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Biophys J. Sep 1994; 67(3): 1345–1357.
PMCID: PMC1225491

A Monte Carlo study of the dynamics of G-protein activation.

Abstract

To link quantitatively the cell surface binding of ligand to receptor with the production of cellular responses, it may be necessary to explore early events in signal transduction such as G-protein activation. Two different model frameworks relating receptor/ligand binding to G-protein activation are examined. In the first framework, a simple ordinary differential equation model is used to describe receptor/ligand binding and G-protein activation. In the second framework, the events leading to G-protein activation are simulated using a dynamic Monte Carlo model. In both models, reactions between ligand-bound receptors and G-proteins are assumed to be diffusion-limited. The Monte Carlo model predicts two regimes of G-protein activation, depending upon whether the lifetime of a receptor/ligand complex is long or short compared with the time needed for diffusional encounters of complexes and G-proteins. When the lifetime of a complex is relatively short compared with the diffusion time, the movement of ligand among free receptors by binding and unbinding ("switching") significantly enhances G-protein activation. Receptor antagonists dramatically reduce G-protein activation and, thus, signal transduction in this case, and significant clustering of active G-proteins near receptor/ligand complexes results. The simple ordinary differential equation model poorly predicts G-protein activation for this situation. In the alternative case, when diffusion is relatively fast, ligand movement among receptors is less important and the simple ordinary differential equation model and Monte Carlo model results are similar. In this case, there is little clustering of active G-proteins near receptor/ligand complexes. Results also indicate that as the GTPase activity of the alpha-subunit decreases, the steady-state level of alpha-GTP increases, although temporal sensitivity is compromised.

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  • Bakardjieva A, Galla HJ, Helmreich EJ. Modulation of the beta-receptor adenylate cyclase interactions in cultured Chang liver cells by phospholipid enrichment. Biochemistry. 1979 Jul 10;18(14):3016–3023. [PubMed]
  • Birnbaumer L, Abramowitz J, Brown AM. Receptor-effector coupling by G proteins. Biochim Biophys Acta. 1990 May 7;1031(2):163–224. [PubMed]
  • Bokoch GM, Bickford K, Bohl BP. Subcellular localization and quantitation of the major neutrophil pertussis toxin substrate, Gn. J Cell Biol. 1988 Jun;106(6):1927–1936. [PMC free article] [PubMed]
  • Brandt DR, Ross EM. GTPase activity of the stimulatory GTP-binding regulatory protein of adenylate cyclase, Gs. Accumulation and turnover of enzyme-nucleotide intermediates. J Biol Chem. 1985 Jan 10;260(1):266–272. [PubMed]
  • Byron KL, Villereal ML. Mitogen-induced [Ca2+]i changes in individual human fibroblasts. Image analysis reveals asynchronous responses which are characteristic for different mitogens. J Biol Chem. 1989 Oct 25;264(30):18234–18239. [PubMed]
  • Cassel D, Levkovitz H, Selinger Z. The regulatory GTPase cycle of turkey erythrocyte adenylate cyclase. J Cyclic Nucleotide Res. 1977 Dec;3(6):393–406. [PubMed]
  • Clapham DE, Neer EJ. New roles for G-protein beta gamma-dimers in transmembrane signalling. Nature. 1993 Sep 30;365(6445):403–406. [PubMed]
  • Fay SP, Posner RG, Swann WN, Sklar LA. Real-time analysis of the assembly of ligand, receptor, and G protein by quantitative fluorescence flow cytometry. Biochemistry. 1991 May 21;30(20):5066–5075. [PubMed]
  • Gorospe WC, Conn PM. Membrane fluidity regulates development of gonadotrope desensitization to GnRH. Mol Cell Endocrinol. 1987 Sep;53(1-2):131–140. [PubMed]
  • Hanski E, Rimon G, Levitzki A. Adenylate cyclase activation by the beta-adrenergic receptors as a diffusion-controlled process. Biochemistry. 1979 Mar 6;18(5):846–853. [PubMed]
  • Im MJ, Riek RP, Graham RM. A novel guanine nucleotide-binding protein coupled to the alpha 1-adrenergic receptor. II. Purification, characterization, and reconstitution. J Biol Chem. 1990 Nov 5;265(31):18952–18960. [PubMed]
  • Johansson B, Wymann MP, Holmgren-Peterson K, Magnusson KE. N-formyl peptide receptors in human neutrophils display distinct membrane distribution and lateral mobility when labeled with agonist and antagonist. J Cell Biol. 1993 Jun;121(6):1281–1289. [PMC free article] [PubMed]
  • Kameyama K, Haga K, Haga T, Kontani K, Katada T, Fukada Y. Activation by G protein beta gamma subunits of beta-adrenergic and muscarinic receptor kinase. J Biol Chem. 1993 Apr 15;268(11):7753–7758. [PubMed]
  • Katada T, Bokoch GM, Smigel MD, Ui M, Gilman AG. The inhibitory guanine nucleotide-binding regulatory component of adenylate cyclase. Subunit dissociation and the inhibition of adenylate cyclase in S49 lymphoma cyc- and wild type membranes. J Biol Chem. 1984 Mar 25;259(6):3586–3595. [PubMed]
  • Klotz KN, Jesaitis AJ. Neutrophil chemoattractant receptors and the membrane skeleton. Bioessays. 1994 Mar;16(3):193–198. [PubMed]
  • Klotz KN, Krotec KL, Gripentrog J, Jesaitis AJ. Regulatory interaction of N-formyl peptide chemoattractant receptors with the membrane skeleton in human neutrophils. J Immunol. 1994 Jan 15;152(2):801–810. [PubMed]
  • Koch WJ, Inglese J, Stone WC, Lefkowitz RJ. The binding site for the beta gamma subunits of heterotrimeric G proteins on the beta-adrenergic receptor kinase. J Biol Chem. 1993 Apr 15;268(11):8256–8260. [PubMed]
  • Moscona-Amir E, Henis YI, Sokolovsky M. Aging of rat heart myocytes disrupts muscarinic receptor coupling that leads to inhibition of cAMP accumulation and alters the pathway of muscarinic-stimulated phosphoinositide hydrolysis. Biochemistry. 1989 Aug 22;28(17):7130–7137. [PubMed]
  • Neubig RR, Gantzos RD, Brasier RS. Agonist and antagonist binding to alpha 2-adrenergic receptors in purified membranes from human platelets. Implications of receptor-inhibitory nucleotide-binding protein stoichiometry. Mol Pharmacol. 1985 Nov;28(5):475–486. [PubMed]
  • Neubig RR, Gantzos RD, Thomsen WJ. Mechanism of agonist and antagonist binding to alpha 2 adrenergic receptors: evidence for a precoupled receptor-guanine nucleotide protein complex. Biochemistry. 1988 Apr 5;27(7):2374–2384. [PubMed]
  • Prentki M, Glennon MC, Thomas AP, Morris RL, Matschinsky FM, Corkey BE. Cell-specific patterns of oscillating free Ca2+ in carbamylcholine-stimulated insulinoma cells. J Biol Chem. 1988 Aug 15;263(23):11044–11047. [PubMed]
  • Rooney TA, Sass EJ, Thomas AP. Characterization of cytosolic calcium oscillations induced by phenylephrine and vasopressin in single fura-2-loaded hepatocytes. J Biol Chem. 1989 Oct 15;264(29):17131–17141. [PubMed]
  • Saxton MJ, Owicki JC. Concentration effects on reactions in membranes: rhodopsin and transducin. Biochim Biophys Acta. 1989 Feb 13;979(1):27–34. [PubMed]
  • Stickle D, Barber R. Evidence for the role of epinephrine binding frequency in activation of adenylate cyclase. Mol Pharmacol. 1989 Sep;36(3):437–445. [PubMed]
  • Stickle D, Barber R. The encounter coupling model for beta-adrenergic receptor/GTP-binding protein interaction in the S49 cell. Calculation of the encounter frequency. Biochem Pharmacol. 1992 May 8;43(9):2015–2028. [PubMed]
  • Taylor CW. The role of G proteins in transmembrane signalling. Biochem J. 1990 Nov 15;272(1):1–13. [PMC free article] [PubMed]
  • Thomsen WJ, Jacquez JA, Neubig RR. Inhibition of adenylate cyclase is mediated by the high affinity conformation of the alpha 2-adrenergic receptor. Mol Pharmacol. 1988 Dec;34(6):814–822. [PubMed]
  • Thomsen WJ, Neubig RR. Rapid kinetics of alpha 2-adrenergic inhibition of adenylate cyclase. Evidence for a distal rate-limiting step. Biochemistry. 1989 Oct 31;28(22):8778–8786. [PubMed]
  • Tolkovsky AM, Levitzki A. Theories and predictions of models describing sequential interactions between the receptor, the GTP regulatory unit, and the catalytic unit of hormone dependent adenylate cyclases. J Cyclic Nucleotide Res. 1981;7(3):139–150. [PubMed]

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