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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 23

Diaphanous-related formin 1 (Dia1) An important feature of Ca 2 + signalling is its dynamic
There are two diaphanous-related formin proteins (Dia1 nature, as exemplified by the fact that Ca 2 + signals invari-
and Dia2) that belong to a formin-related family. They ably appear as a brief transient. The rising phase of each
contain three formin homology domains that are used transient is produced by the ON reactions, whereas the
to bind to various effectors. Dia1 is activated by the falling phase depends on the OFF reactions (Module 2:
Rho signalling mechanism and functions to control actin Figure Ca 2 + signalling dynamics). At any moment, the
polymarization by binding to profilin (Module 2: Figure level of Ca 2 + is determined by the balance between the
Rho signalling). Dia1 has also been implicated in the Ca 2 + ON reactions that increase Ca 2 + and the Ca 2 +
control of polycystin 2. OFF reactions that remove it from the cytosol. An im-
portant aspect of the ON and OFF reactions is their spa-
tial location. An example of this spatial organization is
Ca 2 + signalling the ER/mitochondrial Ca 2 + shuttle (Module 5: Figure
Ca 2 + signalling is one of the major signalling systems in ER/mitochondrial shuttle), where events at the ER are
cells (Module 2: Figure cell signalling pathways). It func-
closely linked to those in the mitochondria. Another im-
tions to regulate many different cellular processes through-
portant spatial aspect is that the ON reactions are often
out their life history. It triggers new life at the time of
closely associated with the effector systems that respond
fertilization. It controls many processes during develop-
to Ca 2 + . For example, voltage-operated channels (VOCs)
ment, and once cells have differentiated, it governs the
in presynaptic endings are associated with the synaptic
activity of most cellular processes, effectively determining
vesicles, thus producing a highly localized puff of Ca 2 + to
how we metabolize, secrete, move and think. There also is
trigger exocytosis (Module 4: Figure Ca 2 + -induced mem-
a darker side to its action, because larger than normal elev-
brane fusion). Similarly, the type 2 ryanodine receptors
ations can cause cell death, either in the controlled manner
(RYR2s) of cardiac cells are lined up close to the contract-
of programmed cell death (apoptosis) or in the more cata- ile filaments to ensure that Ca 2 + will rapidly stimulate
strophic necrotic changes that occur during processes such contraction.
as stroke or cardiac ischaemia. In cases where cells need to be stimulated over a long
The basic mechanism of Ca 2 + signalling is relatively
simple in that it depends upon an increase in the intracel- time, these transients are repeated at set intervals to set
up Ca
2 +
oscillations. These oscillations are part of the
lular concentration of this ion. The Ca 2 + concentration is spatiotemporal aspects of Ca 2 + signalling.
low when cells are at rest, but when an appropriate stimu-
lus arrives, there is a sudden elevation, which is responsible
for a change in cellular activity. However, there are mul- Ca 2 + signalling signalsome
tiple variations of this relatively simple theme. The versat- Cells have access to a large Ca 2 + signalling toolkit (Module
ility of Ca 2 + signalling is achieved by having an extensive 2: Table Ca 2 + signalling toolkit). Many of the toolkit com-
Ca 2 + toolkit from which a large number of Ca 2 + sig- ponents have similar functions (Module 2: Figure Ca 2 +
nalling signalsomes are assembled. This large toolkit con- signalling toolkit), which represents a generic Ca 2 + sig-
tains many different components that can be mixed and nalling system. In reality, however, each cell type has a
matchedtocreatemanydifferent Ca 2 + signalling mod- clearly defined subset of toolkit components that will be
ules.There are Ca 2 + entry channels, which control the referred to as a Ca 2 + signalling signalsome. These cell-
entry of Ca 2 + from the outside. There are Ca 2 + release specific signalsomes are put in place during development
channels, which control the release of Ca 2 + from internal when a process of signalsome expression enables each dif-
stores. The Ca 2 + buffers ensure that the concentration of ferentiating cell to select out those signalling components
Ca 2 + remains within its operation range and does not rise it will require to control its particular functions (Module
to levels that can induce cell death. Once Ca 2 + has car- 8: Figure signalsome expression). There are an enormous
ried out its signalling function, there are Ca 2 + pumps and number of cell-specific Ca 2 + signalsomes (Module 2: Fig-
exchangers that remove it from the cytoplasm by either ex- ure cell-specific Ca 2 + signalsomes). The important point
truding it from the cell or returning it to the internal stores. is that each signalsome generates a cell-specific Ca 2 + signal
Ca 2 + signalling functions are carried out by various Ca 2 + with characteristic spatial and temporal properties.
sensors and Ca 2 + effectors that are responsible for trans- A signalsome is defined here as the collection of sig-
lating Ca 2 + signals into a change in cellular activity. nalling components that make up each cell-specific sig-
nalling system. The Ca 2 + signalsomes of different cell
types often display recurring themes in the form of Ca 2 +
Basic mechanism of Ca 2 + signalling
signalling modules (Module 2: Figure Ca 2 + modules).
Cells at rest maintain a low intracellular concentration
of Ca 2 + (approximately 100 nM), but this increases rap-
idly into the micromolar range when cells are stimulated Ca 2 + signalling modules
(Module 2: Figure basic Ca 2 + signalling mechanism). This The Ca 2 + signalling system in specific cell types is often
increase in intracellular Ca 2 + can operate over a very wide not a single entity, but is made up of distinct modules,
time domain (e.g. microseconds to hours) to regulate many which are mixed and matched to produce the cell-specific
different cellular processes. This very wide temporal range systems found in different cell types. Some of the main
of Ca 2 + signalling is an intrinsic property of the Ca 2 + modules used by cells are summarized in Module 2: Figure
signalling modules. Ca 2 + modules:

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