, Volume 3, Issue 2, pp 157–176 | Cite as

Receptor Oligomerization as a Process Modulating Cellular Semiotics

  • Franco GiorgiEmail author
  • Luis Emilio Bruni
  • Roberto Maggio
Original Paper


The majority of G protein-coupled receptors (GPCRs) self-assemble in the form dimeric/oligomeric complexes along the plasma membrane. Due to the molecular interactions they participate, GPCRs can potentially provide the framework for discriminating a wide variety of intercellular signals, as based on some kind of combinatorial receptor codes. GPCRs can in fact transduce signals from the external milieu by modifying the activity of such intracellular proteins as adenylyl cyclases, phospholipases and ion channels via interactions with specific G-proteins. However, in spite of the number of cell functions they can actually control, both GPCRs and their associated signal transduction pathways are extremely well conserved, for only a few alleles with null or minor functional alterations have so far been found. This would seem to suggest that, beside a mechanism for DNA repairing, there must be another level of quality control that may help maintaining GPCRs rather stable throughout evolution. We propose here receptor oligomerization to be a basic molecular mechanism controlling GPCRs redundancy in many different cell types, and the plasma membrane as the first hierarchical cell structure at which selective categorical sensing may occur. Categorical sensing can be seen as the cellular capacity for identifying and ordering complex patterns of mixed signals out of a contextual matrix, i.e., the recognition of meaningful patterns out of ubiquitous signals. In this context, redundancy and degeneracy may appear as the required feature to integrate the cell system into functional units of progressively higher hierarchical levels.


Triadic causality Autocrine signalling Receptor evolvability and robustness 


  1. Aparicio, S. A., & Powell, J. (2004). Genetic approaches to unravelling G protein-coupled receptor biology. Current Opinion in Drug Discovery and Development, 7, 658–664.Google Scholar
  2. Auletta, G. (2005). Quantum information as a general paradigm. Foundations of Physics, 35, 787–815.CrossRefGoogle Scholar
  3. Baratti-Elbaz, C., Ghinea, N., Lahuna, O., Loosfelt, H., Pichon, C., & Milgrom, E. (1999). Internalization and recycling pathways of the thyrotropin receptor. Molecular Endocrinology, 13, 1751–1765.CrossRefPubMedGoogle Scholar
  4. Barbieri, M. (2008). Biosemiotics: a new understanding of life. Die Naturwissenschaften, 95, 577–599.CrossRefPubMedGoogle Scholar
  5. Barriere, H., & Lukacs, G. L. (2008). Analysis of endocytic trafficking by single cell fluorescence ratio imaging. Current Protocols in Cell Biology, 40, 1–21.Google Scholar
  6. Bateson, G. (1972). Steps to ecology of mind. San Francisco: Chandler.Google Scholar
  7. Bertschinger, N., Olbrich, E., Ay, N., & Jost, J. (2008). Autonomy: an information theoretic perspective. Biosystems, 91, 331–345.CrossRefPubMedGoogle Scholar
  8. Bockaert, J., & Pin, J. P. (1999). Molecular tinkering of G protein-coupled receptors: an evolutionary success. The EMBO Journal, 18, 1723–1729.CrossRefPubMedGoogle Scholar
  9. Brinkerhoff, C. J., Choi, J. S., & Linderman, J. J. (2008). Diffusion-limited reactions in G-protein activation: unexpected consequences of antagonist and agonist competition. Journal of Theoretical Biology, 251, 561–569.CrossRefPubMedGoogle Scholar
  10. Bruni, L. E. (2007). Cellular semiotics and signal transduction. In M. Barbieri (Ed.), Introduction to biosemiotics. The new biological synthesis. Berlin: Springer.Google Scholar
  11. Bruni, L. E. (2008a). Semiotic freedom: emergence and teleology in biological and cognitive interfaces. American Journal of Semiotics, 24, 57–73.Google Scholar
  12. Bruni, L. E. (2008b). Hierarchical categorical perception in sensing and cognitive processes. Biosemiotics, 1, 113–130.CrossRefGoogle Scholar
  13. Bruni, L. E. (2008c). Bateson’s relevance to current molecular biology. In J. Hoffmeyer (Ed.), A legacy for living systems: Gregory Bateson as precursor to biosemiotics. Series: Biosemiotics, Vol. 2. Berlin: Springer.Google Scholar
  14. Buchler, N. E., Gerland, U., & Hwa, T. (2003). On schemes of combinatorial transcription logic. Proceedings of the National Academy of Sciences of the United States of America, 100, 5136–5141.CrossRefPubMedGoogle Scholar
  15. Bundschuh, R., Hayot, F., & Jayaprakash, C. (2003). The role of dimerization in noise reduction of simple genetic networks. Journal of Theoretical Biology, 220, 261–269.CrossRefPubMedGoogle Scholar
  16. Buss, L. (1987). The evolution of individuality. New Jersey: Princeton University Press.Google Scholar
  17. Carlson, J. M., & Doyle, J. (2002). Complexity and robustness. Proceedings of the National Academy of Sciences of the United States of America, 99(Suppl. 1), 2538–2545.CrossRefPubMedGoogle Scholar
  18. Chazenbalk, G. D., Pichurin, P., Chen, C. R., Latrofa, F., Johnstone, A. P., McLachlan, S. M., et al. (2002). Thyroid-stimulating autoantibodies in Graves disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor. Journal of Clinical Investigation, 110, 209–217.PubMedGoogle Scholar
  19. Collier, J. D., & Hooker, C. A. (1999). Complexly organised dynamical systems. Open Systems and Information Dynamics, 6, 241–302.CrossRefGoogle Scholar
  20. Conner, J. K., & Hartl, D. L. (2004). Bringing together population and quantitative genetics. A primer of ecological genetics. Massachusetts: Sinauer.Google Scholar
  21. Crombach, A., & Hogeweg, P. (2008). Evolution of evolvability in gene regulatory networks. PLoS Computational Biology, 4, e1000112.CrossRefPubMedGoogle Scholar
  22. DeLisi, C. (1981). The magnitude of signal amplification by ligand-induced receptor clustering. Nature, 289, 322–323.CrossRefPubMedGoogle Scholar
  23. Devi, L. A. (2001). Heterodimerization of G-protein-coupled receptors: pharmacology, signaling and trafficking. Trends in Pharmacological Sciences, 22, 532–537.CrossRefPubMedGoogle Scholar
  24. DeWitt, A., Iida, T., Lam, H. Y., Hill, V., Wiley, H. S., & Lauffenburger, D. A. (2002). Affinity regulates spatial range of EGF receptor autocrine ligand binding. Developmental Biology, 250, 305–316.PubMedGoogle Scholar
  25. Drummond, D. A., Bloom, J. D., Adami, C., Wilke, C. O., & Arnold, F. H. (2005). Why highly expressed proteins evolve slowly. Proceedings of the National Academy of Sciences of the United States of America, 102, 14338–14343.CrossRefPubMedGoogle Scholar
  26. Edwards, S. W., Tan, C. M., & Limbird, L. E. (2000). Localization of G-protein-coupled receptors in health and disease. Trends in Pharmacological Sciences, 21, 304–308.CrossRefPubMedGoogle Scholar
  27. El-Hani, C. N., Queiroz, J., & Emmeche, C. (2006). A semiotic analysis of the genetic information system. Semiotica, 160, 1–68.CrossRefGoogle Scholar
  28. Gether, U. (2000). Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocrine Reviews, 21, 90–113.CrossRefPubMedGoogle Scholar
  29. Gribble, S. D. (2001). Robustness in Complex Systems. 8th Workshop on Hot Topics in Operating Systems (HotOS-VIII), pp. 21–26.Google Scholar
  30. Guo, C., & Levine, H. (1999). A thermodynamic model for receptor clustering. Biophysical Journal, 77, 2358–2365.CrossRefPubMedGoogle Scholar
  31. Gurevich, V. V., & Gurevich, E. V. (2008). GPCR monomers and oligomers: it takes all kinds. Trends in Neurosciences, 31, 74–81.CrossRefPubMedGoogle Scholar
  32. Hughes, K., Saarikettu, J., & Grundström, T. (2002). Gene expression in transfected cells. Methods in Molecular Biology, 173, 355–363.PubMedGoogle Scholar
  33. Jablonka, E. (2002). Information: its interpretation, its inheritance, and its sharing. Philosophy in Science, 69, 578–605.CrossRefGoogle Scholar
  34. Jordan, B. A., & Devi, L. A. (1999). G-protein-coupled receptor heterodimerization modulates receptor function. Nature, 399, 697–700.CrossRefPubMedGoogle Scholar
  35. Kauffman, S., & Clayton, P. (2006). On emergence, agency, and organization. Biology and Philosophy, 21, 501–521.CrossRefGoogle Scholar
  36. Lauffenburger, D. A., Oehrtman, G. T., Walker, L., & Wiley, H. S. (1998). Real-time quantitative measurement of autocrine ligand binding indicates that autocrine loops are spatially localized. Proceedings of the National Academy of Sciences of the United States of America, 95, 15368–15373.CrossRefPubMedGoogle Scholar
  37. Luporini, P., Miceli, C., Ortenzi, C., & Vallesi, A. (1992). Developmental analysis of the cell recognition mechanism in the ciliate Euplotes raikovi. Developmental Genetics, 13, 9–15.CrossRefPubMedGoogle Scholar
  38. Maggio, R., Innamorati, G., & Parenti, M. (2007). G protein-coupled receptor oligomerization provides the framework for signal discrimination. Journal of Neurochemistry, 103, 1741–1752.CrossRefPubMedGoogle Scholar
  39. Mayr, E. (1961). Cause and effect in biology. Science, 134, 1501–1506.CrossRefPubMedGoogle Scholar
  40. Michod, R. E., & Nedelcu, A. M. (2003). On the reorganization of fitness during evolutionary transitions in individuality. Integrative and Comparative Biology, 43, 64–73.CrossRefGoogle Scholar
  41. Morange, M. (1998). A history of molecular biology (pp. 1–336). New Delhi: Oxford University Press.Google Scholar
  42. Muller, G. B., & Newman, S. A. (2003). Origination of organismal form: beyond the gene in developmental and evolutionary biology (Vienna Series in Theoretical Biology). MIT Press.Google Scholar
  43. Nijhout, H. F. (2002). The nature of robustness in development. BioEssays, 24, 553–563.CrossRefPubMedGoogle Scholar
  44. Nooren, I. M. A., & Thornton, J. M. (2003). Structural characterisation and functional significance of transient protein–protein interactions. Journal of Molecular Biology, 325, 991–1018.CrossRefPubMedGoogle Scholar
  45. Okasha, S. (2005). Multilevel selection and the major transition in evolution. Philosophy in Science, 72, 1013–1025.CrossRefGoogle Scholar
  46. Parnot, C., Miserey-Lenkei, S., Bardin, S., Corvol, P., & Clauser, E. (2002). Lessons from constitutively active mutants of G protein-coupled receptors. Trends in Endocrinology and Metabolism, 13, 336–343.CrossRefPubMedGoogle Scholar
  47. Pattee, H. H. (2008). Physical and functional conditions for symbols, codes, and languages. Biosemiotics, 1, 147–168.CrossRefGoogle Scholar
  48. Rang, H. P. (2006). The receptor concept: pharmacology’s big idea. British Journal of Pharmacology, 147, S9–S16.CrossRefPubMedGoogle Scholar
  49. Riofrio, W. (2008). Understanding the emergence of cellular organization. Biosemiotics, 1, 361–377.CrossRefGoogle Scholar
  50. Ruiz-Mirazo, K., & Mavelli, F. (2008). On the way towards ‘basic autonomous agents': stochastic simulations of minimal lipid-peptide cells. Biosystems, 91, 374–387.CrossRefPubMedGoogle Scholar
  51. Sarkar, S. (2008). A note on frequency dependence and the levels/units of selection. Biology and Philosophy, 23, 217–228.CrossRefGoogle Scholar
  52. Seifert, R., & Wenzel-Seifert, K. (2002). Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch. Pharmacol., 366, 381–416.CrossRefPubMedGoogle Scholar
  53. Shapiro, L. A. (2004). The mind incarnate. Cambridge: MIT Press.Google Scholar
  54. Shvartsman, S. Y., Wiley, H. S., Deen, W. M., & Lauffenburger, D. A. (2001). Spatial range of autocrine signaling: modeling and computational analysis. Biophysical Journal, 81, 1854–1867.CrossRefPubMedGoogle Scholar
  55. Singh, S. P., McDonald, D., Hope, T. J., & Prabhakar, B. S. (2004). Upon thyrotropin binding the thyrotropin receptor is internalized and localized to endosome. Endocrinology, 145, 1003–1010.CrossRefPubMedGoogle Scholar
  56. Taverna, D. M., & Goldstein, R. M. (2000). The evolution of duplicated genes considering protein stability constraints. Pacific Symposium on Biocomputing, 5, 66–77.Google Scholar
  57. Vallesi, A., Giuli, G., Bradshaw, R. A., & Leporini, P. (1995). Autocrine mitogenic activity of pheromones produced by the protozoan ciliate Euplotes raikovi. Nature, 376, 522–524.CrossRefPubMedGoogle Scholar
  58. Vallesi, A., Ballarini, P., Di Pretoro, B., Alimenti, C., Miceli, C., & Luporini, P. (2005). Autocrine, mitogenic pheromone receptor loop of the ciliate Euplotes raikovi: pheromone-induced receptor internalization. Eukaryotic Cell, 4, 1221–1227.CrossRefPubMedGoogle Scholar
  59. Wagner, A. (1999). Redundant gene functions and natural selection. Journal of Evolutionary Biology, 12, 1–16.CrossRefGoogle Scholar
  60. Wagner, A. (2005). Robustness, evolvability, and neutrality. FEBS Letters, 579, 1772–1778.CrossRefPubMedGoogle Scholar
  61. Whorton, M. R., Bokoch, M. P., Rasmussen, S. G., Huang, B., Zare, R. N., Kobilka, B., et al. (2007). A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein. Proceedings of the National Academy of Sciences of the United States of America, 104, 7682–7687.CrossRefPubMedGoogle Scholar
  62. Wilbanks, A. M., Laporte, S. A., Bohn, L. M., Barak, L. S., & Caron, M. G. (2002). Apparent loss-of-function mutant GPCRs revealed as constitutively desensitized receptors. Biochemistry, 41, 11981–11989.CrossRefPubMedGoogle Scholar
  63. Zaccolo, M., & Pozzan, T. (2002). Discrete microdomains with high concentration of camp in stimulated rat neonatal cardiac myocytes. Science, 295, 1711–1715.CrossRefPubMedGoogle Scholar
  64. Zaccolo, M., Di Benedetto, G., Lissandron, V., Mancuso, L., Terrin, A., & Zamparo, I. (2006). Restricted diffusion of a freely diffusible second messenger: mechanisms underlying compartmentalized cAMP signalling. Biochemical Society Transactions, 34, 495–497.CrossRefPubMedGoogle Scholar
  65. Zhang, Y., Devries, M. E., & Skolnick, J. (2006). Structure modeling of all identified G protein-coupled receptors in the human genome. PLoS Computational Biology, 2, e13.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Franco Giorgi
    • 1
    Email author
  • Luis Emilio Bruni
    • 2
  • Roberto Maggio
    • 3
  1. 1.Department of NeuroscienceUniversity of PisaPisaItaly
  2. 2.Department of Media Technology and Engineering ScienceAalborg UniversityAalborgDenmark
  3. 3.Department of Experimental MedicineUniversity of L’aquilaL’aquilaItaly

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