JWS Online

leloup5

leloup5

 Detail
 Download

Reactions

reaction_0

Mb synthesized

∅ > Mb

reaction_1

Mb translated into protein

∅ > Bc

reaction_10

Mp translated into protein

∅ > Pc

reaction_11

Pcp specific degradation

Pcp > ∅

reaction_12

Pc phospholation

Pc > Pcp

reaction_13

Cc and Pc produce PCc

Cc + Pc = PCc

reaction_14

PCc phospholation

PCc > PCcp

reaction_15

PCcp specific degradation

PCcp > ∅

reaction_16

PCc transfered into nuclear

PCc = PCn

reaction_17

PCnp nonspecific degradation

PCnp > ∅

reaction_18

Bcp nonspecific degradation

Bcp > ∅

reaction_19

Bnp nonspecific degradation

Bnp > ∅

reaction_2

Mb nonspecific degradation

Mb > ∅

reaction_20

Mc synthesis

∅ > Mc

reaction_21

PCn phospholation

PCn > PCnp

reaction_22

Mp nonspecific degradation

Mp > ∅

reaction_23

Per_Cry and Clock_Bmal form inactive complex

PCn + Bn = In

reaction_24

Mb specific degradation

Mb > ∅

reaction_25

Mc specific degradation

Mc > ∅

reaction_26

Mp specific degradation

Mp > ∅

reaction_27

Pc nonspecific degradation

Pc > ∅

reaction_28

Cc nonspecific degradation

Cc > ∅

reaction_29

Pcp nonspecific degradation

Pcp > ∅

reaction_3

Bc phosphorylation

Bc > Bcp

reaction_30

Ccp nonspecific degradation

Ccp > ∅

reaction_31

PCcp nonspecific degradation

PCcp > ∅

reaction_32

PCc nonspecific degradation

PCc > ∅

reaction_33

PCnp specific degradation

PCnp > ∅

reaction_34

Bc nonspecific degradation

Bc > ∅

reaction_35

Bcp specific degradation

Bcp > ∅

reaction_36

Bn phospholation

Bn > Bnp

reaction_37

Bnp specific degradation

Bnp > ∅

reaction_38

In nonspecific degration

In > ∅

reaction_39

In specific degradation

In > ∅

reaction_4

Bc transfered from cytosolic to nuclear

Bc = Bn

reaction_40

Bn nonspecific degradation

Bn > ∅

reaction_41

Bcp dephospholation

Bcp > Bc

reaction_42

Bnp dephospholation

Bnp > Bn

reaction_43

Ccp dephospholation

Ccp > Cc

reaction_44

Pcp dephospholation

Pcp > Pc

reaction_45

PCnp dephospholation

PCnp > PCn

reaction_46

PCn nonspecific degradation

PCn > ∅

reaction_47

PCcp dephospholation

PCcp > PCc

reaction_48

Mr synthesized

∅ > Mr

reaction_49

Mr nonspecific degradation

Mr > ∅

reaction_5

Mc translated into protein

∅ > Cc

reaction_50

Mr specific degradation

Mr > ∅

reaction_51

Mr translated into protein

∅ > Rc

reaction_52

Rc transfered into nuclear

Rc = Rn

reaction_53

Rc specific degradation

Rc > ∅

reaction_54

Rc nonspecific degradation

Rc > ∅

reaction_55

Rn specific degradation

Rn > ∅

reaction_56

Rn nonspecific degradation

Rn > ∅

reaction_6

Mc nonspecific degradation

Mc > ∅

reaction_7

Cc phosphorylation

Cc > Ccp

reaction_8

Ccp specific degradation

Ccp > ∅

reaction_9

Mp synthesis

∅ > Mp

Parameters

Global parameters
reaction_0
reaction_1
reaction_10
reaction_11
reaction_12
reaction_13
reaction_14
reaction_15
reaction_16
reaction_17
reaction_18
reaction_19
reaction_2
reaction_20
reaction_21
reaction_22
reaction_23
reaction_24
reaction_25
reaction_26
reaction_27
reaction_28
reaction_29
reaction_3
reaction_30
reaction_31
reaction_32
reaction_33
reaction_34
reaction_35
reaction_36
reaction_37
reaction_38
reaction_39
reaction_4
reaction_40
reaction_41
reaction_42
reaction_43
reaction_44
reaction_45
reaction_46
reaction_47
reaction_48
reaction_49
reaction_5
reaction_50
reaction_51
reaction_52
reaction_53
reaction_54
reaction_55
reaction_56
reaction_6
reaction_7
reaction_8
reaction_9

Fixed species

Initial values

Functions and Rules

Assignment rules

parameter_0000097 = 2.4 + (3.0 - 2.4) * parameter_0000096

parameter_0000096 = function_5(12.0, time)

Function definitions

function_2(V, substrate, Km) = V * substrate / (Km + substrate)

function_3(Vs, B, n, K) = Vs * pow(B, n) / (pow(K, n) + pow(B, n))

function_5(length, tt) = ceil(sin(pi * tt / length + 0.001) / 2)

function_0(vsb, K, m, Bn) = vsb * pow(K, m) / (pow(K, m) + pow(Bn, m))

function_1(k, mRNA) = k * mRNA

Events

Constraints

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.


Species:

Reactions:

Middle-click: pin/unpin nodes
Shift-click: pool/unpool species
Right-click: context menu
Apply alternate model layout to overlapping elements in current model:

log scales

y-axis min/max

x-axis min/max

Toward a detailed computational model for the mammalian circadian clock.

  • Jean-Christophe Leloup
  • Albert Goldbeter
Proc. Natl. Acad. Sci. U.S.A. 2003; 100 (12): 7051-7056
Abstract
We present a computational model for the mammalian circadian clock based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, Clock, and Rev-Erb alpha genes. In agreement with experimental observations, the model can give rise to sustained circadian oscillations in continuous darkness, characterized by an antiphase relationship between Per/Cry/Rev-Erbalpha and Bmal1 mRNAs. Sustained oscillations correspond to the rhythms autonomously generated by suprachiasmatic nuclei. For other parameter values, damped oscillations can also be obtained in the model. These oscillations, which transform into sustained oscillations when coupled to a periodic signal, correspond to rhythms produced by peripheral tissues. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark cycles. Simulations show that the phase of the oscillations can then vary by several hours with relatively minor changes in parameter values. Such a lability of the phase could account for physiological disorders related to circadian rhythms in humans, such as advanced or delayed sleep phase syndrome, whereas the lack of entrainment by light-dark cycles can be related to the non-24h sleep-wake syndrome. The model uncovers the possible existence of multiple sources of oscillatory behavior. Thus, in conditions where the indirect negative autoregulation of Per and Cry expression is inoperative, the model indicates the possibility that sustained oscillations might still arise from the negative autoregulation of Bmal1 expression.

No additional notes are available for this model.