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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 24

Module 2: Figure Ca 2 + signalling dynamics

STIMULUS
2+
[ Ca ]
PMCA

2+
2nd [Ca ]
messengers Resting
+
+
SERCA
ER

Na + Na +
Mitochondria

2+
2+
[Ca ] Ca
Activated
Buffers
ON REACTIONS Effectors OFF REACTIONS

The dynamics of Ca 2 + signalling.
The dynamics of Ca 2 + signalling are governed by an interplay between the ON and OFF reactions that control the fluxes of Ca 2 + across both the
plasma membrane and the internal organelles such as the endoplasmic reticulum (ER) and mitochondria. External stimuli activate the ON reactions,
which introduce Ca 2 + into the cytoplasm either through channels in the plasma membrane or from internal stores such as the ER. Most cells make
use of both sources, but there are examples of cells using either external or internal sources to control specific processes. Most of the Ca 2 + that enters
the cytoplasm is adsorbed on to buffers, while a much smaller proportion activates the effectors to stimulate cellular processes. The OFF reactions
remove Ca 2 + from the cytoplasm using a combination of mitochondria and different pumping mechanisms. When cells are at rest, these OFF
reactions keep the concentration low, but these are temporarily overwhelmed when external stimuli activate the ON reactions. Sequential activationof
the ON and OFF reactions gives rise to the Ca 2 + transients (Module 2: Figure Ca 2 + transient mechanisms), which are such a characteristic feature
of Ca 2 + signalling systems. PMCA, plasma membrane Ca 2 + -ATPase; SERCA, sarco/endo-plasmic reticulum Ca 2 + -ATPase.

1. Agonists such as the neurotransmitters glutamate and DAG formation), which then diffuses into the cell
and ATP act directly on receptor-operated channels to activate the InsP 3 receptor (InsP 3 R) to release Ca 2 +
(ROCs) in the plasma membrane to allow external from the ER.
Ca 2 + to enter the cell.
2. Second messengers such as diacylglycerol (DAG), cyc- Ca 2 + ON reactions
lic AMP, cyclic GMP and arachidonic acid acting from In response to external stimuli, channels in the plasma
the cytoplasmic side open second messenger-operated membrane or ER are opened, and Ca 2 + flows into the
channels (SMOCs) in the plasma membrane. cytoplasm to bring about the elevation of cytosolic Ca 2 +
3. Membrane depolarization (V) activates responsible for cell activation (Module 2: Figure Ca 2 + sig-
voltage-operated channels (VOCs) in the plasma nalling dynamics). During these ON reactions, the cell
membrane to allow a rapid influx of external Ca 2 + . employs a variety of both Ca 2 + entry channels and Ca 2 +
4. Membrane depolarization (V) activates a specific release channels to create Ca 2 + signals with markedly dif-
VOC isoform, the Ca V 1.1 L-type channel, that ac- ferent spatial and temporal properties.
tivates the ryanodine receptor 1 (RYR1) in skeletal The entry of Ca 2 + across the plasma membrane is car-
muscle through a direct conformational-coupling ried out by many different channels whose names indicate
mechanism. how they are opened:
5. Membrane depolarization (V) activates voltage- • Voltage-operated channels (VOCs)
operated channels (VOCs) in the plasma membrane • Agonist-operated channels (AOCs)
to allow a rapid influx of external Ca 2 + (see Mod- • Receptor-operated channels (ROCs)
ule 3) to provide a Ca 2 + trigger that then activates the • Second messenger-operated channels (SMOCs)
ryanodine receptor 2 (RYR2) to release Ca 2 + stored in • Store-operated channels (SOCs)
the sarcoplasmic reticulum (SR) through a process of
Release of Ca 2 + from internal stores is carried out by
Ca 2 + -induced Ca 2 + release (CICR). This mechanism
different types of channels and control mechanisms:
is found in cardiac muscle and neurons.
6. Agonists acting on cell-surface receptors generate inos- • Ryanodine receptors (RYRs)
itol 1,4,5-trisphosphate (InsP 3 )(Module 2: Figure InsP 3 • InsP 3 receptors (InsP 3 Rs)

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