In the furnaces of the stars the elements evolved from
hydrogen. When oxygen and neon captured successive α
particles, the element calcium was born. Roughly 10 billion
years later, cell membranes began to parse the world by
charge, temporarily and locally defying relentless entropy.
To adapt to changing environments, cells must signal, and
signaling requires messengers whose concentration varies
with time. Filling this role, calcium ions (Ca2+) and
phosphate ions have come to rule cell signaling.( Clapham
Calcium ions are important signaling molecules, as once
they enter the cytoplasm they exert allosteric regulatory
effects on many enzymes and proteins. Calcium can act in
signal transduction resulting from activation of ion channels
or as a second messenger caused by indirect signal
transduction pathways such as G protein-coupled
Calcium signaling through ion channels
Movement of calcium ions from the extracellular
compartment to the intracellular compartment
alters membrane potential. This is seen in the
heart, during the plateau phase of ventricular
contraction. In this example, calcium acts to
maintain depolarization of the heart. Calcium
signaling through ion channels is also important
in neuronal synaptic transmission.
Calcium as a secondary messenger
Important physiological roles for calcium signaling range widely.
These include muscle contraction, neuronal transmission as in an
excitatory synapse, cellular motility (including the movement of
flagella and cilia), fertilization, cell growth or proliferation, learning
and memory as with synaptic plasticity, and secretion of saliva.1
Other biochemical roles of calcium include regulating enzyme
activity, permeability of ion channels, activity of ion pumps, and
components of the cytoskeleton.2 The resting concentration of Ca2+
in the cytoplasm is normally maintained in the range of 10–100 nM.
To maintain this low concentration, Ca2+ is actively pumped from the
cytosol to the extracellular space and into the endoplasmic reticulum
(ER), and sometimes in the mitochondria. Certain proteins of the
cytoplasm and organelles act as buffers by binding Ca2+. Signaling
occurs when the cell is stimulated to release calcium ions (Ca2+) from
intracellular stores, and/or when calcium enters the cell through
plasma membrane ion channels.3
Specific signals can trigger a sudden increase in the
cytoplasmic Ca2+ level up to 500–1,000 nM by opening
channels in the endoplasmic reticulum or the plasma
membrane. The most common signaling pathway that
increases cytoplasmic calcium concentration is the
phospholipase C pathway. Many cell surface
receptors, including G protein-coupled receptors and
receptor tyrosine kinases activate the phospholipase C
(PLC) enzyme. PLC hydrolyses the membrane
phospholipid PIP2 to form IP3 and diacylglycerol
(DAG), two classical second messengers. DAG activates
the protein kinase C enzyme, while IP3 diffuses to the
endoplasmic reticulum, binds to its receptor (IP3
receptor), which is a Ca2+ channel, and thus releases
Ca2+ from the endoplasmic reticulum.
Depletion of calcium from the endoplasmic reticulum will
lead to Ca2+ entry from outside the cell by activation of
"Store-Operated Channels" (SOCs). This inflowing
calcium current that results after stored calcium reserves
have been released is referred to as Ca2+-releaseactivated Ca2+ current (ICRAC). The mechanisms
through which ICRAC occurs are currently still under
investigation, although two candidate molecules, Orai1
and stroma interaction molecule 1 (STIM1), have been
linked by several studies, and a model of store-operated
calcium influx, involving these molecules, has been
proposed. Recent studies have cited the phospholipase
A2 beta,4 nicotinic acid adenine dinucleotide phosphate
(NAADP),5 and the protein STIM 16 as possible
mediators of ICRAC.
Many of Ca2+-mediated events occur when the
released Ca2+ binds to and activates the regulatory
protein calmodulin. Calmodulin may activate
calcium-calmodulin-dependent protein kinases, or
may act directly on other effector proteins. Besides
calmodulin, there are many other Ca2+-binding
proteins that mediate the biological effects of Ca2+.
In neurons, concomitant increases in cytosolic and
mitochondrial calcium are important for the
synchronization of neuronal electrical activity with
mitochondrial energy metabolism. Mitochondrial
matrix calcium levels can reach the tens of
micromolar levels, which is necessary for the
activation of isocitrate dehydrogenase, one of the
key regulatory enzymes of the Kreb's cycle.7 8
Calcium ions play an important role in cell signaling, especially
with regards to the ER. In the neuron, the ER may serve in a
network integrating numerous extracellular and intracellular
signals in a binary membrane system with the plasma
membrane. Such an association with the plasma membrane
creates the relatively new perception of the ER and theme of
“a neuron within a neuron.” The ER’s structural
characteristics, ability to act as a Ca2+ sink, and specific CCa2+
releasing proteins, serve to create a system that may produce
regenerative waves of Ca2+ release that may communicate
both locally and globally in the cell. These Ca2+
signals, integrating extracellular and intracellular fluxes, have
been implicated to play roles in synaptic plasticity and
memory, neurotransmitter release, neuronal excitability and
long term changes at the gene transcription level. ER stress is
also related to Ca2+ signaling and along with the unfolded
protein response, can cause ER associated degradation
(ERAD) and autophagy.9
Calcium Signaling Tool Kit:
The calcium signaling network can be divided in to
four functional units as shown in figure 3.
1: Signaling is triggered by a stimulus that generates
various Ca2+ mobilizing.
2: This activates the ON mechanisms that feed Ca2+
into the cytoplasm.
3: Ca2+ functions as a messenger to stimulate
numerous Ca2+ sensitive processes.
4: The OFF mechanisms are composed of pumps and
exchangers which remove Ca2+ ions from the
cytoplasm to restore the resting state as shown in
figure 4.( Berridge 2000)11
Recent Roles of Calcium
The metastasis of cancer is the main cause of mortality in
cancer patients.In metastasis tumour enters the circulation and
establishes cancer cell growth in different organs. The second
messenger Ca2+ ion is a crucial regulation of cell migration.
recently a number of molecular players in cellular calcium
homeostasis which include Ca2+ release activated calcium
channel protein 1,stroma interactions molecule 1 and transient
receptor potential channel have been Implicated in tumour cell
migration and the metastatic cell phenotype. (Prevarskaya N et
Cerella C et al (2010)13 described the dual role of calcium as
messenger and stressor in cell damage, death and survival. It
was described that Ca2+ ion is an important second messenger
participating in many cellular activities. The physicochemical
insult to the cell deregulates the delicate homeostasis of
calcium. This acts as intracellular stressor and producing
increased cell damage. This damage can result in cell death or
in case of survival the cellular repair can occur. The responses
are mediated through Ca2+ as second messenger.
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