International Journal of Modern Mathematical Sciences, 2014, 9(3): 173-197

International Journal of Modern Mathematical Sciences ISSN:2166-286X

Journal homepage:www.ModernScientificPress.com/Journals/ijmms.aspx Florida, USA
Article

Approximate Analytical Solution of Chemo Attractant Gradient

Sensing Based on Receptor-regulated Membrane Phospholipid
Signaling Dynamics

K. M. Dharmalingam*, S. Kalaiselvi and V. Ananthaswamy

Department of Mathematics, The Madura College, Madurai-625011, Tamil Nadu, India

* Author to whom correspondence should be addressed: Email: kmdharma6902@yahoo.in

Article history: Received 5 January 2014, Accepted 3 March 2014, Published 10 March 2014.

Abstract: In this paper the analytical solution of steady state non-linear boundary value
problem in phosphoinositide dynamics is discussed. The analytical expression of the
receptor desensitization and the reaction-diffusion process of the phosphoinositide can be
obtained using Homotopy perturbation method (HPM) for various values of the relevant
parameters. In this study, the analytical results have been compared with perturbation
method and which showed that, the present approach has less computational aspect and are
applicable for solving other non-linear boundary value problem.

Keywords: Cell migration; Chemotaxix; Phosophoinositides; Non-linear reaction-diffusion

equations; Homotopy perturbation method; Numerical simulation.

Mathematics Subject Classification (2000): Mathematical modeling and non-linear

differential equation.

1. Introduction

Cellular migration is a coordinated process that resultsfrom the interaction of specific cell
surface receptorswith ligands of the extracellular matrix ~ECM. Usingwell-controlled, stable, ligand
substrates, a number ofligand properties have been shown to affect activation ofcellmotility, including,
for example, ligand surface concentration, strength of ligand–receptor adhesion, degreeof receptor

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 174

occupancy by the ligand, and ligand affinity[1].The general consensus that, the synthesis of PtdIns is
constitutive and which is the centre of major regulatory mechanisms on the subsequent generationof
the polyphosphoinositides[2]. Actin reorganization is a bidirectional process that orchestratescomplex
cellular events such as, cell migration, neurite extension and bud growth in yeast.The WASP family of
scaffoldingproteins, WASP, N-WASP and WAVE, participate in theseprocesses by relaying signals
from Rho-family GTPases to the actin remodeling machinery [3].Precise regulation of protein-protein
interaction is criticalfor determining the wiring of cellular signaling pathways [4].
Receptors are responsible for transmitting information about theexternal environment to the
cell internum, and therefore theirmechanism of activation and action must be well characterizedbefore
the details of the intracellular networks can be analyzedand modeled mathematically (signaling
network).Two-dimensional molecular gradients in cell membranesare also relevant in signal
transduction. Most signalingpathways involve specific membrane-associated intermediatesthat are
produced or activated through recruitment ofsignaling enzymes to the plasma membrane. Gradients in
thedensity of specific membrane lipids or activated lipidanchoredproteins may form on the nanometer
scale if therates of the reactions that produce them are rapid enough tobe limited by lateral diffusion
and gradients on longer length scales can form whenthe extracellular stimulus is spatially confined or
otherwiseorganized [5].
A fundamental problem of directional sensingis its exquisite sensitivity. Even in the presence
of relativelyshallow chemoattractant gradients, cell projections are extendedprecisely in the region
exposed to the highest chemoattractant concentration. This reflects the existence of a mechanism
foramplifying the external signal.A key problem in directional sensing is the elucidationof the
mechanism underlying the formation of ahighly polarized distribution of actin polymers in responseto
a mild gradient. Indeed, chemoattractant gradients imposed in the extracellular space are often
quitesmall ~1%–2% concentration change over the length of the cell.If a chemo-attractant gradient is
imposed on the cells,GFP–PH migrates within 5–10 s to the leading edge ofthe cell, and persistently
maintains this polarized distribution.This stands in sharp contrast to the results obtainedin response to a
uniform chemo-attractant concentration profile [6].Systems biology modeling of signal transduction
pathwaystraditionally employs ordinary differential equations,deterministic models based on the
assumptions of spatial homogeneity. Cell signaling is an essential, ubiquitous process thatliving
systems use to respond to the environment [7]. Distinguishing modes of Eukaryotic gradient sensing is
developed by Skupsky et.al. [8]. During directional gradient sensing, eukaryotic cells suchas
Dictyostelium and neutrophils exhibit extraordinarysensitivity to external chemical gradients.Shannon
K Hughes-Alford et.al. discussed quantitative analysis of gradient sensing [9]. Noritaka Masaki et.al.
proposed single cell level analysis of PDE expression in Dictyostelium [10].

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 175

The analytical expression of Ligand bound sensitive receptors, membrane phosphoinositicides,

stored phosphoinositicides and cytosolic inosilol phosphates are presented. These concentrations are
derived using Homotopy perturbation method.

2. Mathematical Formulation of the Problem

To simulate the experiments, it is assumed that before the cell is subjected to a chemoattractant
perturbation ( t  0), it is in a homogeneous steady state, ( r10 , p  , ps , i   0), corresponding to a

uniform chemoattractant concentration, say, l  . At t  0, the cell is perturbated by exposing it to a

new chemoattractant concentration profile, l ( ) . The reduced equations are

 r10 D  2 r10

1
 t 1  K l l  ed K10
k 01 ea,t  k10 ed K10  r10  2r (1)
R  2
p Dp  2 p
 k f r10 p 2 p s  k r p i  c p  k p p  2 (2)
t R  2
 ps D p  2 ps
 
  k f r10 p 2 p s  k r p i  c p  k p p  2s (3)
t R  2
i
t
  D  2i
 s k f r10 p 2 p s  k r p i  ci  k i i  2i
R  2
(4)

Here, Dr , D p , D ps and Di denote the lateral diffusivities of R10, P , Ps and I , and R denotes the cell

radius. The factor s , denoting membrane length per unit cell area, is required since synthesis and
removal rates of P are based on the length of the plasma membrane. Since the cell is circular,
concentrations and fluxes must be equal at   0 and   2 . Thus, we require the periodic boundary
conditions
 x(0, t )  x(2 , t )
x (0, t )  x(2 , t ),  ,t 0 (5)
 
where x  r10 , p, p s , i. The initial conditions for the reduced equations are

1  K l l  ed K10

t  0 ; r10  r , p  p  , p s  pt  p  , i  i  (6)
1  K l l    ed K10
10

They reflect the assumptions that:

(1) The total amount of phosphoinositide in the membrane and the endoplasmic reticulum is
conserved, so that the average phosphoinositide concentration, denoted pt is constant.

(2) Information concerning the chemoattractant concentration profile imposed at t  0 , namely,

l   , is transmitted to the receptors instantaneously. Thus, r10 changes during this rapid

process, but p , p s , and i remain unchanged.

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 176

By introducing the dimensionless variables

r10 p p i  t
10  ,  , s  s , ι  ,  ,  (7)

r10 pt pt spt 2 * 3.1416 1 k r spt 
and dimensionless parameters
k 01 e a ,t l ed Dr C 2
 01  ,  a ,t   ,   , d  , r  (8)
k r spt r10 Kl K10 k r spt

k f r10 pt2 c p pt kp Dp C 2
f  , p , p  , p  (9)
k r spt kr spt k r spt k r spt

Dp s C 2 ci spt  k D C2 l
p  , i  , i  i , i  i ,   (10)
s
k r spt k r spt k r spt k r spt Kl

p p s - i 
 

, s 

, ι  (11)
pt pt spt
Where C denotes the circumference of the cell. Thus we get the dimensionless equations of (1)-(6) are
as follows:
 X1 2 X1
 k1 (1  X 1 )   r (12)
  2

 X2 2 X 2
 k 2 X 1 X 2 X 3  X 2 X 4  k3  k 4 X 2   p
2
(13)
  2

 X3 2 X3
   k 2 X 1 X 22 X 3  X 2 X 4  k 3  k 4 X 2   ps (14)
  2

 X4 2 X 4
 k 2 X 1 X 22 X 3  X 2 X 4  k 5  k 6 X 4   r (15)
  2
with initial conditions
  0 , X 1  u1 , X 2  u 2 , X 3 1  u 2 and X 4  u3 (16)

And the periodic boundary conditions

x(0, ) x(1, )
x(0, )  x(1, ),  ,   0, (17)
 
where
x  r10 , p, p s , i. (18)
Here
X 1  10 , X 2   , X 3   s , X 4 = ι (19)

 01  a ,t
k1  , k 2   f , k3   p , k 4   p , k5   i , k6   i (20)
1  1 /     d

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 177

u1 
 
1  1 /    d
, u 2    , u 3  ι- (21)
1  1 /  ( )    d

2 X1 2 X 2 2 X 3 2 X 4
By considering    0 (22)
 2  2  2  2
Then the equations (12)-(15) becomes
 X1
 k1 (1  X 1 ) (23)

 X2
 k 2 X 1 X 22 X 3  X 2 X 4  k 3  k 4 X 2 (24)

 X3


  k 2 X 1 X 22 X 3  X 2 X 4  k 3  k 4 X 2  (25)

 X4
 k 2 X 1 X 22 X 3  X 2 X 4  k 5  k 6 X 4 (26)

with the initial conditions
  0 , X 1  u1 , X 2  u 2 , X 3 1  u 2 and X 4  u3 (27)

3. Solution of the Problem Using Homotopy Perturbation Method

Linear and non-linear phenomena are of fundamental importance in various fields of science
and engineering. Most models of real – life problems are still very difficult to solve. Therefore,
approximate analytical solutions such as Homotopy perturbation method (HPM) [11-24] were
introduced. This method is the most effective and convenient ones for both linear and non-linear
equations. Perturbation method is based on assuming a small parameter. The majority of non-linear
problems, especially those having strong non-linearity, have no small parameters at all and the
approximate solutions obtained by the perturbation methods, in most cases, are valid only for small
values of the small parameter. Generally, the perturbation solutions are uniformly valid as long as a
scientific system parameter is small. However, we cannot rely fully on the approximations, because
there is no criterion on which the small parameter should exists. Thus, it is essential to check the
validity of the approximations numerically and/or experimentally. To overcome these difficulties,
HPM have been proposed recently.
Recently, many authors have applied the Homotopy perturbation method (HPM) to solve the
non-linear problem in physics and engineering sciences [11-14]. This method is also used to solve
some of the non-linear problem in physical sciences [15-17]. This method is a combination of
Homotopy in topology and classic perturbation techniques. Ji-Huan He used to solve the Lighthill
equation [15], the Duffing equation [16] and the Blasius equation [17-18]. The HPM is unique in its

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 178

applicability, accuracy and efficiency. The HPM uses the imbedding parameter p as a small parameter,
and only a few iterations are needed to search for an asymptotic solution. Using this method [19-24],
we can obtain solution of the eqns. (23) - (27) are as follows:

X1 (t )  (u1  1) e   1 (28)
 k k  
 (u 3  5 ) k 3 e 6 
 k  k   k (1  u 2 ) k k k 
2
 32 5    
k6
X 2 (t )   u 2  3  e  k4    3   d1 e  k4    2 3
3  k 4 (k 4  k 6 ) 
 k4   k4   k4 k4 k6 
 
 
 k   k 
 2 k 2 k 3 (1  u 2 ) (u 3  5 )   k 2 (1  u 2 ) (u 2  3 ) 2 e  2 k4  
 e k4   2 5 
v k k6   k4 

 k k4   k4 
 6   
   
 k ( k  2 k )  
2 k 1  k 2 (1  u 2 ) (u1  1) (u 2  3 ) 2 e 1 4 
 k (1  u 2 ) (u1  1) k 3 e   k4 
  2 

2
   
 k 4 ( k 4 k 1 )   ( k 1 k 4 )

 
 k k  (k k )    k ( k  k )  
 (u 2  3 ) (u 3  4 ) e 4 6   2 k 2 k 3 (1  u 2 ) (u1  1) (u 2  3 ) e 4 6 
  
k4 k6 k4
 k6   k1 
    (29)
   
  k  k  
  (u 3  5 ) k 3 e 6 
 
 u 2  k 3  e  k 4    k 3   d 1 e  k 4    k 2 (1  u 2 ) k 3  k 3 k 5   
2
k6 

 
k4     3 2   k (k  k ) 
 4
k  k 4 k 4 k 6 
 4 4 6


  
  k   k  
  2 k 2 k 3 (1  u 2 ) (u 3  5 )   k 2 (1  u 2 ) (u 2  3 ) 2 e  2 k 4   
  e k4   v 2 k 5  k6  

k4  
  k k4   k4  
  6    
     
X 3 (t )  1   
  k 3 2 ( k1  2 k 4 )   
 k (1  u 2 ) (u1  1) (u 2  ) e 
  k 2 (1  u 2 ) (u1  1) k 32 e  k  1   2 k4  
   
 
 
  k 42 (k 4  k1 )   ( k1  k 4 ) 

   
 
  k3 k 4  ( k 4  k6 )    k 3 ( k4  k6 )   
  (u 2  ) (u 3  ) e   2 k 2 k 3 (1  u 2 ) (u1  1) (u 2  ) e  
   k4 k6    k4  
  k6   k1  
     
     
(30)

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 179

 k  k   k (1  u ) k 2 k k 
X 4 (t )   u 3  5  e  k6   5   d 2 e  k6    2 2 2 3  3 25 
 k6   k6   k4 k6 k4k6 
 k k   k k ( k  k )  
 (u 2  3 ) k 5 2 k 2 k 3 (1  u 2 ) (u 3  5 )   (u 2  3 ) (u 3  5 ) e 6 6 
 e  k4 
 k4 k6   k4 k6 
    
    
 6
k k 4 

k 6 k 4
 
k 4

   
 k 2k    k k  
 k 2 (1  u 2 ) (u 2  3 ) 2 e 4  2  k1 
 (u 3  5 ) k 3 t e 6 

k4    k 2 (1  u 2 ) (u1  1) k 3 e  
 
k6 
 ( k 6  2k 4 )   k 4 ( k 6  k1 )
2   
    k4
  (31)
   
 k  ( k  2 k 41 )    k ( k  k )  
 k 2 (1  u 2 )(u1  1) (u 2  3 ) 2 e   2 k 2 k 3 (1  u 2 ) (u1  1) (u 2  3 ) e 1 4 
  
k4 k4
 ( k 6  k1  2 k 4 )   k 4 ( k 6  k1  k 4 ) 
   
   

where d 1 and d 2 are defined in the Appendix B.

Fig. 1: Illustration of experiment for identifying the firstpolarized component in the signal transduction
pathway.

4. Numerical Simulation

The non-linear differential eqns. (23) - (27) are also solved by numerical methods using Scilab
software. Its numerical solution is compared with Homotopy perturbation method in Figs (3) – (6) and
it gives satisfactory result for all small values of the dimensionless parameters. The Scilab program is
also given in Appendix (C).

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 180

Fig. 2: The phosphoinositide cycle (a) and the model scheme (b). In the model scheme, R10 denotes
active receptors; P, I, and Ps denote the pools of membrane phosphoinositicides, cytosolic inosilol and
its phosphates, and phosphoinositicides in the endoplasmic reticulum, respectively.

5. Results and Discussions

Eqns.(28-31) are the new approximate analytical expressions for the ligand –bound sensitive
receptors, membrane phosphoinositicides, stored phosphoinositicides and cytosolic inosilol
phosphates. Figs 3,4 shows the evolution of the solutions when the chemoattractant concentration is

increased from   0.5 to   1000 . The dimensionless concentration of ligand-bound sensitive

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 181

receptors X 1 and dimensionless concentration of membrane phosphoinositicides X 2 versus the

dimensionless time  are indicated in the Fig. 3.

Fig. 3: Dimensionless concentrations of ligand-bound sensitive receptors X 1 and the membrane

phosphoinositicides X 2 versus the dimensionless time  . The curve is plotted for the various values of
dimensionless ligand concentration  , when   0.5, 1, 200 and 1000.

The observation from the Fig. 3, it is evident that when the dimensionless ligand concentrations
 increases, the corresponding concentrations X 1 and X 2 increases. Whereas, the dimensionless
concentration stored phosphoinositicides X 3 and the dimensionless inositol phosphates X 4 versus the
dimensionless time  were represented in Fig. 4.

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 182

Fig. 4: Dimensionless concentration stored phosphoinositicides X 3 and the cytosolic inosilol

phosphates X 4 versus the dimensionless time  . The curve is plotted for the various values of
dimensionless ligand concentration  , when   0.5, 1, 200 and 1000.

From the Fig. 4, it is inferred that, when the dimensionless ligand concentration  increases,
there was a correspond decrease in the concentration of X 3 , and the concentrations of X 4 increases

respectively. The ligand bound receptors concentration and membrane phosphoinositicides

concentration is plotted in Fig.5 is a particular case when   1 and   200 .

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 183

Fig. 5: Dimensionless concentrations of ligand-bound sensitive receptors X 1 and the membrane

phosphoinositicides X 2 versus the dimensionless time  . The curve is plotted for the various values of
dimensionless ligand concentration  , when  1 and 200.

In Fig.6 the concentrations of stored phosphoinositicides and concentrations of cytosolic

inosilol phosphates are varying according to the Ligand concentration. From Fig.7and Fig.8 it is

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 184

observed that the concentration of membrane phosphoinositicides and cytosolic inosilol phosphates are
coinciding with respect to the ligand concentration.

Fig. 6: Dimensionless concentration stored phosphoinositicides X 3 and the cytosolic inosilol

phosphates X 4 versus the dimensionless time  . The curve is plotted for the various values of
dimensionless ligand concentration  , when  1 and 200.

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 185

Fig. 7: Dimensionless concentrations of ligand-bound sensitive receptors X 1 , the membrane

phosphoinositicides X2 , the stored phosphoinositicides X3 and the cytosolicinosilol
phosphates X 4 versus the dimensionless time  . The curve is plotted for the various values of
dimensionless ligand concentration  , when   0.5 and 1.

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 186

Fig. 8: Dimensionless concentrations of ligand-bound sensitive receptors X1 , the

phosphoinositides X 2 , the stored phosphoinositicides X 3 and the inositol phosphates X 4 versus the

dimensionless time  . The curve is plotted for the various values of dimensionless ligand
concentration  , when   200 and 1000.

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 187

6. Conclusions

It has been observed and concluded that, a reaction-diffusion model based on the kinetics of the
phosphoinositicides cycle captures and explains many of the phosphoinositicides dynamics associated
with directional sensing in cell migration. The analytical expressions of the dimensionless
concentrations of ligand-bound sensitive receptors, membrane phosphoinositicides, stored
phosphoinositicides in endoplasmic reticulum and inosilol phosphates for all the small values of the
corresponding dimensionless parameters. The analytical results are compared to the numerical
simulations. The HPM is an extremely simple compared to other method and it is also a promising
method to solve other non-linear equations. This method can be easily extended to find the solution of
all other non-linear equations.

Acknowledgement
The authors are thankful to Shri. S. Natanagopal, Secretary, Madura College Board, Madurai
and Dr. R. Murali, The Principal for their constant encouragement.

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Appendix A
Basic concept of Homotopy perturbation method [11-24]
To explain this method, let us consider the following function:
Do (u)  f (r )  0, r   (A. 1)
with the boundary conditions of
u
Bo (u, )  0, r   (A. 2)
n
where Do is a general differential operator, Bo is a boundary operator, f (r ) is a known analytical

function and  is the boundary of the domain  . In general, the operator Do can be divided into a

linear part L and a non-linear part N . Eq. (A.1) can therefore be written as
L(u)  N (u)  f (r )  0 (A. 3)
By the Homotopy technique, we construct a Homotopy v(r, p) :   [0,1]   that satisfies
H (v, p)  (1  p)[ L(v)  L(u0 )]  p[ Do (v)  f (r )]  0. (A. 4)

H (v, p)  L(v)  L(u0 )  pL(u0 )  p[ N (v)  f (r )]  0. (A. 5)

wherep  [0, 1] is an embedding parameter, and u 0 is an initial approximation of Eq. (A. 1) that
satisfies the boundary conditions. From Eq. (A.4) and Eq. (A.5), we have
H (v,0)  L(v)  L(u0 )  0 (A. 6)

H (v,1)  Do (v)  f (r )  0 (A. 7)

When p=0, Eq. (A.4) and Eq. (A.5) become linear equations. When p =1, they become non-linear
equations. The process of changing p from zero to unity is that of L(v)  L(u0 )  0 to Do (v)  f (r )  0 .

We first use the embedding parameter p as a “small parameter” and assume that the solutions of Eq.
(A.4) and Eq. (A.5) can be written as a power series in p :

v  v0  pv1  p 2 v2  ... (A. 8)

Setting p  1 results in the approximate solution of Eq. (A.1):

u  lim v  v0  v1  v2  ... (A. 9)

p 1

This is the basic idea of the HPM.

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 191

Appendix B
Solution of the boundary value problem eqns. (23) - (27) using Homotopy perturbation method.
In this Appendix, we indicate how eqns. (28) - (31) are derived in this paper. Solving eqns. (23) and
(27) we get the solution is
X 1  (u1  1) e   1 (B.1)
To find the solution of the eqns. (24) – (27), we construct the Homotopy as follows:
 dX   dx 
(1  p)  2  k 4 X 2  k 3   p  2  k 4 X 2  k 2 X 1 X 22 X 3  X 2 X 4  k 3   0 (B.2)
 dt   dt 

 dX   dX 
(1  p)  3  k 4 X 2  k 3   p  3  k 4 X 2  k 2 X 1 X 22 X 3  X 2 X 4  k 3   0 (B.3)
 dt   dt 

 dX   dX 
(1  p)  4  k 6 X 4  k 5   p  4  k 6 X 4  k 2 X 1 X 22 X 3  X 2 X 4  k 5   0 (B.4)
 dt   dt 
The analytical solutions of (B.2), (B.3) and (B.4) is
X 2  X 200  p X 211  p 2 X 222  .......... (B.5)

X 3  X 300  pX 311  p 2 X 322  ......... (B.6)

X 4  X 400  pX 411  p 2 X 422  ......... (B.7)

Substituting the eqns. (B.5), (B.6) and (B.7) in (B.2), (B.3) and (B.4) respectively we get
 d ( X 200  p X 211  p 2 X 222  .....) 
(1  p )   k 4 ( X 200  p X 211  p 2 X 222  .....)  k 3 
 dt 
 d ( X 200  p X 211  p 2 X 222  .....) 
  k 4 ( X 200  p X 211  p 2 X 222  .....) 
 dt 
(B.8)

 p  k 2 X 1 ( X 200  p X 211  p X 222  .....) ( X 300  p X 311  p X 322  .....)  0
2 2 2

 
 ( X 200  p X 211  p 2 X 222  .....)( X 400  p X 411  p 2 X 422  .....)  k 3 
 
 

 d ( X 300  p X 311  p 2 X 322  .....) 

(1  p )   k 4 ( X 200  p X 211  p 2 x 222  .....)  k 3 
 dt 
 d ( X 300  p X 311  p 2 X 322  .....) 
  k 4 ( X 200  p X 211  p 2 X 222  .....)  (B.9)
 dt 
 p  k 2 X 1 ( X 200  p X 211  p 2 X 222  .....) 2 ( X 300  p X 311  p 2 X 322  .....)  0

 
 ( X 200  p X 211  p 2 X 222  .....)( X 400  p X 411  p 2 X 422  .....)  k 3 
 
 

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 192

 d ( X 400  p X 411  p 2 X 422  .....) 

(1  p )   k 6 ( X 400  p X 411  p 2 X 422  .....)  k 5 
 dt 
 d ( X 400  p X 411  p 2 X 422  .....) 
  k 6 ( X 400  p X 411  p 2 X 422  .....) 
 dt 
(B.10)

 p  k 2 X 1 ( X 200  p X 211  p 2 X 222  .....) 2 ( X 300  p X 311  p 2 X 322  .....)  0
 
 ( X 200  p X 211  p 2 X 222  .....)( X 400  p X 411  p 2 X 422  .....)  k 5 
 
 
Comparing the coefficients of like powers of p in (B.8), (B.9) and (B.10) we get

d X 20
p0 :  k 40 X 20  k 3  0 (B.11)
dt
d X 30
p0 :  k3  0 (B.12)
dt
dX 40
p0 :  k 60 X 40  k 5  0 (B.13)
dt
dX 21
p1 :  k 4 X 21  k 2 X 1 X 220 X 30  X 20 X 40 (B.14)
dt
dX 31
p1 :  k 4 X 21  k 2 X 1 x220 X 30  X 20 X 40 (B.15)
dt
dx41
p1 :  k 6 x21  k 2 x1 x220 x30  x20 x40 (B.16)
dt
The initial approximations are as follows
X 10 (0)  u1 , X 20 (0)  u 2 , X 30 (0)  1  u 2 and X 40 (0)  u3 (B.17)

X 1i (0)  X 2i (0)  X 3i (0)  X 4i (0)  0, i  1,2,3...... (B.18)

Solving the eqns. (B.11) - (B.16) and using the initial conditions (B.17) and (B.18) we obtain the
following results:

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 193

 k  k 
X 20   u 2  3  e  k 4    3  (B.19)
 k4   k4 
 k5 
 2 k k (1  u ) (u  )
  2  2 3 2 3
 32 5   t e k4   2 5  6 
k (1 u ) k k k v k k
X 21  d1 e k4    2 2 3
3  k k 
 k4 k4 k6 
 6 4

 
 k 2 2 k    k k  
 k 2 (1  u 2 ) (u 2  3 ) e 4    (u3  5 ) k 3 e 6 
   k 2 (1  u 2 ) (u1  1) k 3 e  
2  k
 
1 k6
k4

 k4   k 4 (k 4  k1 )
2   k (k  k ) 
     4 4 6

   
 k 2 ( k  2 k )   k k  ( k  k ) 
 k 2 (1  u 2 ) (u1  1) (u 2  3 ) e 1 4   (u 2  3 ) (u 3  4 ) e 4 6 

k4  k4 k6 
 (k1  k 4 )   k6 
   
   
 k  ( k  k ) 
 2 k 2 k 3 (1  u 2 ) (u1  1) (u 2  3 ) e 4 6 
 
k4
 k1 
 
  (B.20)
Where

 k 
 k 2 (1  u 2 ) (u 2  3 ) 2 
k k  
k 2 (1  u 2 ) k 32 k 4   k 2 (1  u 2 ) (u1  1) k 32 
d1   32 5  
   
k 43 k   2
 
 4 6
k k   4
 
k 4 ( k 4 k1 ) 
 
 k   k   k k 
 (u 3  5 ) k 3   k 2 (1  u 2 ) (u1  1) (u 2  3 ) 2   (u 2  3 ) (u 3  4 ) 
 
k6 k4   k4 k6 

 k (k  k )   (k1  k 4 )   k6 
 4 4 6
    
     
 k 
 2 k 2 k 3 (1  u 2 ) (u1  1) (u 2  3 ) 

k4 
 k1 
 
  (B.21)

dX 2 dX 3
Since   0, we get
d d
X 3  1 X 2 (B.22)

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 194

 k  k 
X 40   u3  5  e k6   5  (B.23)
 k6   k6 
 k3 k5 
 (u  ) k 2 k k (1  u ) ( u  )
 k 2 (1  u 2 ) k 32 k 3 k 5   e  k4   
2 5 2 3 2 3
 k6  k4 k6 
X 41  d 2 e     
2  

 
k 42 k 6  
 k 4 6   6
k k k 4  k6 k4
 
 
 k 2k    k5  k6 
 k 2 (1  u 2 ) (u 2  3 ) 2 e 4    (u  ) k  e 
 k4   k 2 (1  u 2 ) (u1  1) k 3 e 1  
2  k 3
k6
3

  
 ( k 6  2k 4 )   k 4 (k 6  k1 )
2   k4 
     
   
 k  ( k  2 k 41 )  
 k 2 (1  u 2 )(u1  1) (u 2  3 ) 2 e 
  k4 
 (k 6  k1  2 k 4 ) 
 
 
 k ( k  k )    k k ( k  k )  
 2 k 2 k 3 (1  u 2 ) (u1  1) (u 2  3 ) e 1 4   (u 2  3 ) (u 3  5 ) e 6 6 

k4   k4 k6  (B.24)
 k 4 (k 6  k1  k 4 )   k4 
   
   

where
 k k 
 (u 2  3 ) k 5 2 k 2 k 3 (1  u 2 ) (u 3  5 ) 
k k   1 
k 2 (1  u 2 ) k 32 k4 k6 
d 2   3 25   
   
 
 k4k6 k 42 k 6   k6  k4   k6 k4

 
 k   k k t 
 k 2 (1  u 2 ) (u 2  3 ) 2   (u 3  5 ) k 3 t e 6 
k 4   k 2 (1  u 2 ) (u1  1) k 3  
2


k6
  

 ( k 6  2k 4 )  k 4 (k 6  k1 )
2  k4 
     
   
 k   k 
 k 2 (1  u 2 )(u1  1) (u 2  3 ) 2   2 k 2 k 3 (1  u 2 ) (u1  1) (u 2  3 ) 

k4   k4 

 (k 6  k1  2 k 4 )   k 4 (k 6  k1  k 4 ) 
   
   
 k k 
 (u 2  3 ) (u 3  5 ) 

k4 k6 
 k4 
 
  (B.25)
According to the HPM, we can conclude that
X 2  lim X 2 (t )  X 20 0  X 211 (B.26)
p1

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 195

X3  1 X 2 (B.27)

X 4  lim X 4 (t )  X 40 0  X 411 (B.28)

p1
After putting the eqns. (B.19) and (B.20) into an eqn. (B.26) and (B.23) and (B.24) into an eqn.
(B.28), we obtain the solutions in the text eqns. (29) and (31).

Appendix C
Scilab program to find the solutions of the Equations (23)-(27)
function
options= odeset('RelTol',1e-6,'Stats','on');
%initial conditions
x0 = [10.08174387; .1; .9; .1];
tspan = [0,200];
tic
[t,x] = ode45(@TestFunction,tspan,x0,options);
toc
figure
hold on
%plot(t, x(:,1))
%plot(t, x(:,2))
plot(t, x(:,3))
%plot(t, x(:,4))
legend('x','y','z')
ylabel('x')
xlabel('t')
return
function [dx_dt]= TestFunction(t,x)
k1=.09523809524;k2=1.1;k3=.01;k4=.1;k5=.01;k6=.11;
dx_dt(1)=k1*(1-x(1));
dx_dt(2)=k2*x(1)*x(2)^2*x(3)-x(2)*x(4)+k3-k4*x(2);
dx_dt(3)=-(k2*x(1)*x(2)^2*x(3)-x(2)*x(4)+k3-k4*x(2));
dx_dt(4)=k2*x(1)*x(2)^2*x(3)-x(2)*x(4)+k5-k6*x(4);
dx_dt = dx_dt';
return

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 196

Appendix D
Nomenclature
Symbols Meaning
aij Rate constants for association of E a or E d with Rij
al Rate constants for association of Rij with L
ci Basal synthesis rate of synthesis of inosital phosphates
c Circumference of the cell
Di Lateral diffusivity of inosital phosphates
Dp Lateral diffusivity of phoshoinositides in plasma membrane

D ps Lateral diffusivity of phoshoinositides in endoplasmic

reticulum
Dr Lateral diffusivity of receptors
ea, t Total concentration of activating (dephosphorylating ) enzyme
ed Concentration of deactivating (phosphorylating ) enzyme
i Concentration of inositol phosphates
kf Rate constant for receptor-mediated phoshoinositide formation
ki Rate constant for basal degradation of inositolphosphates
kp Rate constant for basal degradation of phosphoinositides

kr Rate constant for removal of phosphoinositides

k ij Rate constants for sensitization/ desensitization

K ij Dissociation constants for binding of E a or E d to Rij

Kl Dissociation constant for ligand binding
l Concentration of ligand
p Concentration of membrane phosphoinositides
ps Concentration of phosphoinositides on endoplasmic reticulum
pl Average concentration of phosphoinositides in the cell
rij Concentration of receptors with i ligand-bound and j
phosphorylated sites
r* Concentration of complexes between E a or E d and Rij
ij

r p, f Rate of formation of membrane phosphoinositides

r p, r Rate of removal of membrane phosphoinositides

r p, d Degradation rate of membrane phosphoinositides

ri, d Degradation rate of inositol phosphates
R Radius of the cell
s Membrane length per unit cell area

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Int. J. Modern Math. Sci. 2014, 9(3): 173-197 197

p Dimensionless rate of basal synthesis of phosphoinositides

i Dimensionless rate of basal synthesis of inositol phosphates
i Dimensionless angular diffusivity of inositol phosphates
p Dimensionless angular diffusivity of phosphoinositides in
plasma membrane
 ps Dimensionless angular diffusivity of phosphoinositides in
endoplasmic reticulum
r Dimensionless angular diffusivity of receptors
Ι Dimensionless concentration of inositol phosphates
 a, t Dimensionless concentration of activating enzyme
d Dimensionless concentration of deactivating enzyme
f Dimensionless rate constant for formation of
phosphoinositides
i Dimensionless rate constant for degradation of inositol
phosphates
p Dimensionless rate constant for degradation of
phosphoinositides
 Dimensionless ligand concentration
 Dimensionless concentration of phosphoinositides
s Dimensionless concentration stored phosphoinositicides
10 Dimensionless concentration of ligand-bound sensitive
receptors
 Relative gradient of chemoattractant
 Dimensionless time
 Angular coordinate scaled between 0 and 1

Copyright © 2014 by Modern Scientific Press Company, Florida, USA