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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 33

are calsequestrin (CSQ) in the sarcoplasmic reticulum of miniaturize the Ca 2 + component of their signalling sys-
muscle cells and calreticulin (CRT) in the ER of non- tems.
muscle cells. The latter is unusual in that it functions both The ability of CB to buffer internal Ca 2 + mayplayan
as a cytosolic and a luminal buffer. The role of calseques- important role in facilitating Ca 2 + reabsorption by the
trin is discussed elsewhere and here we concentrate on the kidney tubule (Module 7: Figure kidney Ca 2 + reabsorp-
function of the cytosolic buffers. The latter have subtly tion). In the case of Ca 2 + reabsorption by the intestine,
different Ca 2 + -binding properties and are expressed in the flux of Ca 2 + is facilitated by calbindin D-9k (Module
cells in differing combinations and concentrations to cre- 7: Figure intestinal Ca 2 + reabsorption).
ate Ca 2 + signals that are tailored to carry out different An important aspect of the calcium hypothesis of
functions. For example, neurons such as Purkinje cells ex- Alzheimer’s disease is that there is a decrease in the ex-
press large amounts of PV and CB. As a consequence, pression of CB, which increases the sensitivity of neurons
Purkinje cells have a large endogenous Ca 2 + buffering ca- to the enhanced Ca 2 + signals that arise during the onset of
pacity, e.g. their buffers bind approximately 2000 Ca 2 + Alzheimer’s disease (Module 12: Figure amyloid cascade
ions for each free ion. Lower capacities of 50--100:1 are hypothesis).
found in other cells. Motor neurons have a very low buf-
fering capacity and consequently have large Ca 2 + signals
Calretinin (CR)
in both the soma and dendrites during normal physiolo-
Calretinin (CR) is an EF-hand Ca 2 + -binding protein that
gical responses, and this makes them particularly suscept-
is closely related to calbindin D-28k (CB).Ithas six
ible to neurodegeneration. Buffer concentration is one of
EF-hand domains all of which can bind Ca 2 + except for
the important parameters in determining buffer capacity.
domain VI. CR is usually located in the cytoplasm, but can
The other key parameters include affinity for Ca 2 + and
also be found localized to specific sites in the cell where
other metal ions, the kinetics of Ca 2 + binding, release and
it may function as a buffer to regulate microdomains of
mobility.
Ca 2 + .ThisCa 2 + buffer is an excellent biochemical marker
Alterations in Ca 2 + buffers have been linked to
for certain GABAergic inhibitory interneurons such as the
schizophrenia.
Cajal--Retzius neurons and double bouquet neurons in the
dorsolateral prefrontal cortex (DLPFC) (Module 10: Fig-
Parvalbumin (PV) ure dorsolateral prefrontal cortex).
Parvalbumin (PV) is a slow-onset buffer. It has relatively
low on and off rates, which means that it cannot respond
to the rapid onset of most Ca 2 + signals. However, PV Calreticulin (CRT) 2 +
can soak up Ca 2 + once the signal has appeared and thus Calreticulin (CRT) is a low-affinity Ca -binding protein
that is located within the lumen of the endoplasmic retic-
influences the rate at which Ca 2 + recovers. It is strongly ulum (ER). It has also been detected in the nucleus and
expressed in skeletal muscle, where it plays an important cytoplasm and it may also be secreted into the extracellu-
role in facilitating the rate of relaxation. In PV − / − mice, lar environment during periods of cell stress. Its primary
there is a slowing in the recovery of the Ca 2 + transient. location, however, is within the lumen of the ER, where
Some of the effects of removing PV are compensated for by it functions both as a chaperone protein and as the major
an increase in the volume of mitochondria that has a similar ER Ca 2 + buffer. CRT has three main domains; there is
ability to PV of removing free Ca 2 + from the cytoplasm a globular N-domain of unknown function followed by
during the recovery phase.
a proline-rich P-domain, which has sequences unique to
Reductions in the level of PV have been recorded in
CRT and its homologous proteins calnexin and calmegin.
schizophrenia.
Finally, there is a highly acidic C-terminal domain, which
has a large number of low-affinity Ca 2 + -binding sites cap-
Calbindin D-28k (CB) able of binding 20--30 mol of Ca 2 + /mol of protein. This
Calbindin D-28k (CB) is one of the major cytosolic buf- C-terminal region terminates in the KDEL sequence re-
fers, particularly in neurons. It is a fast buffer that can sponsible for retaining CRT in the lumen of the ER.
have a major effect on both the spatial and temporal prop- The chaperone function of CRT is carried out in
erties of Ca 2 + transients. CB thus plays a major role in conjunction with a related chaperone calnexin. A cal-
restricting the size of the elementary Ca 2 + events that nexin/calreticulin cycle ensures the correct folding and
form around Ca 2 + channels. CB is thus of central im- subunit assembly of glycoproteins and is thus essential
portance for the ability of neurons to create the highly for protein trafficking and secretion. The proper folding
localized Ca 2 + events that occur in spines. The existence and assembly of proteins is very dependent on a constant
of these buffers has enabled neurons to increase the num- level of Ca 2 + within the ER lumen and the chaperones.
bers of their synaptic connections, and this neuronal mini- The ability of CRT to bind large amounts of Ca 2 + en-
aturization greatly enhances the signal processing capacity ables it to function as an ER Ca 2 + buffer to help maintain
of the brain. Some support for such a notion emerged this constancy of ER Ca 2 + . In addition to functioning
from the finding of a remarkable compensatory mechan- as a passive buffer, CRT may play a more direct role in
ism whereby the volume of the spines increases markedly maintaining homoeostatic control of their working envir-
in neurons when these buffers are knocked out. In effect, onment by modulating the activity of the Ca 2 + channels
the lack of these buffers reduces the capacity of neurons to and pumps. When the Ca 2 + level within the lumen gets too

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