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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 126

Module 2: Figure omega-3 fatty acids

Omega 3 fatty acids
COOH -Linolenic acid (ALA) Resolvin E1 7
C18:3n-3
CH 3 Resolvin E2 Antiinflammatory and
COX-2 Immunoregulatory functions
COOH Eicosopentaenoic Resolvin D1
C19:5n-3
CH 3 acid (EPA) 6 Protectin D1
COOH Docosahexaenoic
C20:6n-3
acid (DHA)
CH 3
LPS TNF
1
GLP-1
GPR120
TLR4 TNF R
PLC DD
q/11
3 2 4 IRAK-1
+ TRAF2
TRAF6
-arrestin2 IRAK-4
InsP 3 P -arrestin2
Ca 2+ _ 5 TAB1
+ TAK1
IKK
JNK p38 p50 p65
Inflammatory
responses
Omega 3 fatty acid function.
The polyunsaturated fatty acids (PUFAs) have a number of actions. They act through GPR120 receptors to stimulate InsP 3 /Ca 2 + signalling and they also
activate arrestin-2 that can inhibit the inflammatory responses initiated by toll-like receptor 4 (TLR4) or by tumour necrosis factor α receptor (TNFαR).
They can also be converted by cyclooxygenase 2 (COX2) into the resolvins and protectins, which have anti-inflammatory and immunoregulatory
actions.

A decrease in dietary omega-3 fatty acids results in a NAD and NADP as precursors of metabolic
decline in the ability of anandamide to activate long-term messengers
depression (LTD) in neurons and this might be the cause • NAD + is a precursor of cyclic ADP-ribose (cADPR)
of various neuropsychiatric diseases such as depression. signalling pathway that functions in Ca 2 + signalling.
• Metabolism of cADPR generates ADPR, which regu-
NAD signalling pathways lates transient receptor potential melastatin 2 (TRPM2),
As the name implies, the NAD signalling pathways en- a member of the transient receptor potential (TRP) ion
channel family that controls the entry of external Ca 2 +
compass signalling systems that depend on nicotinamide--
(Module 2: Figure cADPR/NAADP function).
+
adenine dinucleotide (NAD ) and nicotinamide--adenine
• NADP + is a precursor of nicotinic acid–adenine dinuc-
+
dinucleotide phosphate (NADP ). These two meta-
bolic cofactors exist in the cell as NAD /NADH and leotide phosphate (NAADP) signalling pathway that
+
NADP /NADPH redox couples and have a number of functions in Ca 2 + signalling.
+
important functions both as messengers and as precursors • NADPH is the substrate used to generate reactive oxy-
of other metabolic messengers. gen species (ROS), which function as second messen-
gers to regulate a number of cellular proteins (Module
2: Figure plasma membrane ROS formation).
NAD and NADP as metabolic messengers
• NAD + functions to regulate a number of cellular pro- Sterol sensing and cholesterol biosynthesis
cesses including energy metabolism, gene transcription, The level of cholesterol in cell membranes is regulated
DNA repair and perhaps ageing as well. by a signalling system that can sense the level of ster-
• NADH activates the C-terminal binding protein ols and then relay information to the nucleus to adjust
(CtBP), which is a transcriptional corepressor that func- the transcription of the genes responsible for cholesterol
tions during growth and development. biosynthesis. The signalling system is based on membrane-
• NADH and NADPH regulate the transcription factors bound transcription factors: the sterol regulatory element-
Clock/BMAL1 and NPAS2/BMAL1 that control gene binding proteins (SREBPs), which are integral membrane
expression during the operation of the circadian clock. proteins located in the endoplasmic reticulum (ER). They
• NADPH appears to regulate the ADP-ribosyl cy- have two membrane-spanning domains with the free ends
clase that is responsible for producing both cyclic projecting into the cytosol. The N-terminal region is
ADP-ribose (cADPR) and nicotinic acid--adenine di- the latent transcriptional regulator, which is cleaved by
nucleotide phosphate (NAADP) (Module 2: Figure a sterol-regulated system of proteases (Module 2: Fig-
cADPR/NAADP function). ure sterol sensing). Once released into the cytosol, these

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