LeBeau1999 - IP3-dependent intracellular calcium oscillations due to agonist stimulation from Cholecytokinin

  public model
Model Identifier
BIOMD0000000965
Short description
The properties of inositol 1,4,5-trisphosphate (IP3)-dependent intracellular calcium oscillations in pancreatic acinar cells depend crucially on the agonist used to stimulate them. Acetylcholine or carbachol (CCh) cause high-frequency (10–12-s period) calcium oscillations that are superimposed on a raised baseline, while cholecystokinin (CCK) causes long-period (.100-s period) baseline spiking. We show that physiological concentrations of CCK induce rapid phosphorylation of the IP3 receptor, which is not true of physiological concentrations of CCh. Based on this and other experimental data, we construct a mathematical model of agonist-specific intracellular calcium oscillations in pancreatic acinar cells. Model simulations agree with previous experimental work on the rates of activation and inactivation of the IP3 receptor by calcium (DuFour, J.-F., I.M. Arias, and T.J. Turner. 1997. J. Biol. Chem. 272:2675–2681), and reproduce both short-period, raised baseline oscillations, and long-period baseline spiking. The steady state open probability curve of the model IP3 receptor is an increasing function of calcium concentration, as found for type-III IP3 receptors by Hagar et al. (Hagar, R.E., A.D. Burgstahler, M.H. Nathanson, and B.E. Ehrlich. 1998. Nature. 396:81–84). We use the model to predict the effect of the removal of external calcium, and this prediction is confirmed experimentally. We also predict that, for type-III IP3 receptors, the steady state open probability curve will shift to lower calcium concentrations as the background IP3 concentration increases. We conclude that the differences between CCh- and CCK-induced calcium oscillations in pancreatic acinar cells can be explained by two principal mechanisms: (a) CCK causes more phosphorylation of the IP3 receptor than does CCh, and the phosphorylated receptor cannot pass calcium current; and (b) the rate of calcium ATPase pumping and the rate of calcium influx from the outside the cell are greater in the presence of CCh than in the presence of CCK.
Format
SBML (L2V4)
Related Publication
  • Agonist-dependent phosphorylation of the inositol 1,4,5-trisphosphate receptor: A possible mechanism for agonist-specific calcium oscillations in pancreatic acinar cells.
  • LeBeau AP, Yule DI, Groblewski GE, Sneyd J
  • The Journal of general physiology , 6/ 1999 , Volume 113 , pages: 851-872 , PubMed ID: 10352035
  • Mathematical Research Branch, National Institutes of Health, Bethesda, Maryland, USA.
  • The properties of inositol 1,4,5-trisphosphate (IP3)-dependent intracellular calcium oscillations in pancreatic acinar cells depend crucially on the agonist used to stimulate them. Acetylcholine or carbachol (CCh) cause high-frequency (10-12-s period) calcium oscillations that are superimposed on a raised baseline, while cholecystokinin (CCK) causes long-period (>100-s period) baseline spiking. We show that physiological concentrations of CCK induce rapid phosphorylation of the IP3 receptor, which is not true of physiological concentrations of CCh. Based on this and other experimental data, we construct a mathematical model of agonist-specific intracellular calcium oscillations in pancreatic acinar cells. Model simulations agree with previous experimental work on the rates of activation and inactivation of the IP3 receptor by calcium (DuFour, J.-F., I.M. Arias, and T.J. Turner. 1997. J. Biol. Chem. 272:2675-2681), and reproduce both short-period, raised baseline oscillations, and long-period baseline spiking. The steady state open probability curve of the model IP3 receptor is an increasing function of calcium concentration, as found for type-III IP3 receptors by Hagar et al. (Hagar, R.E., A.D. Burgstahler, M.H. Nathanson, and B.E. Ehrlich. 1998. Nature. 396:81-84). We use the model to predict the effect of the removal of external calcium, and this prediction is confirmed experimentally. We also predict that, for type-III IP3 receptors, the steady state open probability curve will shift to lower calcium concentrations as the background IP3 concentration increases. We conclude that the differences between CCh- and CCK-induced calcium oscillations in pancreatic acinar cells can be explained by two principal mechanisms: (a) CCK causes more phosphorylation of the IP3 receptor than does CCh, and the phosphorylated receptor cannot pass calcium current; and (b) the rate of calcium ATPase pumping and the rate of calcium influx from the outside the cell are greater in the presence of CCh than in the presence of CCK.
Contributors
Submitter of the first revision: Harish Dharuri
Submitter of this revision: Kausthubh Ramachandran
Modellers: Harish Dharuri, Kausthubh Ramachandran

Metadata information

is (3 statements)
BioModels Database MODEL9200487367
BioModels Database MODEL9200487367
BioModels Database BIOMD0000000965

isDescribedBy (1 statement)
PubMed 10352035

hasTaxon (1 statement)
Taxonomy Homo sapiens

isVersionOf (1 statement)
hasProperty (1 statement)
Mathematical Modelling Ontology Ordinary differential equation model

occursIn (1 statement)
Brenda Tissue Ontology pancreatic acinar cell

Curation status
Curated
Modelling approach(es)
ordinary differential equation model
Tags

Connected external resources

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Model files
LeBeau1999_Phosphorylation_CCK.xml SBML L2V4 file of IP3-dependent intracellular calcium oscillations due to agonist stimulation from Cholecytokinin (CCK) 123.96 KB Preview | Download

Additional files
LeBeau1999_Phosphorylation_CCK.cps COPASI 4.29 (Build 228) file of IP3-dependent intracellular calcium oscillations due to agonist stimulation from Cholecytokinin 123.00 KB Preview | Download
LeBeau1999_Phosphorylation_CCK.omex COMBINE archive of IP3-dependent intracellular calcium oscillations due to agonist stimulation from Cholecytokinin 25.98 KB Preview | Download
LeBeau1999_Phosphorylation_CCK.sedml SED-ML file of IP3-dependent intracellular calcium oscillations due to agonist stimulation from Cholecytokinin 1.72 KB Preview | Download

  • Model originally submitted by : Harish Dharuri
  • Submitted: Sep 29, 2006 10:51:48 PM
  • Last Modified: Sep 24, 2020 8:19:08 PM
Revisions
  • Version: 5 public model Download this version
    • Submitted on: Sep 24, 2020 8:19:08 PM
    • Submitted by: Kausthubh Ramachandran
    • With comment: Automatically added model identifier BIOMD0000000965
  • Version: 4 public model Download this version
    • Submitted on: Sep 24, 2020 8:09:22 PM
    • Submitted by: Kausthubh Ramachandran
    • With comment: Edited model metadata online.
  • Version: 2 public model Download this version
    • Submitted on: Oct 7, 2009 6:47:57 PM
    • Submitted by: Harish Dharuri
    • With comment: Current version of LeBeau1999_IP3R_Phosphorylation
  • Version: 1 public model Download this version
    • Submitted on: Sep 29, 2006 10:51:48 PM
    • Submitted by: Harish Dharuri
    • With comment: Original import of MODEL9200487367.xml.origin

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Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
I2 1.0 mol
S 0.0 mol
c 0.0 mol
I1 0.0 mol
O 0.0 mol
Reactions
Reactions Rate Parameters
I2 => S k5*I2 k5=0.02
I1 => S k3*I1 k3=0.5
S = 1-(O+I1+I2) [] []
=> c; O kflux*O^4 kflux=28.0
=> c Jleak Jleak=0.025
S => O k1*p*S-kminus1*O k1 = 0.0; p = 0.0; kminus1=0.88
O => I1 k2*O k2=0.5
I1 => I2 k4*I1 k4 = 0.0
Curator's comment:
(added: 24 Sep 2020, 20:16:40, updated: 24 Sep 2020, 20:21:44)
Fig 10 (CCK-induced oscillations) is reproduced here. Using parameter scan, kflux parameter value alone was changed to 22 from 28.