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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 71

Module 2: Figure summary of redox signalling

REDOX
SIGNAL
SIGNALLING
PATHWAY

R Messenger
formation
_

SOD Catalase Messenger
O H O H O metabolism
2 2 2 2

Messenger
OH OH action
Oxidation
SH
S
S Recovery
SH
Reduction
Oxidation-sensitive
processes
Cellular
response

Summary of the main features of redox signalling.
The sequential processes that constitute redox signalling begin with an external signal activating a receptor (R) that then generates reactive oxygen
−• −•
species, such as superoxide radical (O 2 ), which is then converted into hydrogen peroxide (H 2 O 2 ) by superoxide dismutase (SOD). O 2 and H 2 O 2
diffuse into the cell where they exert their messenger action by stimulating the oxidation of specific proteins, sometimes forming an internal disulphide
bond. Recovery is carried out by various enzyme systems that return the target protein to its reduced state. The oxidized protein acts to stimulate a
variety of cellular processes.

−• pathways [mitogen-activated protein kinase (MAPK) cas-
Superoxide dismutase (SOD) rapidly converts the O 2
into hydrogen peroxide (H 2 O 2 ), which is one of the main cade and Ca 2 + signalling]. It is therefore not surprising to
messenger molecules used by the redox signalling pathway find a role for redox signalling in proliferation and cancer.
(Module 2: Figure summary of redox signalling). There is also a strong relationship between redox signalling
Rapid reactive oxygen species (ROS) metabolism en- and schizophrenia (Module 12: Figure schizophrenia).
sures that H 2 O 2 , like other intracellular messengers, has a
short half-life. This metabolism of H 2 O 2 is carried out by Reactive oxygen species (ROS)
a range of enzymes, including catalase, glutathione peroxi- Reactive oxygen species (ROS) is a collective term
dase (GPx) and peroxiredoxin (Prx).Since theinsideofthe that refers to those oxygen species [superoxide (O 2 −• ),
cell is a highly reducing environment, the last two enzymes hydrogen peroxide (H 2 O 2 ) and the hydroxyl radical
can draw upon a large reservoir of reducing equivalents in (OH )] that are more reactive than ground-state oxygen
•
order to metabolize the ROS. The cell has a large redox [Module 2: Figure reactive oxygen species (ROS)]. These
buffer capacity in the form of glutathione, which func- are sometimes considered synonymous with free radicals,
tions to maintain the redox balance in the cell. The fact but not all ROS are free radicals. The latter are defined
that H 2 O 2 is metabolized so rapidly means that its site of as atoms or molecules that contain one or more unpaired
action is highly localized close to its site of production. electrons. With regard to signalling, it is the O 2 −• and
The reactive oxygen species (ROS) messenger action of H 2 O 2 that appear to be the most important messengers.
H 2 O 2 depends upon its ability to react with the cysteine Also, there are indications that these two messengers may
residues of a certain group of target proteins. The latter are perform different functions.
marked out by virtue of having hyperreactive thiol groups There are two important sources of reactive oxygen spe-
that are rapidly oxidized to form a disulphide bond. The cies (ROS): one is at the plasma membrane and the other
recovery from this oxidized state back to a fully reduced is within the mitochondria (Module 2: Figure sites of ROS
thiol group is carried out by the glutaredoxin and/or the formation).
thioredoxin systems.
Finally, the oxidized target proteins activate a num- Superoxide (O 2 −• )
ber of oxidation-sensitive processes that bring about a The superoxide radical (O 2 −• ) that is formed by the one-
number of cellular responses such as gene activation, mod- electron reduction of O 2 is short-lived (half-life of 10 − 6
ulation of ion channels and the activity of other signalling s) in that it rapidly dismutates into hydrogen peroxide

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