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BIOCHEMISTRY
MEDICAL FACULTY USU
Intercelluler Communication
All cells detect and respond to
environmental stimuli
Intracelluler communication :
- endocrine
- nervous
- immune
Endocrine glands secrete hormones
BIOCHEMISTRY
MEDICAL FACULTY USU
Long Distance Communication:
Hormones
Signal Chemicals
Made in
endocrine cells
Transported via
blood
Receptors on
target cells
Long distance cell-to-cell communication
BIOCHEMISTRY
MEDICAL FACULTY USU
Paracrines and Autocrines
Local
communication
Signal chemicals
diffuse to target
Example: Cytokines
– Autocrine–
Autocrine–receptor
on same cell
– Paracrine
Paracrine––
neighboring cells
BIOCHEMISTRY
MEDICAL FACULTY USU
Direct and local cell-to-cell communication
Signal Pathways
Signal molecule (ligand)
Receptor
Intracellular signal
Target protein
Response
BIOCHEMISTRY
MEDICAL FACULTY USU
Signal pathways
Hormone Receptors
Receptors : a protein that binds a hormone
with high affinity
All receptors are proteins
Have at least two functional domains :
1. A recognition domain binds the hormone
ligand
2. A second region generates a signal that
couples hormone recognition to some
intracellular function
BIOCHEMISTRY
MEDICAL FACULTY USU
Hormone Receptors
Only the target cells for
a certain hormone have
receptors for that
hormone
Receptor density of
target cells:
– 2000
2000--100,000
receptors/hormone
BIOCHEMISTRY
MEDICAL FACULTY USU
Receptor locations
Cytosolic or Nuclear
– Lipophilic ligand
enters cell
– Often activates gene
– Slower response
Cell membrane
– Lipophobic ligand
can't enter cell
– Outer surface
receptor
– Fast response
BIOCHEMISTRY
MEDICAL FACULTY USU
Hormone - Target Cell Specificity
Receptors are dynamic
structures: they can
respond to rising levels
of hormones by
increasing in number
(up
up--regulation
regulation))
Respond to prolonged
exposure to high
hormone
concentrations by
reducing the number of
receptors (down
(down-regulation))
regulation
BIOCHEMISTRY
MEDICAL FACULTY USU
Receptors Intracelluler
Hormones can diffuse through the lipid bilayer
of the plasma membrane
 receptors intracelluler
The lipid soluble hormone diffuses into the
cell
Binds to the receptor  conformational
change
Binds to specific DNA sequences
response elements (HRE)
BIOCHEMISTRY
MEDICAL FACULTY USU
Receptors Intracelluler
These DNA sequences are in the regulatory
regions of genes.
Stimulating the transcription of messenger
RNA.
The messenger RNA travels to the
cytoplasm
 translated into protein
BIOCHEMISTRY
MEDICAL FACULTY USU
Mechanism of lipid
soluble hormone
action
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MEDICAL FACULTY USU
Action of Steroid Hormones
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MEDICAL FACULTY USU
Receptors on The Plasma Membrane
Receptors for the water soluble hormones
Couple to various second messenger systems
mediate the action of the hormone in the
target cell
Second messenger :
cAMP
cGMP
 Ca 2+
Phosphoinositide/Diacylglycerol(DAG)
Protein Kinase
Membrane-bound Hormone Receptors
Second Messenger Systems
1.Cyclic
1.
Cyclic AMP (cAMP)
Polypeptide or glycoprotein hormones bind
to receptor protein
dissociation of a subunit of GG-protein
The GG-protein is trimer (
(,  and  subunit)
The  subunit:
- bound to GDP in the native G protein
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MEDICAL FACULTY USU
Second Messenger Systems
1. Cyclic AMP (cAMP)
- the hormone receptor complex
exchange of GTP
- dissociates from G
- stimulates the adenylate cyclase
- ATP is converted to cAMP
ATP
cAMP + PPi
BIOCHEMISTRY
MEDICAL FACULTY USU
Activation of adenylate
cyclase by binding
of a hormone to its
receptor
Second Messenger Systems
1. Cyclic AMP (cAMP)
- The generation of
cAMP usually activates
protein kinase A (PKA)
- This results in
activation of cAMPdependent protein
kinase (PKA) with
consequent
Activation of PKA
phosphorylation of
target proteins
BIOCHEMISTRY
MEDICAL FACULTY USU
1. Cyclic AMP (cAMP)
- cAMP hydrolyzed by
cAMP phosphodiesterase
to 55-AMP
- phosphodiesterase
inhibited by
methylxanthine derivatives
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MEDICAL FACULTY USU
Second Messenger Systems
1. Cyclic AMP (cAMP)
Cholera toxin
-block Gs, hydrolysis of GTP to GDP
-severe diarrhea
Pertussis toxin
-block Gi, exchanging GDP for GTP
-whooping cough
Cholera toxin
Pertussis toxin
Action of Vasopressin/VP in Distal Kidney Tubules
Second Messenger Systems
2. Cyclic GMP (cGMP)
Membrane bound Guanylate cyclase
is an integral part of the receptor and
hence is structurally similar to
tyrosine specific protein kinases
GTP Guanylate cyclase cGMP
Protein kinase G
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MEDICAL FACULTY USU
Second Messenger Systems
BIOCHEMISTRY
MEDICAL FACULTY USU
Second Messenger Systems
2. Cyclic GMP (CGMP)
Atrial natriuretic factor (ANF) and brain
natriuretic peptide (BNP)  activate
guanylate cyclase
Increase blood volume : release ANF from
heart atrial cells.
Effects : lowering of BP via vasodilation and
diuresis
ANF  cGMP  increase renal excretion of
Na+ and water
BIOCHEMISTRY
MEDICAL FACULTY USU
Second Messenger Systems
BIOCHEMISTRY
MEDICAL FACULTY USU
Second Messenger Systems
2. Cyclic GMP (CGMP)
Nitric oxide (NO): stimulate synthesis
of cGMP
The resultant rise in cGMP  muscle
relaxation, through activation of PKG,
which phosphorylates myosin lightlightchain kinase and renders it inactive
 used to treat patients with angina
BIOCHEMISTRY
MEDICAL FACULTY USU
Second Messenger Systems
3. Calcium
Many cells respond to extracellular
stimuli by altering their intracellular
calcium concentration
concentration interaction with
calmodulin
Calcium levels controlled by
phosphoinositide system
Calcium ion may be more of a third
messenger
BIOCHEMISTRY
MEDICAL FACULTY USU
Second Messenger Systems
4. Phosphoinositide
Phosphoinositide/
/Diacylglycerol (DAG)
Cytosolic calcium ion levels increased by
release from intracellular calcium stores
Controlled by the phosphoinositide system
Hormonal stimulus  splits phospholipid
PIP2 into IP3 and DAG by phospholipase C
BIOCHEMISTRY
MEDICAL FACULTY USU
Phosphoinositide system - Ca2+
IP3 diffuses through cytoplasm to ER.
Binding of IP3 to receptor protein in ER
causes Ca2+ channels to open.
Ca2+ diffuses into the cytoplasm.
– Ca2+ binds to calmodulin.
Calmodulin activates specific protein
kinase enzymes
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Phosphoinositide system - Ca2+
DAG activates protein kinase C
Alters the metabolism of the cell,
producing the hormone’s effects
The conversion of inositol phosphate to
inositol is inhibited by lithium ion
treatment of manicmanic-deppressive
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Phosphoinositide system
- Ca2+
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Second Messenger Systems
Second messenger systems  a specific
protein kinase enzyme
The generation of second messengers and
activation of specific protein kinase results
in changes in the activity of the target cell
which characterizes the response that the
hormone evokes
Certain receptors have intrinsic kinase
activity
These include receptors for growth factors,
insulin, IGF,EGF, etc
PROTEIN TYROSINE KINASE RECEPTORS
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MEDICAL FACULTY USU
Action of
Insulin
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EICOSANOIDS HORMONE
Roles in inflammation, fever, regulation of
blood pressure, blood clotting, control of
reproductive processes & tissue growth,
sleep/wake cycle regulation
Most affect other cells by interacting with
plasma membrane GG-protein coupled
receptors.
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Prostaglandins
Depending on the cell type, the activated
G-protein may stimulate or inhibit
formation of cAMP (PGE2 and PGI2) by
stimulate or inhibit adenylate cyclase
PGF
PGF
2 can be activate a
phosphatidylinositol signal pathway
leading to intracellular Ca++ release
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MEDICAL FACULTY USU
Prostaglandins
Different prostaglandins may exert antagonistic
effects in some tissues.
– Immune system:
Promote inflammatory process.
– Reproductive system:
Play role in ovulation.
– Digestive system:
Inhibit gastric secretion
– Respiratory system:
May bronchoconstrict or bronchodilate.
– Circulatory system:
Vasoconstrictors or vasodilators.
– Urinary system:
BIOCHEMISTRY
Vasodilation MEDICAL FACULTY USU
REFERENCES
Devlin T M, PhD. Text Book of Biochemistry with
Clinical Correlations 5thed. WileyWiley-Liss, New York.
2002 : 906906-952, 982982-983
McKee Trudy, McKee James R. The molecular
basis of Life. 3rded. McGrawMcGraw-Hill. Americas, New
York. 2003 : 541541-559
Murray R K, et al. Harper’s Biochemistry 26thed.
Appleton & Lange. America 2003: 434434-473
Raff A, et al. Moleculer Biology of The Cell. 4thed.
Garland Science. New York. 2002: 832832-892
Stryer L. Biokimia. Edisi 4. EGC, Jakarta. 2000.:
340--358
340
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