x x signal trans duct ion 333
TRANSCRIPT
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Signal
Transduction
Professor Dr. Eman Shaat
Medical Biochemistry
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Cell signaling
Cells in the multicellular organism need tocommunicate with one another to:
** regulate their development into tissues.** control their growth and division and to
** coordinate their function.
Transmission of the information may occur
either by:** intercellular pores known as gap junctions** cell signaling.
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Signal transduction
Detect extra cellular signal
Transduce into
Intra cellular changes
Integrated into specific biologic function
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Signal transduction
It is the biochemical process in which a
cellconvertssignals(that are detected by
cell receptors)
to cellularresponse.
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Elements of a signal transduction System
1. Sender
2. Signal
3. Nondestructive Medium
4. Selective Receiver
5. Transducer
6. Amplifier7. Effector
8. Response
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Generic Signaling Pathway
Signal
Receptor
(sensor)
TransductionCascade
Targets
Response
AlteredMetabolism
MetabolicEnzyme
Gene Regulator Cytoskeletal Protein
AlteredGene
Expression
Altered CellShape orMotility
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1. Sender ( signaling cell )
- The cell that sends a signal
Such as
1- Endocrine cells (secrete hormones)2- Neural cells (secrete neurotransmitters)
- The released signals sometimes act on the same
cell (autocrine), neighbor cell (paracrine), ordistant cell (endocrine).
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autocrine
paracrine
endocrine
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2. Signal (Ligand ; primary messenger)
Signal = LIGAND
Ligand: A molecule that binds to aspecific site on another molecule,usually a protein, i.e. receptor
- What can be the Signal?External message to the cell
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Examples of signal molecules:
- Hormones
- Growth factors
- Cytokines.- Neurotransmitters.
- Antigens.
[-Excessive, deficient or inappropriate production of thesesignals causes disease
- Oncogenes encode defective signal protein ]
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3. Target cell
A target cell is defined by its ability to selectivelybind a given ligand to its receptor.
At target cells, there are:
- receptor.
- Signal transduction pathway (effector, 2nd
messengers, enzymes, )- Effectors.
- Response (final effect).
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Sender
Signaling cell
Signal; ligand;1stmessenger
Receptor
Transductionpathway
Response
Targetcell
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Molecular Mechanisms (Features) of
Signal Transduction
1- Specificity
2- Amplification3- Desensitization
4- Integration
5- Sensitivity
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Specificity is promoted because the
receptors for a given signal or theintracellular targets of a given signalpathway are present onlyin certain cell
types.
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Epinephrine alters glycogenmetabolism in hepatocytes but not inerythrocytes, although both cell types
have receptors for the hormone.However, hepatocytes have theglycogen-metabolizing enzymes, buterythrocytes do not.
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e.g. the receptor may be internalized (down regulation).
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e) Sensitivity:Three factors account for the sensitivity of signal
transducers:
- The high affinity of receptors for signalmolecules.
- Cooperativity in the ligand- receptor
interaction.
- Amplification of the signal by enzyme cascade.
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Types of receptors
I- Cell-surface receptors (plasma membrane)
a- Gated ion channel.
b-G- protein receptors.
c- Enzyme receptors.
II- Internal receptors
a- Cytoplasmic.b- Nuclear.
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Types of Receptors
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General types of Signal Transducers
1- Gated ion channel (as acetyl cholinereceptor).
2- G- protein Receptors (asb-adrenergicreceptors).
3- Enzyme Receptors (as insulin receptor).
4- Steroid receptors (as thyroid hormonereceptor).
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Signal Transduction
http://en.wikipedia.org/wiki/File:Transmembrane_receptor.png -
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Signal Transduction
Receptor
Hormone Signal
G
Cyclase
Transducer
Effector Enzyme
Effector
Effect
G-protein
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G- proteinCoupled receptors
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Epinephrine Signaling Pathway
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Insulin Tyrosine Kinase Receptors
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Intracellular receptors as Steroid Receptor
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7. EffectorsAlteration of protein structure & function
Modifying protein content (concentration) by:
- Altering rate of gene expression.
Modifying function & activity of specific proteins by:
- Allosteric regulation.
- Covalent modification of enzymes
[phosphorylation - dephosphorylation by
kinases & phosphatases]
Phosphorylation
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Phosphorylation
Conformational
ChangedephosphorylastionPhosphatase
P
Protein
OH
SerThr Tyr(His)
Active Inactive
Glycogen synthase Glycogen synthase
Inactive Active
Glycogen phosphorylase b Glycogen phosphorylase a
Kinasephosphorylation
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8. Response
Homeostatic adaptation to constantlychanging environment, thus, control
diverse effects. e.g.
** ion transport.
** carbohydrate, lipid & protein metabolism.
** cell growth, replication & cell death.
** neurotransmission.
** cell shape & motility.
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Termination of signals
May be through:
Removal of the signal.
Feed-back mechanism.
Receptor internalization.
Protein phosphatases.
G i Si li P h
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Generic Signaling Pathway
Signal
Receptor(sensor)
TransductionCascade
Targets
Response
AlteredMetabolism
MetabolicEnzyme
Gene Regulator Cytoskeletal Protein
AlteredGene
Expression
Altered CellShape orMotility
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Elements of a signal transduction System
1. Sender
2. Signal
3. Nondestructive Medium
4. Selective Receiver5. Transducer
6. Amplifier
7. Effector
8. Response
Termination of signal
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G i
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G- proteinCoupled receptors
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Epinephrine Signaling Pathway
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Disturbed Signal Transduction
1.Cystic fibrosis
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Cystic Fibrosis
is an autosomal recessive diseasecommon among Caucasians by mutationsin the CFTR.
CFTR Regulates the transport ofchlorideand other ions across the cell membraneand hence normal viscosity and function
of mucosal secretions.
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Cystic fibrosis is a recessive disorder, whichmeans that both parents must pass on thedefective gene for any of their children toget the disease. If a child inherits only onecopy of the faulty gene, he or she will be acarrier. Carriers don't actually have the
disease, but they can pass it on to theirchildren.
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Cystic fibrosis affects multiple parts of the body including thepancreas, the sweat glands, and the lungs.
The cause of their lung problems is directly related to basicproblems with diffusion and osmosis in the large airways ofthe lungs.
People without cystic fibrosis have a small layer of salt water
in the large airways of their lungs. This layer of salt water isunder the mucus layer which lines the airways. The mucuslayer in the airways helps to clear dust and other inhaledparticles from the lungs.
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In people without cystic fibrosis, working cystic fibrosis
proteins allow salt (chloride) to enter the air space andwater follows by osmosis. The mucus layer is dilute and
not very sticky.
In people with cystic fibrosis, non-working cystic fibrosis
proteins mean no salt (chloride) enters the air space andwater doesn't either. The mucus layer is concentrated andvery sticky.
Therefore, because ofless diffusion of salt and lessosmosis of water, people with cystic fibrosis have toomuch sticky mucus in the airways of their lungs and getlots of lung infections. Thus, they are sick a lot.
ff
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primarily affects the respiratory, digestive andreproductive systems, as well as the sweat glands.
The mucus secreted is very thick and blockspassageways in the lungs and digestive tracts withrepeated infections and obstructions in bothsystems.
Foul-smelling bowel movements ,Mucus in stool,Bulky bowel movements ,Steatorrhea - bulky softfoul-smelling stool ,Abdominal bloating
,Malnutrition ,Delayed growth ,Weight loss,Pancreatic insufficiency , Enlarged liver ,Enlargedspleen
Salty sweat
http://www.wrongdiagnosis.com/sym/stool_odor.htmhttp://www.wrongdiagnosis.com/sym/mucus_in_stool.htmhttp://www.wrongdiagnosis.com/sym/bowel_movements.htmhttp://www.wrongdiagnosis.com/sym/steatorrhea.htmhttp://www.wrongdiagnosis.com/sym/abdominal_swelling.htmhttp://www.wrongdiagnosis.com/sym/malnutrition.htmhttp://www.wrongdiagnosis.com/sym/poor_growth.htmhttp://www.wrongdiagnosis.com/sym/weight_loss.htmhttp://www.wrongdiagnosis.com/sym/pancreas_symptoms.htmhttp://www.wrongdiagnosis.com/sym/enlarged_liver.htmhttp://www.wrongdiagnosis.com/sym/swollen_spleen.htmhttp://www.wrongdiagnosis.com/sym/swollen_spleen.htmhttp://www.wrongdiagnosis.com/sym/sweat_symptoms.htmhttp://www.wrongdiagnosis.com/sym/sweat_symptoms.htmhttp://www.wrongdiagnosis.com/sym/swollen_spleen.htmhttp://www.wrongdiagnosis.com/sym/swollen_spleen.htmhttp://www.wrongdiagnosis.com/sym/enlarged_liver.htmhttp://www.wrongdiagnosis.com/sym/pancreas_symptoms.htmhttp://www.wrongdiagnosis.com/sym/weight_loss.htmhttp://www.wrongdiagnosis.com/sym/poor_growth.htmhttp://www.wrongdiagnosis.com/sym/malnutrition.htmhttp://www.wrongdiagnosis.com/sym/abdominal_swelling.htmhttp://www.wrongdiagnosis.com/sym/steatorrhea.htmhttp://www.wrongdiagnosis.com/sym/bowel_movements.htmhttp://www.wrongdiagnosis.com/sym/mucus_in_stool.htmhttp://www.wrongdiagnosis.com/sym/stool_odor.htmhttp://www.wrongdiagnosis.com/sym/stool_odor.htmhttp://www.wrongdiagnosis.com/sym/stool_odor.htm -
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Disturbed Signal Transduction
2. Cholera toxin
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cholera toxin
When cholera toxin is released from thebacteria in the infected intestine, it binds tothe intestinal cells known as enterocytes
(epithelial cell in above diagram) through theinteraction of thepentameric B subunitofthe toxin with the GM1 ganglioside receptor
on the intestinal cell, triggering endocytosisof the toxin.
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Next, theA/B cholera toxin must undergo cleavage of
theA1 domain from the A2 domain in order forA1 tobecome an active enzyme.
Once inside the enterocyte, the enzymatic A1
fragment of the toxin A subunit enters the cytosol,where it activates the G protein Gsa through an ADP-ribosylation reaction that acts to lock the G protein inits GTP-bound form,
thereby continually stimulating adenylate cyclase toproduce cAMP.
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The high cAMP levels activate the cysticfibrosis transmembrane conductanceregulator (CFTR)
causing a dramatic efflux of ions andwaterfrom infected enterocytes
leading to watery diarrhoea.
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Cholera toxin catalyzes covalentmodification ofGsa.
ADP-ribose is transferred from NAD+ toan arginine residue at the GTPase activesite ofGsa.
ADP-ribosylation prevents GTPhydrolysis by Gsa.
The stimulatory G-protein ispermanently activated.
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Disturbed Signal Transduction
3. familial hypercholesterolemia
Familial Hypercholestrolemia
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(LDL receptor deficiency)
Familial Hypercholestrolemia is anautosomal dominantsingle gene disease
characterized by elevated cholesterollevels and increased risk for coronaryartery disease due to deposition of
Cholesterol in the vessel wall.
Familial hypercholesterolemia
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Familial hypercholesterolemia
1
Apo-
B100
Apo-E
-due to deficiency in a cell
surfaceLDL-R (the receptor regulatesLDL degradation and
cholesterol synthesis)
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Presenting features:
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Presenting features:
Subcutaneous yellowish nodules seen on
extensor aspects on elbows and knees(xanthomas)
Deposition of lipids in eyelids(xanthelasmas)
Increased risk for cardiovascularandcerebrovasculardisorders due to narrowingof the blood vessels and ischemia.
high cholesterol (since birth)
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Pathophysiology :
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Pathophysiology :
The circulating cholesterol bound to LDL attaches the LDLR
on the cell membrane of hepatocytes.
Once internalized by endocytosis, it separates LDLR which isrecycled back to cell membrane.
Inside lysosomes, cholesterol dissociates from its carriercomplex protein then serves in the synthesis of steroidhormones, bile acids and as a constituent in cell membranes.
Excess cholesterol is stored as esters.
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Five major classes of FH due to LDLR
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Five major classes of FH due to LDLRmutations:
Class I: LDLR is not synthesizedat all.
Class II: LDLR is not properly transportedfrom theendoplasmic reticulum to the Golgi apparatus for expression
on the cell surface. Class III: LDLR does not properly bindLDL on the cell
surface
Class IV: LDLR bound to LDL does not properly cluster in
clathrin-coated pits for receptor-mediated endocytosis.
Class V: LDLR is not recycledback to the cell surface
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