Skip to main content
SpringerLink
Log in

3D Reconstruction of a Full-Size GABAB Receptor

  • Published:
Neurophysiology Aims and scope

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

The three-dimensional (3D) pattern of a full-size GABAB receptor has been reconstructed using computer techniques. To simulate a real microenvironment for the GABAB receptor, the latter was embedded in the lipid bilayer membrane with the corresponding salt-water environment. Since homology modeling of the GABAB receptor is among the computational methods allowing one to predict 3D coordinates when experimental data are not available, we reconstructed the structure of a full-size GABAB receptor by stepwise homology modeling of individual subunit parts. The stability of receptor subunits was evaluated by calculating the molecular dynamics. It has been found that C-terminal domains of the intracellular receptor show a tendency toward compaction, and coiled-coil areas form a structure almost identical to that specified by crystallization of these fragments. The structure obtained can be applied for further examination of the structural mechanisms of GABAB receptor interaction with GABA agonists and antagonists. It is quite evident that molecular dynamics computations might be a valuable tool in probing details of the receptor function.

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

  1. E. Roberts, “GABA: The road to neurotransmitter status,” in: Benzodiazepine/GABA Receptors and Chloride Channels: Structural and Functional Properties, R. W. Olsen and C. J. Venter (eds.), Alan R. Liss, New York (1986), pp. 1-39.

  2. J. Bormann, “Electrophysiology of GABAA and GABAB receptor subtypes,” Trends Neurosci., 11, No. 3, 112-116 (1988).

    Article  CAS  PubMed  Google Scholar 

  3. R. L. Macdonald and R. E. Twyman, “Biophysical properties and regulation of GABAA receptor channels,” Semin. Neurosci., 3, 219-230 (1991).

    Article  Google Scholar 

  4. N. G. Bowery, “GABAB receptor pharmacology,” Annu. Rev. Pharmacol. Toxicol., 33, 109-147 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. A. Couve, S. Moss, and M. Pangalos, “GABAB receptors: A new paradigm in G protein signaling,” J. Mol. Cell Neurosci., 16, No. 4, 296-312 (2000).

    Article  CAS  Google Scholar 

  6. E. Cherubini and F. Conti, “Generating diversity at GABAergic synapses,” Trends Neurosci., 24, No. 3, 155-162 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. W. M. Connelly, S. J. Fyson, A. C. Errington, et al., “GABAB receptors regulate extrasynaptic GABAA receptors,” J. Neurosci., 33, No. 9, 3780-3785 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. K. Kaupmann, K. Huggel, J. Heid, et al., “Expression cloning of GABAB receptors uncovers similarity to metabotropic glutamate receptors,” Nature, 386, 239-246 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. A. Bouron, “Modulation of spontaneous quantal release of neurotransmitters in the hippocampus,” Prog. Neurobiol., 63, No. 6, 613-635 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. J. P. Pin, J. Kniazeff, V. Binet, et al., “Activation mechanism of the heterodimeric GABA(B) receptor,” Biochem. Pharmacol., 68, No. 8, 1565-1572 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Y. Geng, D. Xiong, L. Mosyak, et al., “Structure and functional interaction of the extracellular domain of human GABA(B) receptor GBR2,” Nat. Neurosci., 15, 970-978 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Y. Geng, M. Bush, L. Mosyak, et al., “Structural mechanism of ligand activation in human GABAB receptor,” Nature, 504, 254-259 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. K. Kaupmann, B. Malitschek, V. Schuler, et al., “GABAB receptor subtypes assemble into functional heteromeric complexes,” Nature, 396, 683-687 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. K. A. Jones, B. Borowsky, J. A. Tamm, et al., “GABAB receptors function as a heteromeric assembly of the subunits GABAB1 and GABAB2,” Nature, 396, 674-679 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. J. H. White, A. Wise, M. J. Main, et al., “Heterodimerization is required for the formation of a functional GABAB receptor,” Nature, 396, 679-682 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. R. Kuner, G. Kohr, S. Grunewald, et al., “Role of heteromer formation in GABAB receptor function,” Science, 283, 74-77 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. S. C. Martin, S. J. Russek, and D. H. Farb, “Molecular identification of the human GABAB R2: cell surface expression and coupling to adenylyl cyclase in the absence of GABAB R1,” Mol. Cell Neurosci., 13, No. 3, 180-191 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. B. A. Clark and S. G. Cull-Candy, “Activitydependent recruitment of extrasynaptic NMDA receptor activation at an AMPA receptor-only synapse,” J. Neurosci., 22, No. 11, 4428-4436 (2002).

    CAS  PubMed  Google Scholar 

  19. R. Cossart, M. Esclapez, J. C. Hirsch, et al., “GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells,” Nat. Neurosci., 1, No. 6, 470-478 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. R. Cossart, J. Epsztein, R. Tyzio, et al., “Quantal release of glutamate generates pure kainate and mixed AMPA/kainate EPSCs in hippocampal neurons,” Neuron, 35, No. 1, 147-159 (2002).

  21. S. C. Martin, S. J. Russek, and D. H. Farb, “Human GABAB R genomic structure: evidence for splice variants in GABAB R1 but not GABAB R2,” Gene, 278, 63-79 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. C. H. Davies, S. J. Starkey, M. F. Pozza, and G. L. Collingridge, “GABAB autoreceptors regulate the induction of LTP,” Nature, 349, 609-611 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. D. D. Mott and D. V. Lewis, “The pharmacology and function of central GABAB receptors,” J. Int. Rev. Neurobiol., 36, 97-223 (1994).

    Article  CAS  Google Scholar 

  24. Y. Xiang, Y. Li, Z. Zhang, et al., “Nerve growth cone guidance mediated by G protein-coupled receptors,” Nat. Neurosci., 5, 843-848 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. K. M. McClellan, A. R. Calver, and S. A. Tobet, “GABAB receptors role in cell migration and positioning within the ventromedial nucleus of the hypothalamus,” Neuroscience, 151, No. 4, 1119-1131 (2008).

  26. N. G. Bowery, B. Bettler, W. Froestl, et al., “GABAB receptors: structure and function,” Pharmacol. Rev., 54, No. 2, 247-254 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. A. R. Calver, C. H. Davies, and M. Pangalos, “GABAB receptors: from monogamy to promiscuity,” Neurosignals, 11, No. 6, 299-314 (2002).

  28. B. Bettler, K. Kaupmann, J. Mosbacher, and M. Gassmann, “Molecular structure and physiological functions of GABA(B) receptors,” Physiol. Rev., 84, No. 3, 835-867 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. V. Schuler, C. Luscher, C. Blanchet, et al., “Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABAB responses in mice lacking GABAB R1,” Neuron, 31, No. 1, 47-58 (2001).

  30. C. Zhou, C. Li, H. M. Yu, et al., “Neuroprotection of gamma-aminobutyric acid receptor agonists via enhancing neuronal nitric oxide synthase (Ser847) phosphorylation through increased neuronal nitric oxide synthase and PSD95 interaction and inhibited protein phosphatase activity in cerebral ischemia,” J. Neurosci. Res., 86, No. 13, 2973-2983 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. S. Burmakina, Y. Geng, Y. Chen, and Q. R. Fan, “Heterodimeric coiled-coil interactions of human GABAB receptor,” Proc. Natl. Acad. Sci. USA, 111, No. 19, 6958-6963 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. “The UniProt Consortium. The universal protein resource (UniProt),” Nucl. Acids Res., 36, 190-195 (2008).

  33. J. Marvin, D. Padilla, V. Ravichandran, et al., “The protein data bank,” Biol. Crystallogr., 58, 899-907 (2002).

    Article  Google Scholar 

  34. H. Venselaar, E. Krieger, and G. Vriend, “Homology modeling,” in: Structural Bioinformatics, P. E. Bourne and H. Weissig (eds.), John Wiley & Sons, Hoboken NJ (2009), pp. 715-732.

    Google Scholar 

  35. J.-M. Claverie and C. Noterdame, Bioinformatics for Вummies, Wiley Publ., New York (2007).

    Google Scholar 

  36. I. W. Davis, L. W. Murray, J. S. Richardson, and D. C. Richardson, “MOLPROBITY: Structure validation and all-atom contact analysis for nucleic acids and their complexes,” Nucleic Acids Res., 32, 615-619 (2004).

    Article  Google Scholar 

  37. J. W. Ponder and D. Case, “Force fields for protein simulations,” Adv. Prot. Chem., 66, 27-85 (2003).

    Article  CAS  Google Scholar 

  38. H.-D. Holtje, W. Sippl, D. Rognan, and G. Folkers, Molecular Modeling: Basic Principles and Applications, John Wiley & Sons (Wiley-VCH), Hoboken NJ (2008).

  39. K. I. Ramachandran, G. Deepa, and K. Namboori, Computational Chemistry and Molecular Modeling: Principles and Applications, Springer-Verlag, Heidelberg, Berlin (2008).

    Google Scholar 

  40. N. Guex and M. Peitsch, “SWISS-model and the Swiss-PdbViewer: An environment for comparative protein modeling,” Electrophoresis, 18, No. 15, 2714-2723 (1997).

  41. D. Schneidman-Duhovny, Y. Inbar, R. Nussinov, and H. J. Wolfson, “PatchDock and SymmDock: Servers for rigid and symmetric docking,” Nucleid Acid Res., 33, 363-367 (2005).

    Article  Google Scholar 

  42. S. Pronk, S. Pall, R. Schulz, et al., “GROMACS 45: a high throughput and highly parallel open source molecular simulation toolkit,” Bioinformatics, 29, 845-854 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. A. D. MacKerell Jr., N. Banavali, and N. Foloppe, “Development and current status of the CHARMM force field for nucleic acids,” Biopolymers, 56, 257-265 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. A. D. Mackerell, Jr., M. Feig, and C. L. 3rd Brooks, “Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations,” J. Comput. Chem., 25, 1400-1415 (2004).

  45. W. Humphrey, A. Dalke, and K. Schulten, “VMD –visual molecular dynamics,” J. Mol. Graph., 14, No. 1, 33-38 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of High Technology, Taras Shevchenko National University, Kyiv, Ukraine

    A. Yu. Nyporko, A. M. Naumenko, O. V. Tsymbaliuk & T. L. Davidovska

  2. Jackson State University, Jackson, Mississippi, USA

    A. Golius

  3. Bogomolets Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine

    L. M. Shapoval

Authors
  1. A. Yu. Nyporko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. M. Naumenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Golius
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. O. V. Tsymbaliuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. M. Shapoval
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. L. Davidovska
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to A. M. Naumenko, A. Golius or L. M. Shapoval.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nyporko, A.Y., Naumenko, A.M., Golius, A. et al. 3D Reconstruction of a Full-Size GABAB Receptor. Neurophysiology 47, 364–375 (2015). https://doi.org/10.1007/s11062-016-9544-3

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11062-016-9544-3

Keywords

Search

Navigation