Download Chapter 34-4B: Second Messengers

Chapter 21b (Summary)
1
Takusagawa’s note
Chapter 21B: Hormons and Receptors
1.
-
Hormone classes
Autocrine, paracrine, and endocrine hormones
2.
-
Functions
Maintain homeostasis, respond to stimuli, and control cyclic and developmental processes.
3.
-
Receptors
Some of membrane proteins are receptors of signal transduction.
Hormones, growth factors and neurotransmitters bind the signal transduction receptors located on
the surface of target cell membranes.
Signals are transferred to the inside of target cell through the transmembrane receptor protein.
Signals are converted to some biochemical signals, such as phosphorylation of proteins and GDPGTP exchanges.
Responses are produced by “second messengers”, such as 3’,5’-cyclic AMP (cAMP), inositol
triphosphate (IP3) and Ca2+.
-
4.
H2
C
Four classes of receptors
Steroid receptors.
Growth factor receptors.
Adrenoreceptors.
Acetylcholine receptors
A
O
O
P
-
6.
-
A
O
O
O
OH
-
O
-
P O
OH
OH
-
O
O
cAMP
5.
-
H2
C
O
AMP
Steroid receptors
are not transmembrane proteins.
Steroid hormones can pass freely through cell membrane, and bind the specific receptor protein in
cytosol.
The receptor activated by the steroid hormone moves into the nucleus.
The active receptor binds a specific region of DNA and activates or inactivates the replication
and/or transcription processes.
-
Growth factor receptors
are receptor tyrosine kinases.
are transmembrane proteins consisted of α-subunit (receptor site) and β-subunit (transmembrane
and tyrosine-specific protein kinase).
Binding growth factor such as insulin on the receptor triggers autophosphorylation of the Tyr
residue in the C-terminal domain of β-subunit.
This phosphorylation allows the tyrosine kinase domain to catalyze phosphorylation of other target
proteins.
Phosphorylated target proteins activate various enzymes.
7.
-
Adrenoreceptors
are transmembrane proteins attached to G-proteins.
G-proteins are peripheral proteins and are composed of α, β, γ subunits.
-
1
Chapter 21b (Summary)
2
Takusagawa’s note
8.
Example-1: β -Adrenoreceptors
Signal transduction flow is as follows:
1
Epinephrine binds to a specific receptor.
2
The occupied receptor causes replacement of the GDP bound to Gs by GTP, activating Gs.
3
Gsα (α subunit) separates from Gβγ subunits, and moves to adenylate cyclase (AC) and activates
it.
4
Activated AC catalyzes the formation of 3’,5’-cyclic AMP (cAMP) from ATP.
5
cAMP-dependent protein kinase (protein kinase A) is activated by cAMP.
6
Phosphorylation of cellular proteins by protein kinase A causes the cellular response to
epinephrine.
Inhibitions of signal transduction flow are:
1
GTP bound on activated Gsα, Gsα•GTP is hydrolyzed Gsα•GDP + Pi. (step 3)
2
cAMP is degraded to AMP by phosphodiesterase. (step 5)
3
Phosphorylated proteins are dephosphorylated by phosphoprotein phosphatase. (step 4)
4
The binding of hormone to the inhibitory receptor, Ri, triggers an almost identical chain of events
except that the presence of Giα•GTP complex inhibits AC from synthesizing cAMP.
Some inhibitors of the system are: (Note: These inhibitors increase the cAMP activity).
1
Cholera toxin inhibits the Gsα•GTP → Gsα•GDP + Pi hydrolysis.
2
Caffeine & theophylline inhibit the (cAMP → AMP) reaction catalyzed by phosphodiesterase.
3
Pertussis toxin (whooping cough) inhibits the replacement of GDP by GTP in Giα subunit.
9.
1
2
3
4
Example-2: Phosphatidylinositol system
Second messengers are: Inositol triphosphate (IP3), Ca2+ and diacylglycerol.
Signal transduction flow is as follows:
Hormone binds to a specific receptor.
The occupied receptor causes GDP-GTP exchange on Gq.
Gq, with bound GTP, moves to phospholipase C (PLC) and activate it.
Active PLC cleaves phosphatidylinositol-4,5-bisphosphate to inositol-triphosphate (IP3) and
diacylglycerol.
5
IP3 binds to a specific receptor on the endoplasmic reticulum, releasing sequestered Ca2+ to
cytosol.
6
Diacylglycerol and Ca2+ activate protein kinase C at the surface of the plasma membrane.
7
Phosphorylation of cellular proteins by protein kinase C produces the cellular response to the
hormone.
8.
1.
2.
3.
4.
5.
Example-3: Nitric oxide (NO) activation system
NO synthase that is activated by Ca2+ catalyzes NO production from the Arg breakdown reaction.
The produced NO activates guanylate cyclase.
Guanylate cyclase catalyzes the cGMP formation reaction from GTP.
cGMP activates cGMP-dependent protein kinase (protein kinase G).
Protein kinase G activates target proteins by phosphorylation, consequently, the smooth muscle
cells are relaxed.
2