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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 122

Module 2: Figure metabolic signalling

Metabolic messengers

Stimuli ROS/RNS Substrates Oxygen
1 3
+
NAD / NADH
+
NADP / NADPH
AMP/ATP
_
9 HCO 3 8
SIGNALLING PATHWAYS NAADP METABOLISM

cADPR

7
4
Energy
6
CELLULAR
2 RESPONSES 5

Function of metabolic hormones in integrating the operation of cell metabolism and cell signalling pathways.
The signalling cascade begins with the arrival of an agonist (1) that recruits specific signalling pathways to activate a cellular response (2). Metabolism
uses oxygen and substrates (3) to provide the energy (4) that not only powers the cellular responses (5), but also drives signalling pathways (6). The
signalling pathways can also regulate the supply of energy by direct effects on metabolism (7). Superimposed on these more direct interactions, there
are a variety of metabolic messengers that form a complex signalling network (8 and 9) that integrate the activity of both the signalling and metabolic
cascades.

Module 2: Figure pyruvate and Ca 2 + signalling

The effect of pyruvate on Ca 2 + signalling in cardiac myocytes.
The traces represent the Ca 2 + spikes that are generated when isolated cardiac myocytes are electrically stimulated at 0.5 Hz. Under control conditions
(0’), there are constant amplitude transients resulting from the release from the internal store. The size of this store is indicated by the amplitude of
the much larger transient when caffeine (10 mM) is added. The next series of transients were taken 1, 2 and 8 min after addition of 10 mM pyruvate,
which caused an increase in both the resting level and the transient amplitudes. This increase in the amplitude of the Ca 2 + transients may have
resulted from an increase in the content of the internal store, as indicated by the very large caffeine-induced transient apparent at the end of the 8-min
sequence. The effect of pyruvate was reversible because the signalling system was back to its control values 4 min after washing out the pyruvate
(W). A possible interpretation of this experiment is that pyruvate enhanced metabolism and the increase in ATP concentration may have enhanced the
formation of cyclic ADP-ribose (cADPR) to stimulate the pump that transfers Ca 2 + into the internal store (Module 2: Figure cADPR/NAADP function).
Reproduced from Zima, A.V., Kocksk¨ amper, J., Meijia-Alvarez, R. and Blatter, L.A. (2003) Pyruvate modulates cardiac sarcoplasmic reticulum Ca 2 +
release in rats via mitochondria-dependent and -independent mechanisms. J. Physiol. 550:765--783, with permission from Blackwell Publishing; see
Zima et al. 2003.

genes that function in the metabolism of glucose, fatty AMP-activated protein kinase (AMPK)
acids and cholesterol. The AMPK signalling pathway may AMP-activated protein kinase (AMPK) plays a critical role
also play a role in stimulating mitochondrial biosynthesis. in regulating the usage of fuels such as glucose and fatty
AMPK has also been implicated in cell growth control, acids. However, it can have additional functions such as
where it functions to regulate the protein kinase TOR that the regulation of insulin secretion by pancreatic β-cells,
controls protein synthesis. and may also play a role in controlling satiety centres in

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