Dataset Information

Scaramellini1997 - Two-receptor:One-transducer (2R1T) model for analysis of interactions between agonists

ABSTRACT: The two-receptor:one-transducerm odel (Leff, 1987) is here extended to analyze interactions between agonistsd isplaying E/[A] curves of different shapes, by incorporating slope factors into the separate and common parts of the transduction pathway. Interactions were modelled as the effect of one agonist, at fixed concentration, on the curve to the other. A variety of patterns of position and slope changes are predicted. These do not depend on the shape of the control curve, rather, they depend on the slope factors in the separate and common pathways. The following specific predictions are made: (1) when the common pathway is steep, curves undergo potentiation and flattening; (2) when the common pathway is flat, curves undergo right-shift and steepening; (3) when the common pathway is hyperbolic, curves undergo right-shift, with no slope change; (4) when the slope depends on the separate pathways, curves only undergo right-shift with no change in slope. The model provides a sound basis for classifying agonist interactions and for detecting additional, synergistic or antagonistic properties. This analysisin dicatest hat methodsb asedo n dose-additivity or independencea re less reliable for these purposes. The model provides a practical test, based on slope changes, to detect and quantify additional properties

SUBMITTER: Kausthubh Ramachandran

PROVIDER: BIOMD0000001008 | BioModels | 2024-09-02

REPOSITORIES: BioModels

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	BIOMD0000001008?filename=Scaramellini1997-biopax2.owl	Owl
	BIOMD0000001008?filename=Scaramellini1997-biopax3.owl	Owl
	BIOMD0000001008?filename=Scaramellini1997-matlab.m	Other
	BIOMD0000001008?filename=Scaramellini1997.cps	Other
	BIOMD0000001008?filename=Scaramellini1997.ode	Other

Items per page:

1 - 5 of 12

Publications

Analysis of agonist-agonist interactions: the crucial influence of curve shape.

Scaramellini C C Bennett G G Leff P P

Journal of pharmacological and toxicological methods 19970401 3

The two-receptor:one-transducer model (Leff, 1987) is here extended to analyze interactions between agonists displaying E[A] curves of different shapes, by incorporating slope factors into the separate and common parts of the transduction pathway. Interactions were modelled as the effect of one agonist, at fixed concentration, on the curve to the other. A variety of patterns of position and slope changes are predicted. These do not depend on the shape of the control curve, rather, they depend on ...[more]

PMID: 9253753

Similar Datasets

Project 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.