Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Recruitment of functional GABAA receptors to postsynaptic domains by insulin


Modification of synaptic strength in the mammalian central nervous system (CNS) occurs at both pre- and postsynaptic sites1,2. However, because postsynaptic receptors are likely to be saturated by released transmitter, an increase in the number of active postsynaptic receptors may be a more efficient way of strengthening synaptic efficacy3,4,5,6,7. But there has been no evidence for a rapid recruitment of neurotransmitter receptors to the postsynaptic membrane in the CNS. Here we report that insulin causes the type A γ-aminobutyric acid (GABAA) receptor, the principal receptor that mediates synaptic inhibition in the CNS8, to translocate rapidly from the intracellular compartment to the plasma membrane in transfected HEK 293 cells, and that this relocation requires the β2 subunit of the GABAA receptor. In CNS neurons, insulin increases the expression of GABAA receptors on the postsynaptic and dendritic membranes. We found that insulin increases the number of functional postsynaptic GABAA receptors, thereby increasing the amplitude of the GABAA-receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) without altering their time course. These results provide evidence for a rapid recruitment of functional receptors to the postsynaptic plasma membrane, suggesting a fundamental mechanism for the generation of synaptic plasticity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Insulin induces a rapid translocation of GABAA receptors from intracellular compartments to the plasma membrane and potentiates.
Figure 2: The β-subunit is required for insulin-mediated translocation of recombinant GABAA receptors transiently expressed in HEK 293 cells.
Figure 3: Insulin causes membrane translocation and clustering of native GABAA receptors in CNS neurons.
Figure 4: Potentiation of GABAA receptor-mediated current responses by insulin in cultured hippocampal neurons.

Similar content being viewed by others


  1. Jessell, T. M. & Kandel, E. R. Synaptic transmission: A bidirectional and self-modifiable form of cell–cell communication. Neuron 10 (suppl.), 1–10 (1993).

    Google Scholar 

  2. Bliss, T. V. P. & Collingridge, G. L. Asynaptic model of memory: Long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    Article  ADS  CAS  Google Scholar 

  3. Busch, C. & Sakmann, B. Synaptic transmission in hippocampal neurons: numerical reconstruction of quantal IPSCs. Cold Spring Harb. Quant. Biol. 55, 69–80 (1990).

    Article  CAS  Google Scholar 

  4. Redman, S. Quantal analysis of synaptic potentials in neurons of the central nervous system. Physiol. Rev. 70, 165–198 (1990).

    Article  CAS  Google Scholar 

  5. Tong, G. & Jahr, C. E. Multivesicular release from excitatory synapses of cultured hippocampal neurons. Neuron 12, 51–59 (1994).

    Article  CAS  Google Scholar 

  6. Edwards, F. A. Anatomy and electrophysiology of fast central synapses lead to a structural model for long-term potentiation. Physiol. Rev. 75, 759–787 (1995).

    Article  CAS  Google Scholar 

  7. Mody, I., Koninck, Y., Otis, T. S. & Soltesz, I. Bridging the cleft at GABA synapses in the brain. Trends Neurosci. 17, 517–525 (1994).

    Article  CAS  Google Scholar 

  8. Macdonald, R. L. & Olsen, R. W. GABAAreceptor channels. Annu. Rev. Neurosci. 17, 569–602 (1994).

    Article  CAS  Google Scholar 

  9. Hamilton, B. J. et al. Stable expression of cloned rat GABAAreceptor subunits in a human kidney cell line. Neurosci. Lett. 153, 206–209 (1993).

    Article  CAS  Google Scholar 

  10. McKernan, R. M. & Whiting, P. J. Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci. 19, 139–143 (1996).

    Article  CAS  Google Scholar 

  11. O'Dell, T. J., Kandel, E. R. & Grant, S. G. Long-term potentiation in the hippocampus is blocked by tyrosine kinase inhibitors. Nature 353, 558–560 (1991).

    Article  ADS  CAS  Google Scholar 

  12. Wang, Y. T. & Salter, M. W. Regulation of NMDA receptors by protein-tyrosine kinases and phosphatases. Nature 369, 233–235 (1994).

    Article  ADS  CAS  Google Scholar 

  13. Wozniak, M., Rydzewski, B., Baker, S. P. & Raizada, M. K. The cellular and physiological actions of insulin in the central nervous system. Neurochem. Int. 22, 1–10 (1993).

    Article  CAS  Google Scholar 

  14. Benson, D. L. & Cohen, P. A. Activity-independent segregation of excitatory and inhibitory synaptic terminals in cultured hippocampal neurons. J. Neurosci. 16, 6424–6432 (1996).

    Article  CAS  Google Scholar 

  15. Nusser, Z., Roberts, J. D., Baude, A., Richards, J. G. & Somogyi, P. Relative densities of synaptic and extrasynaptic GABAAreceptors on cerebellar granule cells as determined by a quantitative immunogold method. J. Neurosci. 15, 2948–2960 (1995).

    Article  CAS  Google Scholar 

  16. Thompson, S. M., Copogna, M. & Scanziani, M. Presynaptic inhibition in the hippocampus. Trends Neurosci. 16, 222–227 (1993).

    Article  CAS  Google Scholar 

  17. Cohen, G. A., Doze, V. A. & Madison, D. V. Opioid inhibition of GABA release from presynaptic terminals of rat hippocampal interneurons. Neuron 9, 325–335 (1992).

    Article  CAS  Google Scholar 

  18. Liao, D., Hessler, N. A. & Malinow, R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature 375, 400–404 (1995).

    Article  ADS  CAS  Google Scholar 

  19. Kamatchi, G. L., Bhakthavatsalam, P., Chandra, D. & Bapna, J. S. Inhibition of insulin hyperphagia by gamma aminobutyric acid antagonists in rats. Life Sci. 34, 2297–2301 (1984).

    Article  CAS  Google Scholar 

  20. Garry, D. J., Sorenson, R. L., Elde, R. P., Maley, B. E. & Madsen, A. Immunohistochemical colocalization of GABA and insulin in beta-cells of rat islet. Diabetes 35, 1090–1095 (1986).

    Article  CAS  Google Scholar 

  21. Rorsman, P. et al. Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels. Nature 341, 233–236 (1989).

    Article  ADS  CAS  Google Scholar 

  22. Otis, T. S., De Koninck, Y. & Mody, I. Lasting potentiation of inhibition is associated with an increased number of gamma-aminobutyric acid type A receptors activated during miniature inhibitory postsynaptic currents. Proc. Natl Acad. Sci. USA 91, 7698–7702 (1994).

    Article  ADS  CAS  Google Scholar 

  23. Kullmann, D. M. Amplitude fluctuations of dual-component EPSCs in hippocampal pyramidal cells: Implications for long-term potentiation. Neuron 12, 1111–1120 (1994).

    Article  CAS  Google Scholar 

  24. Edwards, F. LTP is a long term problem. Nature 350, 271–272 (1991).

    Article  ADS  CAS  Google Scholar 

  25. Isaac, J. T., Nicoll, R. A. & Malenka, R. C. Evidence for silent synapses: implications for the expression of LTP. Neuron 15, 427–434 (1995).

    Article  CAS  Google Scholar 

  26. Wang, Y. T., Neuman, R. S. & Bieger, D. Nicotinic cholinoceptor-mediated excitation in ambigual motoneurones of the rat. Neuroscience 40, 759–767 (1991).

    Article  CAS  Google Scholar 

  27. Ewert, M., Shivers, B. D., Luddens, H., Mohler, H. & Seeburg, P. H. Subunit selectivity and epitope characterization of mAbs directed against the GABAA/benzodiazepine receptor. J. Cell Biol. 110, 2043–2048 (1990).

    Article  CAS  Google Scholar 

  28. Ueno, S., Zorumski, C., Bracamontes, J. & Steinbach, J. H. Endogenous subunits can cause ambiguities in the pharmacology of exogenous gamma-aminobutyric acid A receptors expressed in human embryonic kidney 293 cells. Mol. Pharmacol. 50, 931–938 (1996).

    CAS  PubMed  Google Scholar 

  29. MacDonald, J. F., Mody, I. & Salter, M. W. Regulation of N-methyl-D-aspartate receptors revealed by intracellular dialysis of murine neurones in culture. J. Physiol. (Lond.) 414, 17–34 (1989).

    Article  CAS  Google Scholar 

  30. Bekkers, J. M., Richerson, G. B. & Stevens, C. F. Origin of variability in quantal size in cultured hippocampal neurons and hippocampal slices. Proc. Natl Acad. Sci. USA 87, 5359–5362 (1990).

    Article  ADS  CAS  Google Scholar 

Download references


We thank M. Wojtowicz and F. Dorri for assistance with slice experiments; C. Kaufman and D. Gunnersen for GABAA receptor β2 and γ2 subunit cDNAs; J. H. Steinbach for the α1FLAGcDNA; D. Carter for the 4D4 cells; C. C. Yip for insulin; and M. W. Salter for helpful comments on the manuscript. This work was supported by the Medical Research Council of Canada and Neuroscience Network of Centers of Excellence of Canada. Y.T.W. is a research scholar of the Heart and Stroke Foundation of Canada/Ontario; Z.G.X. is a MRC-NCE fellow and W.Y.L. is a NCE fellow. H.Y.M. is supported by a studentship from the Canadian Foundation for the Study of Infant Death.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Y. T. Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wan, Q., Xiong, Z., Man, H. et al. Recruitment of functional GABAA receptors to postsynaptic domains by insulin. Nature 388, 686–690 (1997).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing