into the cell resulting in a potential of about +30mV. The cell is said to
be "depolarized.“
Then, K channels open, and since the concentration of K is higher inside the cell, K
rushes out. This brings the polarity back down to -70mV, and then a little bit past it
to -90mV. At this point the cell is said to be "hyperpolarized."
The Na/K pump then gradually restores the potential back to the resting -70mV,
and the cell can then transmit another action potential.
If the cell's potassium channels do not open, the cell will be constantly
depolarized, and therefore be unable to conduct an action potential.
Decreased release of neurotransmitter
acetylcholine contributes to heart failure
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It reduces the cardiomyocytes demand of oxygen rendering them
more resistant to the reduced oxygen supply which may result
from the obstruction of coronary arteries by atherosclerosis. The
area of experimental infarction was reduced by ~50% in animals in
which cardiomyocytes acetylcholine synthesis was largely increased
by genetic manipulations.
It controls growth of cardiomyocytes. They increase their volume
(hypertrophy) in animals in which acetylcholine synthesis has been
eliminated. Cardiomyocytes are hypertrophied when the heart is
mechanicaly overloaded for example in arterial hypertension.
Cardiomyocytes of animals devoid of acetylcholine synthesis are
more susceptible to the overload. Hypertrophy of cardiomyocytes
may lead to the heart failure. So the non-neuronal acetylcholine
contributes to prevention of heart failure.
It is necessary for the balance between parasympathetic and
sympathetic heart innervation. In the heart failure parasympathetic
tone is decreased, and sympathetic increased.
Iron uptake in different cells
MCF
hephaestin or
ceruloplasmin
Fe3+
Fe2+
Haem
Haem
Diferric Tf
HCP1
DMT1
Dcytb
FPN1
STEAP 3
HO
Fe-Tf-TFR1
Ferritin
Duodenal enterocyte
Diferric Tf in
serum
HO
Endosome
pH < 6
Ferritin
Hepatocyte
Haem from
RBCs
Apo Tf in serum
Ferritin
Macrophage
Lecture prepared from
The Cell: A Molecular Approach. 2nd
edition
http://www.ncbi.nlm.nih.gov/books/NBK989
8/
 Molecular Cell Biology, Lodish and co
5Edition, Chapter 15

Assignment 1
Role of acetylcholine in the body.
 Heart diseases related to abnormal levels
of acetylcholine.
 http://neuroscience.uth.tmc.edu/s1/chapte
r11.html
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