Skip to main content
SpringerLink
Log in

Modelling of signalling via G-protein coupled receptors: Pathway-dependent agonist potency and efficacy

  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

A mathematical model is constructed to study promiscuous coupling of receptors to G-proteins and to simulate events leading to the activation of multiple effector pathways within a cell. The model is directed at a better understanding of the factors that determine the efficacy and potency of a drug. Assuming that the receptors can exist in multiple conformational states, and allowing for agonist specific conformation, a system of ordinary differential equations is constructed and subsequently pathway-dependent agonist efficacy and potency order is predicted. A simple case of the compartmentalization of receptors and G-proteins is also given, using the current model to illustrate the effects of spatial heterogeneity on the predicted response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Berg, K. A., J. D. Cropper, C. M. Niswender, E. Sanders-Bush, R. B. Emeson and W. P. Clarke (2001). RNA-editing of the 5-HT2C receptor alters agonist-receptor-effector coupling specificity. Brit. J. Pharmacol. 134, 386–392.

    Article  Google Scholar 

  • Berg, K. A., S. Maayani, J. Goldfarb, C. Scaramellini, P. Leff and W. P. Clarke (1998). Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol. Pharmacol. 54, 94–104.

    Google Scholar 

  • Cordeaux, Y., S. J. Briddon, A. E. Megson, J. McDonnell, J. M. Dickenson and S. J. Hill (2000). Influence of receptor number on functional responses elicited by agonists acting at the human adenosine A1 receptor: evidence for signalling pathway-dependent changes in agonist potency and relative intrinsic activity. Mol. Pharmacol. 58, 1075–1084.

    Google Scholar 

  • Cordeaux, Y. and S. J. Hill (2002). Mechanisms of cross-talk between G-protein-coupled receptors. Neurosignals 11, 45–57.

    Article  Google Scholar 

  • De Lean, A, J. M. Stadel and R. J. Lefkowitz (1980). A TCM explains the agonist-specific binding properties of the adenylate cyclase-coupled β-adrenergic receptor. J. Biol. Chem. 255, 7108–7117.

    Google Scholar 

  • Kenakin, T. (1995). Agonist-receptor efficacy II: agonist trafficking of receptor signals. Trends Pharmacol. Sci. 16, 232–238.

    Article  Google Scholar 

  • Kenakin, T. (2002). Drug efficacy at G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol. 42, 349–379.

    Article  Google Scholar 

  • Leff, P. and C. Scaramellini (1998). Promiscuity, pre-coupling and instability. Trends Pharmacol. Sci. 19, 13.

    Article  Google Scholar 

  • Leff, P., C. Scaramellini, C. Law and K. McKechnie (1997). A three-state receptor model of agonist action. Trends Pharmacol. Sci. 18, 355–362.

    Google Scholar 

  • Ostrom, R. S. (2002). New determinants of receptor-effector coupling: trafficking and compartmentation in membrane microdomains. Mol. Pharmacol. 61, 473–476.

    Article  Google Scholar 

  • Riccobene, T. A., G. M. Omann and J. J. Linderman (1999). Modelling activation and desensitization of G-protein coupled receptors provides insight into ligand efficacy. J. Theor. Biol. 200, 207–222.

    Article  Google Scholar 

  • Samama, P., S. Cotecchia, T. Costa and R. J. Kefkowitz (1993). A mutation-induced activated state of the β2-adrenergic receptor: extending the TCM. J. Biol. Chem. 268, 4625–4636.

    Google Scholar 

  • Seifert, R. and K. Wenzel-Seifert (2002). Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn-Schmiedeberg’s Arch Pharmacol. 366, 381–416.

    Article  Google Scholar 

  • Shea, L. D. and J. J. Linderman (1998). Compartmentalization of receptors and enzymes affects activation for a collision coupling mechanism. J. Theor. Biol. 191, 249–258.

    Article  Google Scholar 

  • Shea, L. D., R. R. Neubig and J. J. Linderman (2000). Timing is everything—the role of kinetics in G protein activation. Life Sci. 68, 647–658.

    Article  Google Scholar 

  • Steinberg, S. F. and L. L. Brunton (2001). Compartmentation of G protein-coupled signaling pathways in cardiac myocytes. Annu. Rev. Pharmacol. Toxicol. 41, 751–773.

    Article  Google Scholar 

  • Tucek, S., P. Michal and V. Vlachova (2002). Modelling the consequences of receptor-G-Protein promiscuity. Trends Pharmacol. Sci. 23, 171–176.

    Article  Google Scholar 

  • Vaz, W. (1994). Diffusion and chemical-reaction in phase-separated membranes. Biophys. Chem. 50, 139–145.

    Article  Google Scholar 

  • Weiss, J., P. Morgan, M. Lutz and T. Kenakin (1995a). The cubic ternary complex receptor-occupancy model I. Model description. J. Theor. Biol. 178, 151–167.

    Article  Google Scholar 

  • Weiss, J., P. Morgan, M. Lutz and T. Kenakin (1995b). The cubic ternary complex receptoroccupancy model II. Understanding apparent affinity. J. Theor. Biol. 178, 169–182.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Mathematical Medicine, Division of Theoretical Mechanics, School of Mathematical Science, The University of Nottingham, Nottingham, UK

    C. Y. Chen & J. R. King

  2. Institute of Cell Signalling and School of Biomedical Sciences, Medical School, Queen’s Medical Centre, Nottingham, UK

    Y. Cordeaux & S. J. Hill

Authors
  1. C. Y. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. Cordeaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. J. Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. R. King
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Y. Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, C.Y., Cordeaux, Y., Hill, S.J. et al. Modelling of signalling via G-protein coupled receptors: Pathway-dependent agonist potency and efficacy. Bull. Math. Biol. 65, 933–958 (2003). https://doi.org/10.1016/S0092-8240(03)00055-7

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1016/S0092-8240(03)00055-7

Keywords

Search

Navigation