An improved quantitative kinetic model for ATP-induced intracellular

Ca2+ oscillations
Graduate student: Stephanie Fraley (swilso56@jhu.edu )
Undergraduate student: Amy Fu (afu4@jhu.edu)

Abstract

Ca2+ is an important signaling molecule and cycles of Ca2+ oscillations are observed in the cell.
There have been many theories regarding the dominant mechanism responsible for Ca2+
oscillations. Our mathematical model is based on a paper which states that the oscillations are
mainly due to the interaction between Ca2+ release from the ER and ATP-dependent Ca2+ pumps
that pump Ca2+ back into the ER. A Ca2+ feedback loop has been added in our improved model
to demonstrate Ca2+ feedback on PLC may have a significant contribution towards Ca2+
oscillations.

1. Introduction that opens Ca2+ channels present on the

Calcium ions (Ca2+) act as important
intracellular second messengers, which take
part in many signal transduction pathways.
They relay information from receptors and
are involved in various physiological
processes like cell fertilization,
differentiation, growth and death.1
In mammals, the fertilization of an
egg with a sperm marks the beginning of life.
At fertilization, a Ca2+ oscillation is
triggered that prevents multiple fertilizations
of the egg and initiates the onset of
embryonic development by stimulating the
enzymatic machinery necessary for the cell
division cycle. Later during development,
Ca2+ oscillations are used to control cell
differentiation and develop the nervous
system. Ca2+ has also been linked to
apoptosis, through the interaction of Ca2+ on
mitochondrial proteins that ultimately leads
to programmed cell death. 2
The reason why calcium ions can be
used as messengers in signaling pathways is
because in a resting cell, the Ca2+
concentration is normally very low in the
cytosol ([Ca2+]cyt ~10-7M), while its
concentration in the endoplasmic reticulum
(ER) and in the extracellular fluid is high
([Ca2+] ~10-3M).3 When a signal is present
plasma membrane and ER membrane, Ca2+
rushes into the cytosol down its
concentration gradient, increases the local
Ca2+ concentration by up to 20-fold and
triggers downstream signaling cascades.
2. Ca2+ Oscillations
In order for calcium ions to influence
intracellular processes, cells experience
cycles of Ca2+ oscillations. Ca2+ oscillations
were first directly observed in fertilized
mouse ooyctes and hepatocytes in the
1980s 4 . Since then, this phenomenon has
been widely studied and has been found in
many different types of mammalian cells.
2.1 Calcium stores in the cell
In mammalian cells, Ca2+ comes
from external and internal sources.
Extracellular calcium ions can enter the cell
through channels that span the plasma
membrane. This external route is believed to
maintain constant Ca2+ supplies to the cell’s
intracellular stores.5 Calcium ions can also
be released from internal Ca2+ sources
through channels in the endoplasmic
reticulum (ER) or sarcoplasmic reticulum
(SR). The ER and SR, which is a specialized
form of ER, represent the main calcium

1
stores in the cell. ATP-dependent Ca2+
pumps are present on the ER membrane that
pump calcium ions back into the ER.
The concentration of cytosolic Ca2+
can be monitored using Ca2+ sensitive
fluorescent indicators, such as fura-2 which
binds to free intracellular calcium 6 . Ca2+
oscillation profiles can then be generated.
2.2 Frequency and amplitude
The frequency of Ca2+ oscillations
can influence a cell’s response.1 Frequency
modulation (FM) is used by cells to reflect
the strength of extracellular stimulus and to
vary the intensity of physiological output.
This mechanism is believed to depend on
intracellular Ca2+ sensitive proteins that
respond and alter their activity depending on
the frequency of Ca2+ oscillations.
Calmodulin-dependent protein kinases
(CaM-Kinases) are presumably the best
known examples3
The amplitude of Ca2+ oscillations
can also play a factor in influencing a cell’s
response.1 However, because of the
difficulties of detecting small Ca2+ changes
above the background level, amplitude
modulation (AM) has generally been
considered to be less reliable than frequency
modulation.
2.3 Oscillation mechanism
Ca2+ oscillations arise in response to
external stimulation by an agonist, usually a
hormone or a neurotransmitter. Oscillation
characteristics such as frequency and peak
value of cytoplasmic Ca2+ concentration
have been shown to depend on both the type
and concentration of agonists. An example
of an agonist is extracellular ATP. It acts via
membrane bound receptors, including P2X
receptor class of ligand-gated ion channels
and P2Y receptor class of G-protein coupled
receptors.5
When ATP binds to extracellular G-
protein coupled receptors, it activates a G-
2
protein called Gq. G-proteins serve as relay
molecules and are attached to the
cytoplasmic side of the plasma membrane.
They are composed of 3 protein subunits – α,
β and γ. Unstimulated G-proteins have a
GDP bound to its α subunit and the G-
protein is inactive. When ATP binds to the
receptor, it catalyzes the release of GDP on
the α subunit of Gq and allows GTP to bind
its place. This GDP-GTP exchange causes
the trimer to dissociate into two activated
components – a α subunit and βγ complex.
The α subunit is still membrane
bound and activates phospholipase C-β
(PLC). PLC acts on an inositol phospholipid
called phosphotidylinositol 4,5-bisphosphate
(PIP2), which is present in the inner half of
the plasma membrane lipid bilayer, and
cleaves it to generate two products: inositol
1,4,5-triphosphate (IP3) and diacylglycerol
(DG).
IP3 being a small, water-soluble
molecule, leaves the plasma membrane and
diffuses into the cytosol. It binds to and
opens IP3-gated Ca2+-release channels on the
ER membrane, causing an influx of Ca2+
from the ER into the cytosol down its
concentration gradient.
The other cleavage product of PIP2 –
diacylglycerol also exerts effects on Ca2+
concentrations in the cytosol. DG remains
embedded in the plasma membrane and
activates a crucial serine/threonine protein
kinase called protein kinase C (PKC). The
initial rise in Ca2+ concentration caused by
IP3 alters PKC so that it translocates from
the cytosol to the plasma membrane, where
it is activated by DG and Ca2+. Activated
PKC can then go on to phosphorylate target
proteins depending on the cell type.
The Ca2+ influx caused by IP3 can be
terminated in several ways. IP3 can be
rapidly dephosphorylated by certain
phosphatases (5’phosphatases) to form IP2.
IP3 can also be phosphorylated to IP4 by a
protein kinase (3’-kinase). 7 These two
mechanisms result in the decrease in IP3
concentration in the cytosol. Ca2+ that has
entered the cytosol is also rapidly pumped
back to the ER or to the exterior of the cell
via ATP-dependent calcium pumps. The
rapid influx and pumping out of Ca2+ in the
cytosol is what some believe to be the major
cause of Ca2+ oscillations.5
Figure 1. Diagram illustrating the opening of IP3-
gated-Ca2+-release channels through the activation
of a G-protein coupled receptor by an agonist
(Lehninger. Principles of Biochemistry 4th edition
Fig. 12-19)
It is believed that patterns of calcium
oscillations induced by agonist ATP vary
with concentration of the ATP dose.6 It has
been experimentally shown that when cells
are stimulated with low concentrations of
ATP (below 0.5µM), only a single spike in
3
[Ca2+]cyt is observed, which did not result in
oscillatory responses. At ATP
concentrations higher than 1µM, sinusoidal
oscillatory changes in [Ca2+]cyt were
observed. As the ATP concentration
increased, the number of oscillatory spikes
increased as well until concentrations of
100µM was reached. At this concentration, a
plateau-like increase was observed with
little or no oscillations.
3. Different views on oscillations
As previously mentioned, some have
stated that intracellular Ca2+ oscillations are
mainly due to the interaction between Ca2+
release from the ER via IP3-gated-Ca2+-
realease channels and ATP-dependent Ca2+
pumps that serve to pump Ca2+ back into the
ER or to the exterior of the cell. Some have
questioned this assumption, debating that if
this was the only dominant processes,
agonist stimulation would lead only to the
rising and falling of Ca2+ concentration,
without clear oscillations. 8 They proposed
that feedback loops contributed to the
existence of Ca2+ oscillations. Below we
mention two mechanisms that are believed
to have significant contributions to Ca2+
oscillations.
3.1 Ca2+ feedback processes
Some believe that the main
mechanism behind Ca2+ oscillations are
feedback processes that control the
concentration of Ca2+ in the cytosol. There
are two principle classes of feedback
mechanisms that form the basis their
argument.8 (Fig.2)
Firstly, Ca2+ exerts both positive and
negative feedback on IP3 receptors. On a fast
time scale, Ca2+ binds to the IP3 receptors
and activates them, thus forming a positive
feedback loop and increase the amount of
Ca2+ flowing into the cytosol. On a slower
time scale, Ca2+ also binds to IP3 receptors at
a different site and deactivating it, forming a
slower negative feedback loop.
Secondly, Ca2+ also exerts positive
and negative feedback on IP3 metabolism.
Ca2+ can activate PLC, leading to the
increase in formation of IP3. At the same
time, it can also activate a protein kinase (3’
kinase) that phosphorylates IP3 into IP4.
These two feedback mechanisms can
both give rise to sustained Ca2+ oscillations
and as a result, two classes of mathematical
models have been developed throughout the
years – Class I assuming IP3 receptor gating
drives Ca2+ oscillations and class II
assuming that oscillations depend on Ca2+
dependent IP3 metabolism.
3.2 Role of the mitochondria
Recently, it has been suggested that
mitochondria also plays an important role in
intracellular cellular signaling.9
Mitochondria in the cell are located
near the mouths of release channels of the
ER. It is believed that mitochondria can thus
sequester the large amount of Ca2+ released
from the ER when its IP3 gated-Ca2+ release
channels are opened. It has been observed
that in chromaffin cells, the mitochondria
can effectively take up 80% of the Ca2+
Figure2. Schematic diagram illustrating the feedback loop central to the formation of Ca2+ oscillations (Domijan M.,
Murray R., Sneyd J. Dynamical probing of the mechanisms underlying calcium oscillations. Journal of Nonlinear
Science 16 (2006) 483-506)
4
released from the ER. Ca2+ release from the
mitochondria is much slower and prolonged
and could play an important role in Ca2+
oscillations, especially in amplitude
regulation.10
There are three main mechanisms by
which Ca2+ can be transported across the
inner mitochondrial membrane. The influx is
aided by a specific uniporter called the
mitochondrial calcium uniporter, and the
efflux is driven by Na+ or H+ exchangers.11
The influx of Ca2+ through the uniporter is
dependent on the cytosol Ca2+ concentration
and the transmembrane potential, which is
maintained by the electron transport chain.
The Ca2+/2H+ exchanger and the Ca2+/2Na+
exchanger are responsible for the release of
Ca2+ from the mitochondria back into the
cytosol, which is believed to operate at a
much lower rate when compared to Ca2+
release from the ER.
The mitochondria has also been
shown to exhibit Ca2+-induced-Ca2+-
release 12 , which further reinforces that
mitochondria may play an important role in
Ca2+ oscillations. Further research is being
done to investigating the link between
energy metabolism governed by the
mitochondria and cell calcium signaling.
4. Literature Oscillation Model
Quantitative kinetic models for Ca2+
oscillations in cells are prevalent in the
literature. Each takes into account a variety
of the different parameters mentioned above
that are thought to play a role in Ca2+
oscillations. A recent paper by Wang,
Xudong, and Weidong5 is the basis for the
improved model presented in this paper. In
the Wang et.al. model, which builds on
many earlier literature models, five
differential equations are solved that relate
the five major molecules in the Ca2+
oscillation cascade stimulated by ATP: Gα-
GTP, PLC, IP3, Ca2+cyt, and Ca2+ER. Figure
3 shows the cascade simulated in the model.
Figure 3. Mechanisms Simulated by Wang et al. for
the calcium oscillation cascade following stimulation
of cellular receptors by ATP.5
The first variable in the model is the
concentration of active G-protein, [Gα-GTP].
The time dependent change of [Gα-GTP] is
given by equation 1.
d[Gα − GTP]
= k0 + k1[Gα − GTP]
dt
−k 2 R APLC[Gα − GTP] − k 3 R PKC [Gα − GTP]
The constant and autocatalytic terms
k0+k1[Gα-GTP] represent the spontaneous
formation of Gα-GTP (Kummer etal. 2000).
The constant k1 is proportional to the
concentration of stimulant (ATP). The third
term in equation 1 accounts for the
accelerated hydrolyzation of Gα-GTP by
PLC (Bourne and Stryer, 1992). The last
term accounts for the decrease in Gα-GTP
via phosphorylation by PKC (Cuthbertson
and Chay, 1991). The fractions of active
PLC and PKC are given by equations 1a and
1b.
[ APLC]
(1a)
RAPLC =
K P + [ APLC]
[ DG] [Ca 2+ ]cyt
RPKC = (1b).
K D + [ DG] K R + [Ca 2+ ]cyt
All constants used in these equations are
given in Table 1.
The concentration of active PLC,
[APLC] is the second variable in the model
and is given by differential equation 2
d[APLC]
= k4 RGαGTP RDG [ PLC ] − k5[APLC] (2).
dt
The conservation equation [PLC]+[APLC]
=CPLC,total is also used. In equation 2 the
authors cite that the activation of PLC relies
on the relative fractions of active G-proteins
and DG less an enzymatic deactivation term.
It is this equation that we have chosen to
modify based on recent experiments
verifying the positive feedback effect of
Ca2+ on the activation of PLC.11 Our
modifications will be discussed in the
following sections. The fractions of active
Gα-GTP and DG are given by equations 2a
and 2b.
[Gα − GTP]4
RGα −GTP = (2a)
KG 4 + [Gα − GTP]4
(1).
[ DG ]2
RDG = (2b).
K D 2 + [ DG ]2
5
 The second messenger IP3 is formed Free Ca2+ in the ER is the fifth model
via the hydrolyzation of PIP2 by active PLC variable and is given by differential equation
(Figure 1). IP3 concentration is the third 5.
variable in the model and is represented in
differential equation 3 d[Ca2+ ]ER
= λ (−k8 RIP 3RER + k9 Rcyt1) (5)
dt
d[IP3 ] Buffering proteins in the ER give rise to the
= k6[ APLC] − k7 [IP3 ] (3).
dt constant λ (Table 1). The variable RER is
given by
The second term in equation 3 represents the [Ca 2+ ]ER3
metabolization of IP3 into the other products RER = (5a)
K ER3 + [Ca 2+ ]ER3
mentioned previously. Additionally, the
and represents experimental evidence that
assumption that [DG]=[IP3] is used in the
shows maximal IP3 activity requires a
model.
threshold amount of [Ca2+]ER. This is
Differential equation 4 represents the
formulated by Michaelis-Menten kinetics
change in free cytosolic Ca2+ over time.
with high exponents.
d[Ca2+ ]cyt Table 1
= β {ρ (k8 RIP 3 RER − k9 Rcyt1 ) Parameters and values used in the literature model by Wang et al.
dt
−k10Rcyt 2 + k11} (4) Parameter Value (unit) Parameter Value (unit)

k0 0.1 ((nmol/Lcyt)s -1) CPLC,tot 10 (nmol/Lcy t )

2+
The cytosolic concentration of Ca is k2 4 (s -1) KD 10 (nmol/Lcy t )
4.5 (s -1)
assumed to depend mainly on the release of k3
1.2 (s -1)
KP 4 (nmol/Lcy t )
k4 KR 200 (nmol/Lcy t )
intracellular Ca2+ stores stimulated by IP3 k5 0.12 (s -1) KG 25 (nmol/Lcy t )
and the influx of extracellular Ca2+ through k6 14 (s -1) KS 25 (nmol/Lcy t )
cell membrane channels (k8RIP3RER). A k7 2 (s -1) KER 75 (nmol/Lcy t )

consistent flux of Ca2+ from the extracellular k8 10500 ((nmol/LER )s -1) KC1 1000 (nmol/Lcy t )
k9 600 ((nmol/LER )s -1) KC2 2000 (nmol/Lcy t )
fluid is also assumed to provide constant, k 10 3000 ((nmol/LER )s -1) β 0.05
slow supply of intracellular Ca2+ (k11). k 11 260 ((nmol/Lcy t )s -1) λ 0.001
ATP-dependent ion pumps that pump Ca2+ ρ 0.2

back into the ER and the extracellular space

are also accounted for (-k9Rcyt1-k10Rcyt2). The paper by Wang et al. explored many
The volume ratio between the ER and the conditions with their model. Model graphs
cytoplasm is given by ρ (0< ρ<1). Buffering of typical ATP stimulating conditions were
proteins in the cytoplasm give rise to the presented as well as a study of the effect of
constant β (Table 1). The fraction of active ATP concentration on oscillations. These
IP3 and Cyt 1, 2 are given by equations 4a two aspects will serve as points of
and 4b respectively. comparison between our improved model
and the literature model.
[ IP3]3
RIP 3 = (4a) 5. Improved Oscillation Model
K S 3 + [ IP3]3
Although kinetic models for
[Ca 2+ ]cyt
RIcyti = (i = 1,2) (4b) intracellular Ca2+ oscillations are common in
KCi + [Ca 2+ ]cyt the literature, some mechanisms suspected
of significantly participating in the signaling
cascade have yet to be modeled. This is

6
mostly due to the lack of quantitative
experimental data. One of these [Ca 2+ ]cyt 4
mechanisms is the positive feedback of Ca2+ RCa = (6a).
KCa4 + [Ca 2+ ]cyt 4
on PLC. The positive feedback of Ca2+ on
Experimental evidence indicates that PLC is
PLC has long been considered a dominant
not accelerated by Ca2+ levels at or below
feedback mechanism in certain cell types.13
resting conditions.14 This suggests that a
Recently, Horowitz et al. showed that
threshold amount of Ca2+cyt is required for
“calcium release induced by PLC activation
positive feedback. For this reason, equation
feeds back immediately on PLC,
6a is formulated using Michaelis-Menten
accelerating it during muscarinic stimulation
kinetics with high exponents. This method
in strong positive feedback”.14 When
is similar to that used by Wang et al. in
intracellular calcium levels were buffered to
deriving equation 5a.
mimic stable resting conditions and stimulus
A preliminary study was conducted
was applied, Ca2+ levels in the cytosol
to determine the most likely KCa and
remained at baseline leves, but PLC levels
exponent, n, values for equation 6a. Figures
oscillated reaching much lower peaks than
A-2 and A-3 in the appendix show possible
those of control cells. Figure A-1 in the
values of these parameters for common Ca2+
appendix shows these results graphically.
concentrations and the resulting trends of
These experiments showed that PLC can be
RCa. A fitting RCa trend was chosen based
activated at resting Ca2+ levels, but that
on the fact that no positive feedback (RCa ~
considerable acceleration of PLC activation
0) is experimentally shown for low
occurs when IP3 is allowed to raise Ca2+
[Ca2+]cyt.14 Accordingly, n must equal 3 or 4
levels above the baseline(150-200nM).14
(refer to Figures A-2 and A-3). Also, for the
In the Wang et al. model, active PLC
Wang et al. model, [PLC]max = 10nM and
concentration is given by equation 2. Here,
[Ca2+]cyt,high = 700nM. Hence, only a very
positive feedback of Ca2+ on PLC is not
small fraction of the total [Ca2+]cyt may act
considered. Our improved model includes a
on PLC at these maximum levels (RCa =
term for feedback of this type. Since
10/700=0.014). A KCa value of 2000nM and
quantitative data for comparison is lacking,
an n value of 4 give a curve that follows
our model and simulations are regarded as
these requirements.
exploratory exercises in identifying possible
relationships among Ca2+ and the cascade
5.1 Results of Model Improvement and
molecule PLC. The improved equation for
Discussion
PLC activation is given by
A replicated simulation of the Wang
et al. model is shown in Figure 4. The initial
d[APLC]
= k4 ( RGαGTP + RCa ) RDG [ PLC ] conditions for this model are: k1 = 3.4s-1
dt
([ATP] = 2.4µM), [Gα-GTP] = 1nM, [PLC]
−k5[APLC] (6)
= 9nM, [IP3] = 1nM, [Ca2+]cyt = 200nM,
[Ca2+]ER = 1000nM.
where the new variable RCa represents the
PLC activating fraction of Ca2+ given by

7

Figure 4. Model of Ca2+ oscillations in an ATP-
stimulated cell.5
For this model, the average oscillation value
is about 640nM, with the highest peak
reaching about 700nM. The oscillations
begin to decay at 290s and reach resting
levels of [Ca2+]cyt by 570s.
When the new parameters for
positive feedback of Ca2+ on PLC are added
to the simulation (initial conditions held
constant) the results change dramatically
(Figure5).
Figure 5. Improved model of Ca2+ oscillations in
ATP stimulated cells.
Here, a short burst/overshoot is observed in
the first seconds of oscillation where
[Ca2+]cyt levels exceed 720nM. Oscillation
8
values then average about 590nM
(compared to 640nM) with a maximum
value of 650nM (compared to 700nM). The
oscillations begin to decay at 317s
(compared to 290s) and reach resting levels
by 600s (compared to 570s). With positive
feedback, oscillations are nearly 8% less in
magnitude and last 27s longer in their
oscillatory state.
A second comparison study was
completed for a different set of initial
conditions where ATP stimulant
concentration was increased: k1 = 3.79s-1
([ATP] = 100µM), [Gα-GTP] = 1nM, [PLC]
= 9nM, [IP3] = 1nM, [Ca2+]cyt = 150nM,
[Ca2+]ER = 1000nM. The resulting graph for
the Wang et al. model is shown in Figure 6.
Figure 6. Model of Ca2+ oscillations in cells with
increased stimulus by ATP.5
Increased ATP stimulus causes higher
frequency oscillations, a shorter oscillation
time overall, and a higher average
oscillation value compared to the previous
results (Figure 4). However, the rounded
shape of the graph is slightly inconsistent
with experimental data that show a gradually
sloping decline from the first oscillation
onward. The experimental data used for
comparison to this case is shown in Figure
7.15

Figure 7. Experimental intracellular Ca2+ oscillations
with various ATP stimulant concentrations. Ratio
(F340/F360) = [Ca2+]cyt, relative.15
The improved model results are shown in
Figure 8. The improved model captures the
gradually declining [Ca2+]cyt seen in Figure
7D slightly better than the original model.
was successfully improved upon by the
addition of a term representing the positive
feedback of [Ca2+]cyt on PLC. Effectively,
the addition of positive feedback on PLC
enabled the model to give evidence of
bursting phenomena, regulation of
amplitude and average oscillation value, and
overall length of oscillation time—all of
which are observed in many instances in the
literature.9,10
More quantitative kinetic studies of
the role of PLC in this signaling pathway
will allow for even better fit of the model to
experimental data. Specifically, experiment
data showing [Ca2+]cyt oscillations at various
buffered levels between a buffered resting-
state cell to a non-buffered control cell
would be enlightening. There are also many
other members of the signaling pathway
whose roles are not yet quantitatively
understood, such as the mitochondria, but
that may play significant roles in Ca2+
oscillation phenomenon.

Figure 8. Improved model of Ca2+ oscillations in

cells with increased stimulus by ATP.

Also, the amplitude of the oscillations is

smaller for higher [ATP] in both the
experimental data and the improved model.

4.2 Conclusions and Recommendations

The Wang et al. kinetic model of
2+
Ca oscillations induced by ATP stimulus

9
Appendix
14
Figure A-1

Figure A-2
Determination of Ksteph and exponenet n: Ksteph=2000

0.3

0.25

0.2
n=1
n=2
RCa

0.15
n=3
n=4
0.1

0.05

0
200 300 400 500 600 700

[Ca2+]cyt (nmol/Lcyt)

Figure A-3
Determination of Ksteph and exponent n: Ksteph=3000

0.3

0.25

0.2
n=1
n=2
RCa

0.15
n=3
n=4
0.1

0.05

0
200 300 400 500 600 700

2+
[Ca ]cyt (nmol/Lcyt)

10
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