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Cubic Spline Approach to Study Calcium
Diffusion in Neuron Cell for Rapid
Buffering Approximation

Neeta Bhargava and K.R.Pardasani

AbstractCalcium is one of the most important intracellular second messengers and has a wide range of actions. Calcium
concentration is coupled to electrical activity of neurons through calcium permeable channels. In response to depolarization,
calcium channels open, and calcium flows in. The influx depends on the difference between the membrane potential and the
reversal potential and the number of open calcium channels. A numerical model has been developed incorporating the diffusion
and reaction of calcium in a neuron cell for rapid buffer. The model has been developed for a one dimensional steady state
case. The boundary conditions have been modeled using biophysical condition. Cubic Spline Interpolation has been employed
to obtain the solution and perform simulation. The relationships among various parameters have been studied.
Keywords-- Calcium Diffusion ,Cubic Spline, Rapid Buffers.

1 INTRODUCTION

Calcium is one of the most important second messenger
molecules, with a diverse array of effectors [3].Calcium
directly moderates electrical activity, on a relatively fast
time scale, through its control of calcium dependent
potassium channels. Long term effects are mediated by
various kinases and phosphatases. Calcium is one of
the activators of protein kinase C, which plays a role in
synaptic plasticity. In a complex with calmodulin,
calcium is an activator or regulator of several enzymes,
including calcium-calmodulin dependent protein ki-
nase, which plays a role in synaptic plasticity, and
adenylate cyclase, which produces cAMP, another
important second messenger [2,7]. Neurons have nu-
merous sources and sinks of calcium in order to tightly
control this very active molecule. Sources include
voltage dependent calcium channels (which allows
electrical activity to moderate calcium concentration)
and intracellular stores; sinks include buffers and
membrane pumps [3,5,7]. Neuromodulators act
through intracellular second messenger pathways to
influence the electrical properties of neurons. Neuro-
modulators may modify gene expression, produce
plasticity of various synaptic channels, or modify prop-
erties of voltage dependent channels, depending on
both the specific neuromodulator and the target neuron
[3,5,8,9]. Channel modulation shapes electrophysiologi-
cal integration of neuronal inputs, spatio-temporal
firing dynamics of neuronal networks, and, ultimately,
systems behavior. For example, dopamine modulates
several voltage dependent and synaptic channels of
striatal spiny projection neurons; the lack of dopamine
alters the firing dynamics of these neurons and the
striatum as a whole. In contrast to traditional synaptic
transmission, the time course of neuromodulation is
slow and prolonged. Also, due to activation of diffusi-
ble second messengers, the action of neuromodulators
may be relatively widespread and distant from the
synapse. Neuromodulator interactions may be syner-
gistic or antagonistic depending on the time course of
Neeta Bhargava is with the Maulana Azad National Institute ofTechnology, Bhopal, MP
462051 INDIA (phone: 91-9926436562; fax: 91-755-2670562)
K. R. Pardasani, is with the Maulana Azad National Institute of
Technology, Bhopal, MP 462051 INDIA (phone: 91-9425358308; fax: 91-755-2670562)



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the activated second messenger reactions. Consequent-
ly, the complexity of second messenger pathways
constitute a formidable obstacle to the complete under-
standing of neuromodulatory effects. Calcium is the
second messenger molecule with the most effectors,
and thus is highly regulated by buffers, pumps and
intracellular stores. Computational modeling provides
an innovative, yet practical method to evaluate the
spatial extent, time course and interaction among
second messenger pathways, and the interaction of
second messengers with neuron electrical properties.
These processes occur both in compartments where the
number of molecules are large enough to describe
reactions deterministically, and in compartments where
the number of molecules is small enough that reactions
occur stochastically.
G. D. Smith[9] obtained an analytical steady state solu-
tion to rapid buffering approximation near a point
source of calcium ions. Wanger and Keizer [4] have
studied the effect of rapid buffers on calcium diffusion
and oscillation in neuron cells using analytical method.
Naraghi and Neher[12] investigated linearised buffeed
calcium diffusion in microdomains and its implication
for calculation of calcium at the mouth of a calcium
channel. Brridge M.J.[10] discussed in detail about
elementary and global aspect of calcium signaling.
Gregory D. Smith, Joel E. Keizer, Michael D. Stern, W.
Jonathan Lederer, and Heping Cheng[15], constructed A
Simple Numerical Model of Calcium Spark Formation and
Detection in Cardiac Myocytes and studied about the
effect of overlapping calcium microdomains on neuro-
transmitter release and they also gave a brief introduc-
tion about the electric activity in neuron cells. Carl
White and J Graham [21] constructed a model for inosi-
tol 1,4,5 triphosphate receptors modulate calcium
sparks and calcium store content. Hinch R .[21] devel-
oped a mathematical model for the generation and
termination of calcium sparks. Yun-gui Tang, Thomas
Schlumpberger, Tae-sung Kim, Martin Lueker, and Robert S.
Zucker [17] explained the effects of mobile buffers on
facilitation by experimental and computational studies.
All the above studies have been conducted either using
analytical methods or using finite difference method.
But no attempt is reported in the literature for model-
ing of calcium diffusion in neuron cells using Cubic
Spline approach.In this paper an attempt has been
made to develop a cubic spline approach to study the
calcium diffusion in neuron cells involving rapid buf-
fers for a one dimensional steady state case.
3.Mathematical Model:
Calcium kinetics in neurons is governed by a set of
reaction-diffusion equations which can be framed
assuming the following bimolecular reaction be-
tween Ca
2+
and buffer Species. The buffered diffu-
sion of calcium near isolated point sources can be
described mathematically by a system of reaction
diffusion equation with spherical symmetry.
It is standard to assume homogeneity, isotropy and
Fickian diffusion as well as bimolecular association
reaction between calcium and buffer of the
form.[8,9,13]


j
j
j
j
CaB
k
k
B Ca

+
+
+
2
(1)
Where Bj and CaBj are free and bound buffer and j
is an index over the buffer species. Based on these
assumptions the concentration of free, Ca
2+
free
buffer ([Bj ]) and bound buffer ([CaBj]) is written in
the following form.[8]
[Ca
2+
] / t = D
Ca
V [Ca
2+
] + Rj (2)
[B
j
] / t = D
Bj
V [B
j
] + R
j
(3)
[CaB
j
] / t = D
CaBj
V [CaB
j
] R
j
(4)
Where reaction term R
j
is given by
R
j
= - k
j
+
[ Ca
2+
] [B
j
] + k
j
-
[CaB
j
] (5)
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In this equation
j Ca
B D
,
and
CaBj
D
are
diffusion coefficients for free , free buffer and
bound buffer, respectively j j k k
+
, are the
association and dissociation constant for buffer
j, respectively. Buffers that do not diffuse are re-
ferred to as stationary, immobile or fixed and
are accounted for by setting DBj = DCaBj=0.
We know that the association and dissociation
rate constant for the bimolecular association
reaction between
+ 2
Ca and buffer j can be
combined to obtain dissociation constant
j
K

j
j
j
k
k
K
+

=
+ 2
Ca has a molecular weight that is small in
comparison to most
+ 2
Ca binding species.
If we further assumed that the diffusion constant
of each mobile buffer is not affected by the bind-
ing of
+ 2
Ca and also assume that
T j
B ] [ is initial-
ly uniform then
T j
B ] [ will remain uniform for all
time. Thus we can omit (3) and rewrite (2) and (4)
as
]) [ ] ([ ] ][ [
2
j T j j j j j
B B k Ca B k R + =
+
(6)
For fixed buffers 0 = =
CaBj Bj
D D
If all the buffers are fixed then the steady state
+ 2
Ca distribution is the unbuffered steady state
solution. For mobile buffers on the other hand the
reaction term is not zero at general. At steady
state case; net production of buffer at a point in
space can be balanced by diffusion of free buffer
away from that point if there is standing gra-
dient.[8,9,16]
For boundary condition we assume a point
source
+ 2
Ca at the origin and a fixed background
+ 2
Ca concentration. There is no source for buffer
and the buffers are assumed to be equilibrium
with
+ 2
Ca for from the source. A reasonable ini-
tial condition for their simulation is a uniform
background o t =
c
c
+
)
] [
4 (
2
2
t
Ca
r D
c
profile
of [
+ 2
Ca ]=.01 u m. We further assume that all
buffers are initially in equilibrium with
+ 2
Ca and
boundary conditions are given by[]
r
lim [
+ 2
Ca ]=[
+ 2
Ca ]

(7)

And
r
lim

= ] [ ] [
j j
B B

=

+
+ ] [
] [
2
Ca K
B K
j
T j
(8)
Near the source we enforce the boun-
dary condition.
Limr o t =
c
c
+
)
] [
4 (
2
2
t
Ca
r D
c
(9)
0 )
] [
4 (
2
=
c
c
t
B
r D
j
c
t (10)

Implying an influx of free
+ 2
Ca at the rate , o by
Faradays Law
zF
iCa
= o .
For notational simplicity we write
c
D and
b
D for
the diffusion coefficient of free
+ 2
Ca and free
buffer, respectively and
2
V as an abbreviation
for equations for the buffered diffusion of
+ 2
Ca .

r r r c
c
+
c
c
= V
2
2
2
2

3.1 RAPID BUFFERING APPROXIMATION
For rapid buffering approximation we take total concentra-
tion of Ca
2+
is a simple function of [Ca
2+
].Thus we
have[8,9].
[Ca
2+
]
T
= [Ca
2+
] + [CaB]
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= [Ca
2+
] +
2
2
[ ][ ]
[ ]
T
Ca B
K Ca
+
+
+

Where [CaB ]=
2
2
[ ][ ]
[ ]
T
B
Ca
K Ca
+
+
+

And [B] =
2
[ ]
[ ]
T
K B
K Ca
+
+

The rate of change in bound calcium with respect to free
calcium is given by[8].

k = { }
2
[ ]
[ ]
d
CaB
d Ca
+

Again rate of change in free calcium with respect to total
calcium[8].
| =
2
2
[ ] 1
[ ] 1
T
d Ca
d Ca k
+
+
=
+

Using above parameters we can express Calcium Diffusion
Equation in the following form


t
Ca
c
c
+
] [
2
= |[(D
C
+ D
b
k) V
2
[Ca
2+
] -
2
2
[ ]
b
D
K Ca
k
+
+
(V
[Ca
2+
])
2
] (11)

There are two conditions:
(1) When the [Ca
2+
] >> K,

(2) When the [Ca
2+
] << K,
For first case the [Ca
2+
] >> K, k approaches 0
and | approaches one,
Then the equation (11) becomes

t
Ca
c
c
+
] [
2
= D
C
V
2
[Ca
2+
] (12)
For One Dimensional steady state case in polar coordi-
nates it will take the following form
(13)
Applying Cubic Splines in (13) we get the following
form
(14)

here u(r) is the function of r ,and represents Cal-
cium Concentration.
For second condition [Ca
2+
] << K, the value of k and |
is given by [8]
k =
[ ]
T
B
K

and | =
[ ]
T
K
K B +




t
Ca
c
c
+
] [
2
= |[(D
C
+ D
b
k) V
2
[Ca
2+
] -

2
2
[ ]
b
D
K C a
k
+
+
(V[Ca
2+
])
2
](15)
becomes in
Or
t
Ca
c
c
+
] [
2
=D
eff
V
2
[Ca
2+
]B
2
1
[ ] K Ca
+
| |
|
+
\ .
(V
[Ca
2+
])
2(16)

Where
D
eff
=
[ ]
[ ]
T
c b
T
B K
D D
K B K
| |
| |
+
| |
+
\ .
\ .
and
B=
2 [ ]
[ ]
b T
T
D B
K B
| |
|
+
\ .


For a one dimensional steady state case equation (18) in
polar coordinate will take the following form(16)

D
eff
=0
(17)
Applying Cubic Splines we get the following equation

(18)
where u(r) is the function of r ,and represents Calcium
Concentration.
Now from (18) we get
(19)
These equation can be written in matrix form as given
below .
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=
=
The above system of equation is solved using MAT-
LAB to obtain nodal values which are
substituted in Cubic Spline Function to obtain solution
in the region.
RESULTS & DISCUSSION
The following numerical values for various parameters
have been used to compute the numerical results[16].
Table-1 Numerical values of various calcium buffers
RBA is appropriate when there is signifi-
cant saturability of mobile buffer and when buffer
kinetics is fast relative to Ca
2+
diffusion. This is often
the case near Ca
2+
channels in synapses. Smith et al.
[8] did an asymptotic analysis of buffered Ca
2+
dif-
fusion near a point source, and determined follow-
ing mathematical condition for the case where RBA
is appropriate.
0
lim
r
B = 0 (RBA), buffer saturates.
Here buffer and the source parameters are chosen
such that RBA is valid.

Calcium Concentration Profile With respect to
radius

0. 0 0. 1 0. 2 0. 3 0. 4 0. 5 0. 6 0. 7 0. 8 0. 9 1. 0
0.1
1
10
100
1000
10000
C
a
l
c
i
u
m

C
o
n
c
e
n
t
r
a
t
i
o
n

i
n

m
i
c
r
o

m
o
l
e
s
Radius in micro meter
0 2 4 6 8 10
0
2
4
6
8
10

Figure-1: Calcium concentration profile with respect to posi-
tion, for, Dc =250 um
2
/s, [B]T=50uM, K= 1 uM,o =1 pA, Db=75
um
2
/s

In fig-1 we observe that calcium concentration falls
very sharply for r between 0-0.3um and then falls
gradually up to r =0.7um and thereafter converges
to 0.1 uM .
Bound calcium concentration profile with respect to
position
0.0 0.2 0.4 0.6 0.8 1.0
0
25
50
75
100
125
150
[
C
a
B
]

C
o
n
c
e
n
t
r
a
t
i
o
n

i
n

m
i
c
r
o

m
o
l
e
s
Radius in micro meter
0 2 4 6 8 10
0
2
4
6
8
10
Figure-2: Bound calcium concentration profile with re-
spect to position, for, Dc =250 um
2
/s, [B]T=50uM, K= 1 uM,o
Ca
2+
buf-
fer
(Endogenous)
k
+
uM
-
1
s
-1

k
-
s
-1

K
uM
[B]T

uM
Troponin-C

9
0-100
7
-300
0.05
-3 0
50(vari
ed)
Calmodulin
D28K

1
00-500
3
7-470
0.2-
2.0
32
Triponin C

3
9
2
0
0.51 70
Parvalbumin

6 1
0.00
037
36
(Exogenous)
EGTA
1.5 0.3 0.2 113
BAPTA

600 100 0.1-0.7 95
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=1 pA, Db=75 um
2
/s
In figure-2 we observe that bound calcium concen-
tration falls sharply for r between 0-0.3um and then
it radully upto r=0.8uM and then becomes becomes
almost constant beyond r=0.8uM.

Calcium Concentration profile with respect to
source Amplitude

0.01 0.1 1
1
10
100
C
a
lc
iu
m

C
o
n
c
e
n
t
r
a
t
io
n

in

M
ic
r
o

m
o
le
s
Source Amplitude in pA
k=100
k=10
k=1
0 2 4 6 8 10
0
2
4
6
8
10

Figure-3: Calcium concentration profile with respect to Source
Amplitude, for Dc =250 um
2
/s, [B]T=50uM, r=0.03um, Db=75
um
2
/s

In figure-3 we see that when the source amplitude
(o) is greater than 10
-2
pA and for high dissociation
constant (K=100 uM, K=10 uM, K=1 uM,), the cal-
cium concentration increases slowly for source am-
plitude between 0 to .01 pA and then it increases
sharply for source amplitude has significant effect
on calcium concentration profiles.Also the calcium
concentration is higher for higher dissociation rate
k.
The results obtained are in agreement with the
biological facts as well as comparable with those
obtained by earlier research workers[8,9,16].The
cubic spline approach developed here is quite
effective and flexible in solving problems of calcium
diffusion in neuron cells.This approach can be
further developed to study the problems of calcium
diffusion in higher dimension.

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