Cells and Immunity
Week 8
Phil Dash
Nitric Oxide
Signal transduction pathways tightly regulated [spatially and temporally]
Signalling involves;
- Proteins [kinases, phosphatases] / lipids [phosphatidylinositol’s] / cyclic nucleotides
[cAMP, cGMP] / metals [Calcium] / gases [NO]
Nitric Oxide;
- Colorless, odorless, composed on 1 atom nitrogen and 1 atom oxygen [NO]
- Highly reactive and highly diffusible
- Role discovered in 1987 – help regulate vasodilation, first identified in mammals but
found in all vertebrates, insects [nervous system] plants [pathogen defense] bacteria
[denitrification]
o NO produced by endothelial cells in response to shear stress
o NO diffuses from endothelial cells to neighboring vascular smooth muscle
cells
o Triggers vasodilation
- Gaseous signaling molecules;
o Nitric Oxide [NO]; produced by nitric oxide synthase [NOS]
o Carbon Monoxide [CO]; produced by haem oxygenase [HO]
o Hydrogen sulfide [H2S]; produced by cystathionine γ-lyase [CSE] //
cystathionine-β synthase
o Ethylene [C2H4]; produced by amino cyclopropane carboxylic acid synthase
[ACS]
- Role of NO in mammals;
o Regulates blood vessel relaxation, neurotransmission, immunity, apoptosis,
cell migration and division, cancer, autoimmune diseases and heart diseases.
Nitric Oxide Production;
- NOS; 3 isoforms neuronal [nNOS] / inducible [iNOS] / endothelial [eNOS]
- Arginine + O2 + NADPH Citrulline + NO + NADP [catalyzed by NOS]
- eNOS and nNOS response to changes in intracellular calcium [produced in small
amounts for small periods of time]
- iNOS binds calmodulin [doesn’t respond to changes in calcium] – transcriptionally
regulated producing high concn of NO for extended periods
- Splice variants of both n/iNOS [uncertain roles]
Factor which alters NO production Mechanism of Action
Cytokines [IFNγ, TNF-α, IL-1] Increased iNOS transcription
Growth Factors [HGF/EGF] Increased calcium, activation of PI3-
kinase/AKT [eNOS phosphorylation],
increased iNOS transcription [β-catenin
transcription factor]
Shear stress Increased eNOS transcription [MAP
kinase / NFkB transcription factor]
Endogenous inhibitors [ADMA] Inhibits NOS activity
Week 8
Phil Dash
Nitric Oxide
Signal transduction pathways tightly regulated [spatially and temporally]
Signalling involves;
- Proteins [kinases, phosphatases] / lipids [phosphatidylinositol’s] / cyclic nucleotides
[cAMP, cGMP] / metals [Calcium] / gases [NO]
Nitric Oxide;
- Colorless, odorless, composed on 1 atom nitrogen and 1 atom oxygen [NO]
- Highly reactive and highly diffusible
- Role discovered in 1987 – help regulate vasodilation, first identified in mammals but
found in all vertebrates, insects [nervous system] plants [pathogen defense] bacteria
[denitrification]
o NO produced by endothelial cells in response to shear stress
o NO diffuses from endothelial cells to neighboring vascular smooth muscle
cells
o Triggers vasodilation
- Gaseous signaling molecules;
o Nitric Oxide [NO]; produced by nitric oxide synthase [NOS]
o Carbon Monoxide [CO]; produced by haem oxygenase [HO]
o Hydrogen sulfide [H2S]; produced by cystathionine γ-lyase [CSE] //
cystathionine-β synthase
o Ethylene [C2H4]; produced by amino cyclopropane carboxylic acid synthase
[ACS]
- Role of NO in mammals;
o Regulates blood vessel relaxation, neurotransmission, immunity, apoptosis,
cell migration and division, cancer, autoimmune diseases and heart diseases.
Nitric Oxide Production;
- NOS; 3 isoforms neuronal [nNOS] / inducible [iNOS] / endothelial [eNOS]
- Arginine + O2 + NADPH Citrulline + NO + NADP [catalyzed by NOS]
- eNOS and nNOS response to changes in intracellular calcium [produced in small
amounts for small periods of time]
- iNOS binds calmodulin [doesn’t respond to changes in calcium] – transcriptionally
regulated producing high concn of NO for extended periods
- Splice variants of both n/iNOS [uncertain roles]
Factor which alters NO production Mechanism of Action
Cytokines [IFNγ, TNF-α, IL-1] Increased iNOS transcription
Growth Factors [HGF/EGF] Increased calcium, activation of PI3-
kinase/AKT [eNOS phosphorylation],
increased iNOS transcription [β-catenin
transcription factor]
Shear stress Increased eNOS transcription [MAP
kinase / NFkB transcription factor]
Endogenous inhibitors [ADMA] Inhibits NOS activity
