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Modelling of the activation of G-protein coupled receptors: drug free constitutive receptor activity. (English) Zbl 1311.92097

Summary: G-protein coupled receptors (GPCRs) form a crucial component of approximately 80% of hormone pathways. In this paper, the most popular mechanism for activation of GPCRs – the shuttling mechanism – is modelled mathematically. An asymptotic analysis of this model clarifies the dynamics of the system in the absence of drug, in particular which reactions dominate during the different timescales. Equilibrium analysis of the model demonstrates the model’s ability to predict constitutive receptor activity.

MSC:

92C45 Kinetics in biochemical problems (pharmacokinetics, enzyme kinetics, etc.)
92C40 Biochemistry, molecular biology
Full Text: DOI

References:

[1] Adams JA, Omann GM, Linderman JJ (1998) A mathematical model for ligand/receptor/G-protein dynamics and actin polymerisation in human neutrophils. J Theo Biol 193: 543–560 · doi:10.1006/jtbi.1998.0721
[2] Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD (1994) Molecular biology of the cell. Garland Publishing, New York
[3] Chen CY, Cordeaux Y, Hill SJ, King JR (2003) Modelling of signalling via G-protein coupled receptors: the pathway-dependent agonist potency and efficacy. B Math Biol 65: 933–958 · Zbl 1334.92130 · doi:10.1016/S0092-8240(03)00055-7
[4] Chidiac P (1998) Rethinking receptor-G protein-effector interactions. Biochem Pharmacol 55: 549–556 · doi:10.1016/S0006-2952(97)00361-4
[5] Clément F, Monniaux D, Stark J, Hardy K, Thalabard JC, Franks S, Claude D (2001) Mathematical model of FSH-induced cAMP production in ovarian follicles. J Physiol Endocrinol Metab 281: E35–E53
[6] De Lean A, Stadel JM, Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled {\(\beta\)}-adrenergic receptor. J Biol Chem 255: 7108–7117
[7] Fitzgerald LR, Manna IJ, Dytko GM, Wu H-L, Nambi P (1999) Measurement of responses from Gi-, Gs- or Gq-coupled receptors by a multiple response element/cAMP response element-directed reporter assay. Anal Biochem 275: 54–61 · doi:10.1006/abio.1999.4295
[8] Kenakin T (1993) Pharmacological analysis of drug-receptor interaction. Raven Press, New York
[9] Kenakin T (1997) Molecular pharmacology. Blackwell Science, Oxford
[10] Kenakin T (2001) Inverse, protean and ligand-selective agonism: matters of receptor conformation. FASEB 15: 598–611 · doi:10.1096/fj.00-0438rev
[11] Kenakin T (2002) Drug efficacy at G protein-coupled receptors. Annu Rev Pharmacol Toxicol 42: 349–379 · doi:10.1146/annurev.pharmtox.42.091401.113012
[12] Kinzer-Ursem TL, Linderman JJ (2007) Both ligand- and cell-specific parameters control ligand agonism in a kinetic model of G protein-coupled receptor signaling. PLoS Comput Biology 3: 84–94 · doi:10.1371/journal.pcbi.0030006
[13] Krakauer DC, Page KM, Sealfon S (2002) Module dynamics of the GnRH signal transduction network. J Theo Biol 218: 457–470 · doi:10.1016/S0022-5193(02)93092-4
[14] Kukkonen JP, Näsman J, Åkerman KEO (2001) Modelling of promiscuous receptor G_i/G_s protein coupling and effector response. TiPS 22: 616–622
[15] Leff P, Scaramellini C, Law C, McKechnie K (1997) A three-state receptor model of agonist action. TiPS 18: 355–362
[16] Lemon G, Gibson WG, Bennett MR (2003) Metatropic receptor activation, desensitization and sequestration–I: modelling calcium and inositol 1,4,5-triphosphate dynamics following receptor activation. J Theo Biol 223: 93–111 · doi:10.1016/S0022-5193(03)00079-1
[17] Lidow MS, Roberts A, Zhang L, Koh P-O, Lezcano N, Bergson C (2001) Receptor crosstalk protein, calcyon, regulates affinity state of Dopamine D1 receptors. Eur J Pharmacol 427: 187–193 · doi:10.1016/S0014-2999(01)01265-1
[18] Murray JD (1993) Mathematical biology. Springer, New York · Zbl 0779.92001
[19] Nauroschat J, ander Heiden U (1996) A theoretical approach to G-protein modulation of cellular responsiveness. J Math Biol 35: 609–627 · Zbl 0879.92009 · doi:10.1007/s002850050068
[20] Riccobene TA, Omann GM, Linderman JJ (1999) Modeling activation and desensitization of G-protein coupled receptors provides insight into ligand efficacy. J Theo Biol 200: 207–222 · doi:10.1006/jtbi.1999.0988
[21] Shea L, Neubig R, Linderman J (2000) Timing is everything–the role of kinetics in G protein activation. Life Sci 68: 647–658 · doi:10.1016/S0024-3205(00)00977-2
[22] Watson S, Arkinstall S (1994) The G-protein linked receptor factsbook. Academic Press Ltd, London
[23] Woodroffe PJ, Bridge LJ, King JR, Hill SJ (2009) Modelling of the activation of G-protein coupled receptors by a single drug. Math Biosci (in press). doi: 10.1016/j.mbs.2009.02.003 · Zbl 1187.92043
[24] Woolf PJ, Kenakin TP, Linderman JJ (2001) Uncovering biases in high throughput screens of G-protein coupled receptors. J Theo Biol 208: 403–418 · doi:10.1006/jtbi.2000.2227
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