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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 34

high, CRT and calnexin inhibit the sarco/endo-plasmic re- same enzyme that possesses both synthase and hydrolase
ticulum Ca 2 + -ATPase (SERCA) pump and, when Ca 2 + is activity. The cADPR control of Ca 2 + release is somewhat
released, this inhibition is relieved and the SERCA pumps controversial, as its precise mode of action is still unclear.
can restore Ca 2 + to its normal level. In addition to its role A cADPR working hypothesis has been put forward to
as an ER buffer, CRT may play an active role in ensur- provide a framework to understand some of the current
ing that the Ca 2 + concentration within the ER lumen is information on how this messenger appears to operate. A
maintained at the optimal level for protein folding to occur. relationship between cADPR and cell regulation has been
established in a number of different cell types.
Ca 2 + signalling function
The function of Ca 2 + as an intracellular second messenger cADPR working hypothesis
is carried out by a combination of Ca 2 + sensors and Ca 2 + There is sufficient evidence to take seriously the possibility
effectors (Module 2: Figure Ca 2 + signalling toolkit). The that cADPR functions to regulate Ca 2 + signalling. What
major sensors are the EF-hand proteins troponin C (TnC), seems to be in question is exactly how it functions. This
calmodulin (CaM), neuronal Ca 2 + sensor proteins (NCS) working hypothesis has two main components:
and the S100 proteins. However, there are a number of
other sensors (Module 2: Table Ca 2 + signalling toolkit). • Firstly, the generation of cADPR is closely coupled to
These sensors are then responsible for relaying inform- cellular metabolism, as described in cADPR generation
ation through a range of effectors: and metabolism (Module 2: Figure cADPR/NAADP
function). The idea is that cADPR may function as a
• Ca 2 + -sensitive K + channels
metabolic messenger responsible for relaying informa-
• Ca 2 + -sensitive Cl − channels (CLCAs)
tion about the state of metabolism to various systems in
• Ca 2 + /calmodulin-dependent protein kinases (CaMKs)
the cell, especially those that require a heavy expenditure
• Calcineurin
of energy. An example would be Ca 2 + signalling and the
• Phosphorylase kinase downstream elements regulated by Ca 2 + . When energy
• Myosin light chain kinase (MLCK) is abundant, an increase in cADPR will set the stage for
• Ca 2 + -promoted Ras inactivator (CAPRI) (Module 2: Ca 2 + signalling to occur.
Figure Ras signalling)
• Secondly, the cADPR control of Ca 2 + release
may occur indirectly through an activation of the
Spatiotemporal aspects of Ca 2 + signalling sarco/endo-plasmic reticulum Ca 2 + -ATPase (SERCA)
The use of Ca 2 + as a universal signal for cell regulation is pump to increase the uptake of Ca 2 + into the endoplas-
somewhat paradoxical because this ion can be very toxic mic reticulum/sarcoplasmic reticulum. This increased
to cells if its level remains high for a prolonged period. loading of the internal store will serve to sensitize re-
Such toxicity is avoided by presenting Ca 2 + signals in a lease channels such as the RYRs, thus leading to an in-
pulsatile manner (Module 2: Figure temporal aspects). In crease in Ca 2 + signalling. This messenger should thus
addition to this temporal aspect, the Ca 2 + signal is also be considered as a modulator rather than a mediator of
highly organized in space. The elementary and global as- Ca 2 + signalling.
pects of Ca 2 + signalling greatly increase the versatility of
the Ca 2 + signalling system in that it can act either locally cADPR generation and metabolism
or globally. For example, muscle contraction is activated The generation and metabolism of cADPR are described
by a global elevation in Ca 2 + , whereas the release of neur-
together because both processes are carried out by the
otransmitters results from a minute punctate pulse of Ca 2 +
same enzyme: the ADP-ribosyl cyclase (Module 2: Fig-
delivered directly to the docked vesicle by a Ca 2 + sensor
ure cADPR metabolism). The hydrolysis of cADPR pro-
tightly associated with exocytotic machinery (Module 4:
duces ADPR, which has been implicated as a messenger
Figure Ca 2 + -induced membrane fusion). In between these
regulating melastatin-related transient receptor potential 2
two extremes, there are many variations in the way the
(TRPM2), which is a Ca 2 + channel in the plasma mem-
Ca 2 + signal is presented to cells. Perhaps the most dra-
brane (Module 2: Figure cADPR/NAADP function). This
matic are the Ca 2 + waves that initiate at fixed localities
is a highly versatile enzyme. In addition to synthesizing
and then process through the cytoplasm in a regenerative
and metabolizing cADPR, it is also responsible for syn-
manner through the process of CICR (Module 2: Figure
thesizing NAADP. In mammals, this bifunctional enzyme
Ca 2 + -induced Ca 2 + release).
appears to be the lymphocyte antigen CD38, which is ex-
These spatiotemporal aspects greatly enhance the ver-
pressed widely and is located both in the plasma membrane
satility of Ca 2 + signalling, thus providing the flexibility to
and at internal sites. With regard to the former location, its
regulate so many cellular processes.
enzymatic region is located on the outside. This is unusual
because its substrate and its site of action are on the inside
Cyclic ADP-ribose (cADPR) signalling of the cell. It has been suggested that the enzyme might
Cyclic ADP-ribose (cADPR) is one of the messengers as- use NAD + derived from dying cells at sites of infections
sociated with the NAD + signalling pathways.cADPR has to generate cADPR, which is then transported into the
attracted considerable attention as a putative messenger to cell.
regulate the Ca 2 + signalling pathway. cADPR generation The intracellular enzyme is more likely to be the one
and metabolism is unusual in that it is carried out by the that functions in most cells. Just how the cyclase is

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