Page 125 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 125

phosphorylating Thr-172 on the α-subunit (Module 2: linoleic acid can activate the TREK subfamily of two-pore
Figure AMPK structure). The activation of AMPK is very domain K + (K 2P ) channels.
dependent upon LKB1. Inactivation of the latter is re- The positive-feedback loop that free fatty acids (FFAs)
sponsible for Peutz-Jeghers syndrome. As such, LKB1 is exert on the process of lipogenesis (i.e. Step 7 in Module
considered to be one of the tumour suppressors. 7: Figure metabolic energy network) may exacerbate the
onset of obesity by enhancing fat storage.
The build-up of FFAs that occur during obesity play a
Adenosine triphosphate (ATP) critical role in inducing the insulin resistance (Module 12:
ATP is an important metabolic messenger in that it has Figure insulin resistance) that leads to the development of
a number of different actions both as an internal and an diabetes.
external signal (Module 2: Figure metabolic messengers).
With regard to the former, one of its main functions is
to regulate the activity of the ATP-sensitive K + (K ATP ) Omega 3 fatty acids
channel, which is particularly important in regulating the The omega-3 fatty acids such as α-linolenic acid (ALA),
release of insulin (Module 7: Figure β-cell signalling). It eicosapentaenoic acid (EPA) and docosahexaenoic acid
also plays a role in regulating the activity of the ADP- (DHA) are typical polyunsaturated fatty acids (PUFAs).
ribosyl cyclase that generates the Ca 2 + -mobilizing mes- These PUFAs are essential for normal cellular function.
sengers cyclic ADP-ribose (cADPR) and nicotinic acid-- ALA and α-linolenic acid, which are the precursors of
dinucleotide phosphate (NAADP) (Module 2: Figure arachidonic acid and DHA respectively, are not synthes-
cADPR/NAADP function). ATP is also released from ized de novo but are obtained from the diet. Arachidonic
the cell and can activate P2X receptors that activate Ca 2 + acid is the precursor of the endocannabinoids,suchas
entry or P2Y receptors that are coupled to phospholipase anandamide and 2-arachidonoylglycerol (2-AG),which
C (PLC) to generate inositol 1,4,5-trisphosphate (InsP 3 ) have important signalling functions (Module 1: Figure
and diacylglycerol (DAG) (Module 2: Figure metabolic anandamide).
messengers). The first double bond of these omega-3 fatty acids is
located at the third carbon atom from the methyl (CH 3 )
end of the molecule (see white arrow in Module 2: Fig-
−
Bicarbonate (HCO 3 )
ure omega-3 fatty acids). These omega-3 fatty acids have
The CO 2 produced during cellular metabolism is rapidly
a number of specific signalling functions as outlined in
converted into bicarbonate (HCO 3 ), which acts as a
−
Module 2: Figure omega-3 fatty acids:
messenger to report the current state of metabolism. The
− activates soluble adenylyl cyclase (Module 2: Fig-
HCO 3 1. When GPR120 was first identified, it was classed as
ure cyclic AMP signalling) to generate cyclic AMP that has
many signalling functions, including an effect on cellular an orphan receptor as there was no known ligand.
metabolism through its activation of glycogen metabolism. Subsequently, the omega-3 fatty acids were identified
as stimuli for this typical G-protein-coupled receptor
(GPCR).
Fatty acids 2. GPR120 is coupled through G q/11 and phospholipase C
Fatty acids come in two main forms: saturated and poly- to activate the Inositol 1,4,5-trisphosphate (InsP 3 )and
unsaturated. There are two main types of polyunsaturated Ca 2 + release signalling pathway.
fatty acid: omega-6 and omega-3 fatty acids. These are re- 3. One of the functions of the increase in Ca 2 + might
ferred to as essential fatty acids since they are not made be to stimulate the release of glucagon-like peptide 1
by the body but are components of the diet: omega-6 (GLP-1).
fatty acids are derived mainly from vegetable oils, whereas 4. Another function of the GPR120 receptors is to activate
the omega-3 fatty acids are found in certain plants (li- the multifunctional adaptor protein arrestin-2.
nolenic acid) or from marine fish and shellfish (eicos- 5. The anti-inflammatory responses of omega-3 fatty
apentanoic acid and docosahexanoic acid). Fatty acids not acids might be carried out by arrestin-2 inactivating the
only provide an important energy source but can also TAK1-binding protein 1 (TAB1), which can inhibit the
be considered as metabolic messengers that contribute signalling pathways used by the Toll receptor signalling
to a number of metabolic control mechanisms. For ex- pathway (Module 2: Figure Toll receptor signalling)
ample, they control gluconeogenesis in liver cells by ac- or by the tumour necrosis factor α (TNFα) signalling
tivating the peroxisome-proliferator-activated receptor α pathway (Module 2: Figure NF-κB activation).
(PPARα) (Module 7: Figure liver cell signalling). Free fatty 6. Apart from the intracellular signalling pathways de-
acids are also responsible for activating the uncoupling scribed above, the omega-3 fatty acids are metabolized
protein 1 (UCP1) that provides the proton leak dur- by cyclooxygenase 2 (COX2) to form the resolvins and
ing noradrenaline-induced heat production by brown fat the protectins, which are potent anti-inflammatory and
cell mitochondria (Module 7: Figure brown fat cell). The immunoregulatory agents.
omega-3 fatty acids have a number of specific signalling 7. The anti-inflammatory action of the omega-3 fatty
functions. acids might have beneficial effects for coronary artery
Arachidonic acid (AA) and other polyunsaturated fatty disease, cardiac disease and for the insulin resistance
acids (PUFAs) such as docosahexenoic acid, linolenic and that results in metabolic syndrome.

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