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Allosteric potentiation of glycine receptor chloride currents by glutamate

Nature Neuroscience volume 13, pages 1225–1232 (2010)Cite this article

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A Corrigendum to this article was published on 26 August 2011

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Abstract

Neuronal excitability in the CNS is primarily controlled by a balance between synaptic excitation and inhibition. In the brainstem and spinal cord, synaptic excitation and inhibition are mediated by the excitatory transmitter glutamate acting on ionotropic glutamate receptor–gated cationic channels and the inhibitory transmitter glycine acting on glycine receptor (GlyR)-gated chloride channels. We found that glutamate and its analog ligands potentiated GlyR-mediated currents in both cultured spinal neurons and spinal cord slices of rats. This potentiation was not dependent on activation of any known glutamate receptor and manifested as an increase in single-channel open probability. Moreover, this glutamate potentiation was seen in HEK293 cells that transiently expressed GlyRs. Our data strongly suggest that glutamate allosterically potentiates GlyR-gated chloride channels, thereby blurring the traditional distinction between excitatory and inhibitory transmitters. Such a rapid homeostatic regulatory mechanism may be important for tuning functional balance between synaptic excitation and inhibition in the CNS.

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Figure 1: AP5 potentiates glycinergic mIPSCs.
Figure 2: AP5 and NMDA potentiate GlyR-mediated currents via a NMDAR-independent mechanism.
Figure 3: Potentiation of GlyR-mediated currents by glutamate ligands in cultured spinal neurons.
Figure 4: AP5 increases GlyR-mediated single-channel activities in the outside-out mode.
Figure 5: AP5 increases GlyR-mediated single-channel activities in the on-attached mode.
Figure 6: Glutamate-like ligands potentiate recombinant GlyR function.
Figure 7: Glutamate potentiation of GlyR-mediated IPSCs in laminae I-II neurons in spinal cord slices.

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Change history

  • 13 April 2011

    In the version of this article initially published, the vertical scale bars in Figures 2c and 3a,c,d were labeled with incorrect units (μA). The correct units should be pA. Also, the vertical scale bar label (50 pA) was missing from Figure 7a, and the labels "burst duration" and "mean Po" in Figure 4e were reversed. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank Y.P. Li for preparation and maintenance of spinal cord neuronal cultures and L. Oschipok for his excellent editorial assistance. This work was supported by the Canadian Institutes for Health Research, the Heart and Stroke Foundation of British Columbia and Yukon, and the Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH99-TD-B-111-004). J.L. was supported by postdoctoral fellowships from National Sciences and Engineering Research Council, the Michael Smith Foundation for Health Research and the British Columbia Epilepsy Society. Y.T.W. is a Howard Hughes Medical Institute International Scholar and the holder of the Heart and Stroke Foundation of British Columbia and Yukon chair in stroke research.

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Author notes

  1. Jun Liu and Dong Chuan Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Brain Research Centre and Department of Medicine, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

    Jun Liu, Dong Chuan Wu & Yu Tian Wang

  2. Translational Medicine Research Center and Center for Neuropsychiatry and Graduate Institute for Immunology, China Medical University Hospital, Taichung, Taiwan

    Dong Chuan Wu & Yu Tian Wang

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Contributions

J.L., D.C.W. and Y.T.W. designed the experiments. J.L. performed and analyzed the experiments in cultured spinal neurons and spinal cord slices. D.C.W. performed and analyzed the experiments in HEK293 cells. J.L., D.C.W. and Y.T.W. wrote the manuscript.

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Correspondence to Yu Tian Wang.

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Liu, J., Wu, D. & Wang, Y. Allosteric potentiation of glycine receptor chloride currents by glutamate. Nat Neurosci 13, 1225–1232 (2010). https://doi.org/10.1038/nn.2633

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