Skip to main content
SpringerLink
Log in

Receptor Oligomerization as a Process Modulating Cellular Semiotics

  • Original Paper
  • Published:
Biosemiotics Aims and scope Submit manuscript

Abstract

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.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • 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.

    CAS  Google Scholar 

  • Auletta, G. (2005). Quantum information as a general paradigm. Foundations of Physics, 35, 787–815.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Barbieri, M. (2008). Biosemiotics: a new understanding of life. Die Naturwissenschaften, 95, 577–599.

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Bateson, G. (1972). Steps to ecology of mind. San Francisco: Chandler.

    Google Scholar 

  • Bertschinger, N., Olbrich, E., Ay, N., & Jost, J. (2008). Autonomy: an information theoretic perspective. Biosystems, 91, 331–345.

    Article  PubMed  Google Scholar 

  • Bockaert, J., & Pin, J. P. (1999). Molecular tinkering of G protein-coupled receptors: an evolutionary success. The EMBO Journal, 18, 1723–1729.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Bruni, L. E. (2007). Cellular semiotics and signal transduction. In M. Barbieri (Ed.), Introduction to biosemiotics. The new biological synthesis. Berlin: Springer.

    Google Scholar 

  • Bruni, L. E. (2008a). Semiotic freedom: emergence and teleology in biological and cognitive interfaces. American Journal of Semiotics, 24, 57–73.

    Google Scholar 

  • Bruni, L. E. (2008b). Hierarchical categorical perception in sensing and cognitive processes. Biosemiotics, 1, 113–130.

    Article  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Buss, L. (1987). The evolution of individuality. New Jersey: Princeton University Press.

    Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Collier, J. D., & Hooker, C. A. (1999). Complexly organised dynamical systems. Open Systems and Information Dynamics, 6, 241–302.

    Article  Google Scholar 

  • Conner, J. K., & Hartl, D. L. (2004). Bringing together population and quantitative genetics. A primer of ecological genetics. Massachusetts: Sinauer.

    Google Scholar 

  • Crombach, A., & Hogeweg, P. (2008). Evolution of evolvability in gene regulatory networks. PLoS Computational Biology, 4, e1000112.

    Article  PubMed  Google Scholar 

  • DeLisi, C. (1981). The magnitude of signal amplification by ligand-induced receptor clustering. Nature, 289, 322–323.

    Article  CAS  PubMed  Google Scholar 

  • Devi, L. A. (2001). Heterodimerization of G-protein-coupled receptors: pharmacology, signaling and trafficking. Trends in Pharmacological Sciences, 22, 532–537.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • El-Hani, C. N., Queiroz, J., & Emmeche, C. (2006). A semiotic analysis of the genetic information system. Semiotica, 160, 1–68.

    Article  Google Scholar 

  • Gether, U. (2000). Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocrine Reviews, 21, 90–113.

    Article  CAS  PubMed  Google Scholar 

  • Gribble, S. D. (2001). Robustness in Complex Systems. 8th Workshop on Hot Topics in Operating Systems (HotOS-VIII), pp. 21–26.

  • Guo, C., & Levine, H. (1999). A thermodynamic model for receptor clustering. Biophysical Journal, 77, 2358–2365.

    Article  CAS  PubMed  Google Scholar 

  • Gurevich, V. V., & Gurevich, E. V. (2008). GPCR monomers and oligomers: it takes all kinds. Trends in Neurosciences, 31, 74–81.

    Article  CAS  PubMed  Google Scholar 

  • Hughes, K., Saarikettu, J., & Grundström, T. (2002). Gene expression in transfected cells. Methods in Molecular Biology, 173, 355–363.

    CAS  PubMed  Google Scholar 

  • Jablonka, E. (2002). Information: its interpretation, its inheritance, and its sharing. Philosophy in Science, 69, 578–605.

    Article  Google Scholar 

  • Jordan, B. A., & Devi, L. A. (1999). G-protein-coupled receptor heterodimerization modulates receptor function. Nature, 399, 697–700.

    Article  CAS  PubMed  Google Scholar 

  • Kauffman, S., & Clayton, P. (2006). On emergence, agency, and organization. Biology and Philosophy, 21, 501–521.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Maggio, R., Innamorati, G., & Parenti, M. (2007). G protein-coupled receptor oligomerization provides the framework for signal discrimination. Journal of Neurochemistry, 103, 1741–1752.

    Article  CAS  PubMed  Google Scholar 

  • Mayr, E. (1961). Cause and effect in biology. Science, 134, 1501–1506.

    Article  CAS  PubMed  Google Scholar 

  • Michod, R. E., & Nedelcu, A. M. (2003). On the reorganization of fitness during evolutionary transitions in individuality. Integrative and Comparative Biology, 43, 64–73.

    Article  Google Scholar 

  • Morange, M. (1998). A history of molecular biology (pp. 1–336). New Delhi: Oxford University Press.

    Google Scholar 

  • 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.

  • Nijhout, H. F. (2002). The nature of robustness in development. BioEssays, 24, 553–563.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Okasha, S. (2005). Multilevel selection and the major transition in evolution. Philosophy in Science, 72, 1013–1025.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Pattee, H. H. (2008). Physical and functional conditions for symbols, codes, and languages. Biosemiotics, 1, 147–168.

    Article  Google Scholar 

  • Rang, H. P. (2006). The receptor concept: pharmacology’s big idea. British Journal of Pharmacology, 147, S9–S16.

    Article  CAS  PubMed  Google Scholar 

  • Riofrio, W. (2008). Understanding the emergence of cellular organization. Biosemiotics, 1, 361–377.

    Article  Google Scholar 

  • Ruiz-Mirazo, K., & Mavelli, F. (2008). On the way towards ‘basic autonomous agents': stochastic simulations of minimal lipid-peptide cells. Biosystems, 91, 374–387.

    Article  CAS  PubMed  Google Scholar 

  • Sarkar, S. (2008). A note on frequency dependence and the levels/units of selection. Biology and Philosophy, 23, 217–228.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Shapiro, L. A. (2004). The mind incarnate. Cambridge: MIT Press.

    Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Wagner, A. (1999). Redundant gene functions and natural selection. Journal of Evolutionary Biology, 12, 1–16.

    Article  Google Scholar 

  • Wagner, A. (2005). Robustness, evolvability, and neutrality. FEBS Letters, 579, 1772–1778.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Zaccolo, M., & Pozzan, T. (2002). Discrete microdomains with high concentration of camp in stimulated rat neonatal cardiac myocytes. Science, 295, 1711–1715.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuroscience, University of Pisa, Pisa, Italy

    Franco Giorgi

  2. Department of Media Technology and Engineering Science, Aalborg University, Aalborg, Denmark

    Luis Emilio Bruni

  3. Department of Experimental Medicine, University of L’aquila, L’aquila, Italy

    Roberto Maggio

Authors
  1. Franco Giorgi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luis Emilio Bruni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roberto Maggio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Franco Giorgi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Giorgi, F., Bruni, L.E. & Maggio, R. Receptor Oligomerization as a Process Modulating Cellular Semiotics. Biosemiotics 3, 157–176 (2010). https://doi.org/10.1007/s12304-010-9085-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12304-010-9085-x

Keywords

Search

Navigation