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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 121

Module 2: Figure metabolic messengers

+
+
Ca 2+ K + Ca 2+
ATP
TRPM2 P2Y P2X
K
ATP
Ca 2+ + PLC Ca 2+

DAG InsP
3
ADPR ATP
Cyclic AMP
NAD signalling
NADP HCO pathway
3
ADP ribosyl H S
cyclase Metabolic
messengers
cADPR AMP
AMP
signalling
+ NADH
NAADP pathway
NAD
+
Calcium
signalling Gene
pathway transcription

Interaction between metabolic messengers and cell signalling pathways.
A number of metabolic intermediates can interact with various cell signalling pathways. ATP plays a significant role through its ability to close
ATP-sensitive K + channels as occurs in insulin-secreting β-cells (Module 7: Figure β-cell signalling). ATP that is released from the cell functions
to activate ATP-sensitive P2X channels (Module 3: Figure P2X receptor structure). ATP may also play an important role in regulating the activity of
ADP-ribosyl cyclase that produces the Ca 2 + -mobilizing messengers cyclic ADP-ribose (cADPR) and nicotinic acid--adenine dinucleotide phosphate
(NAADP) (Module 2: Figure cADPR/NAADP function). AMP is an important activator of the AMP signalling pathway (Module 2: Figure AMPK control of
metabolism). The breakdown product of cADPR is ADP-ribose (ADPR), which is an activator of the transient receptor potential melastatin 2 (TRPM2)
−
channel. Bicarbonate (HCO 3 ) is an activator of soluble adenylyl cyclase and thus contributes to the cyclic AMP signalling pathway (Module 2: Figure
cyclic AMP signalling).

certain substrates or products function as positive or neg- pathway has been described in cardiac myocytes, where the
ative regulators of the enzymes that synthesize or metabol- addition of pyruvate to increase metabolism has a marked
ize them. They are not signalling mechanisms in the strict effect on Ca 2 + signalling (Module 2: Figure pyruvate and
sense, but are based on relatively straightforward mass ac- Ca 2 + signalling).
tion reactions that ensure that metabolism proceeds in an
orderly and regulated manner. However, some of the meta-
bolic components can be considered to be metabolic mes- AMP signalling pathway
sengers because they activate or modulate clearly defined
Adenosine monophosphate (AMP)
signalling pathways. There are a number of such metabolic
messengers: Cells have an AMP signalling pathway that is activated by
an increase in the AMP/ATP ratio, which results in the
• Adenosine triphosphate (ATP) activation of an AMP-activated protein kinase (AMPK).
• Adenosine monophosphate (AMP) AMP thus functions as a second messenger, since it is re-
• Fatty acids sponsible for activating the signalling pathway. The AMPK
• Bicarbonate (HCO 3 ) that responds to AMP has been referred to as the “fuel
−
• NAD + signalling pathways gauge” in that it responds to a decrease in the level of ATP.
This signalling cascade is sensitive to many stimuli, such as
The AMP signalling pathway is of major importance cell stress, oxidative damage, hypoxia and glucose depriva-
with regard to metabolic signalling systems. Components tion. Once activated, AMPK induces an up-regulation
of various redox signalling systems, such as the nitric ox- of ATP-generating systems (fatty acid oxidation, glyco-
ide signalling pathway, are also related to such metabolic lysis and mitochondrial biogenesis) while simultaneously
signalling pathways. down-regulating processes that consume energy (fatty acid
Signalling through metabolites is a highly integrated sys- synthesis and gluconeogenesis). One of its important ac-
tem because some of the signalling pathways activated by tions is to reduce protein synthesis when energy levels are
the metabolic messengers can feed back to regulate meta- low by regulating the activity of the target of rapamycin
bolism (Module 2: Figure metabolic signalling). An ex- (TOR) (Module 9: Figure target of rapamycin signalling).
ample of how a change in metabolism can affect a signalling Another of its actions is to regulate the transcription of

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