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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 30

Module 2: Table continued
Component Comments
Ca 2 + PUMPS AND EXCHANGERS
Na /Ca 2 + exchanger (NCX) See Module 5: Table Ca 2 + pumping toolkit for further details
+
NCX1
NCX2
NCX3
Na /Ca 2 + /-K + exchanger (NCKX)
+
NCKX1
NCKX2
NCKX3
NCKX4
Mitochondrial channels and exchangers Module 5: Figure mitochondrial Ca 2 + signalling
Permeability transition pore (PMT)
Na /Ca 2 + exchanger
+
MCU Mitochondrial Ca 2 + uniporter
Plasma membrane Ca 2 + -ATPases (PMCAs) See Module 5: Table Ca 2 + pumping toolkit for further details
PMCA1
PMCA2
PMCA3
PMCA4
Sarco/endo-plasmic reticulum Ca 2 + -ATPases (SERCAs) See Module 5: Table Ca 2 + pumping toolkit for further details
SERCA1
SERCA2
SERCA3
Secretory-pathway Ca 2 + -ATPase (SPCA) pumps
SPCA1 Ubiquitous; located in the Golgi
SPCA2
The Ca 2 + signalling system has a very large toolkit of signalling components. The ways in which the major components are organized
are summarized in Module 2: Figure Ca 2 + signalling toolkit. Components from this toolkit can be mixed and matched to create a diverse
array of cell-specific Ca 2 + signalsomes (Module 2: Figure cell-specific Ca 2 + signalsomes) that are capable of delivering Ca 2 + signals
with very different spatial and temporal properties.

Ca 2 + ON reactions usually occurs for a relatively brief and the resting level (Module 5: Figure Ca 2 + uptake and
period during which there is a rapid increase in the in- extrusion).
tracellular concentration of Ca 2 + . In fact, the increase in Some of these OFF reactions interact with each other
free Ca 2 + that can be measured in the cytoplasm using during the recovery period, and this is particularly evident
aequorin or fluorescent indicators is a very small propor- in the case of the ER/mitochondrial Ca 2 + shuttle (Module
tion of the total amount of Ca 2 + that enters during the 5: Figure ER/mitochondrial shuttle). When Ca 2 + is re-
ON reactions. Much of this Ca 2 + is rapidly bound by the leased from the ER, Ca 2 + is rapidly taken up by the mi-
cytosolic buffers or is taken up by the mitochondria. As tochondria and this is then released slowly back to the ER
the Ca 2 + concentration returns to its resting level, Ca 2 + once Ca 2 + has returned to the resting level.
leaves the buffers and the mitochondria and is returned to In addition to its role of returning the level of Ca 2 +
the ER or is pumped out of the cell resulting in a brief to its resting level following a stimulus, the Ca 2 + OFF
Ca 2 + transient. reactions are in constant operation to maintain the rest-
The recovery process thus depends upon a complex in- ing level of Ca 2 + within a fairly narrow range. This cal-
terplay between cytosolic Ca 2 + buffers, mitochondria and ciostat is a dynamic system in that the OFF reactions
Ca 2 + pumps and exchangers on the internal stores and on are operating continuously to reverse the constant basal
the plasma membrane (Module 2: Figure Ca 2 + signalling rate of Ca 2 + entry through various ‘Ca 2 + leak pathways’
dynamics). These Ca 2 + OFF reactions operate at different that remain poorly defined. There is increasing evidence
stages during the recovery phase of a typical Ca 2 + spike. that presenilins may function as such a leak channel and
The buffers and mitochondria operate early, and the Ca 2 + this has been incorporated into the calcium hypothesis of
pumps and exchangers are responsible for restoring the Alzheimer’s disease (see step 10 in Module 12: Figure amyl-
status quo by pumping Ca 2 + out of the cell or back into oid processing and Ca 2 + signalling). The latter can result
the ER. These pumps and exchangers operate at different in an elevation of cytosolic Ca 2 + if the OFF reactions
times during the recovery process. The Na /Ca 2 + ex- are inhibited. For example, agents such as thapsigargin,
+
changers have low affinities for Ca 2 + , but have very high which inhibit the SERCA pumps on the ER, will result
capacities and this enables them to function at the begin- in an increase in Ca 2 + concentration. Indeed, the rate at
ning of the recovery process to rapidly remove large quant- which the Ca 2 + concentration rises following pump in-
ities of Ca 2 + . On the other hand, the plasma membrane hibition provides a measure of the activity of these leak
Ca 2 + -ATPase (PMCA) and sarco/endo-plasmic reticulum pathways.
Ca 2 + -ATPase (SERCA) pumps have lower capacities, but In pathological situations, the lack of oxygen reduces
their higher affinities mean that they can complete the re- the supply of energy, thus compromising the function of
covery process and can continue to pump at lower Ca 2 + the OFF reactions, resulting in the rise of Ca 2 + that is
levels, thus enabling them to maintain the internal stores so damaging during stroke or cardiac ischaemia. Under

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