Abstract
Despite its importance in the cerebellum, the functions of the orphan glutamate receptor δ2 are unknown. We examined a mutant δ2 receptor channel in lurcher mice that was constitutively active in the absence of ligand. Because this mutation was within a highly conserved motif (YTANLAAF), we tested its effect on several glutamate receptors. Mutant δ2 receptors showed distinct channel properties, including double rectification of the current–voltage relationship, sensitivity to a polyamine antagonist and moderate Ca2+ permeability, whereas other constitutively active mutant glutamate channels resembled wild-type channels in these respects. Moreover, the kinetics of ligand-activated currents were strikingly altered. We conclude that the δ2 receptor has a functional ion channel pore similar to that of glutamate receptors. The motif may have a role in the channel gating of glutamate receptors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hollmann, M. & Heinemann, S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994).
Araki, K. et al. Selective expression of the glutamate receptor channel delta 2 subunit in cerebellar Purkinje cells. Biochem. Biophys. Res. Commun. 197, 1267–1276 ( 1993).
Lomeli, H. et al. The rat delta-1 and delta-2 subunits extend the excitatory amino acid receptor family. FEBS Lett. 315, 318 –322 (1993).
Kashiwabuchi, N. et al. Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR delta 2 mutant mice. Cell 81, 245–252 ( 1995).
Ito, M. Long-term depression. Annu. Rev. Neurosci. 12, 85– 102 (1989).
Hirano, T., Kasono, K., Araki, K., Shinozuka, K. & Mishina, M. Involvement of the glutamate receptor delta 2 subunit in the long-term depression of glutamate responsiveness in cultured rat Purkinje cells. Neurosci. Lett. 182, 172– 176 (1994).
Jeromin, A., Huganir, R. L. & Linden, D. J. Suppression of the glutamate receptor delta 2 subunit produces a specific impairment in cerebellar long-term depression. J. Neurophysiol. 76, 3578–3583 (1996).
Hirano, T., Kasono, K., Araki, K. & Mishina, M. Suppression of LTD in cultured Purkinje cells deficient in the glutamate receptor delta 2 subunit. Neuroreport 6, 524– 526 (1995).
Landsend, A. S. et al. Differential localization of delta glutamate receptors in the rat cerebellum: coexpression with AMPA receptors in parallel fiber-spine synapses and absence from climbing fiber-spine synapses. J. Neurosci. 17, 834–842 ( 1997).
Zuo, J. et al. Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene. Nature 388, 769 –773 (1997).
Seeburg, P. H., Higuchi, M. & Sprengel, R. RNA editing of brain glutamate receptor channels: mechanism and physiology. Brain Res. Rev. 26, 217– 229 (1998).
Bowie, D. & Mayer, M. L. Inward rectification of both AMPA and kainate subtype glutamate receptors generated by polyamine-mediated ion channel block. Neuron 15, 453– 462 (1995).
Koike, M., Iino, M. & Ozawa, S. Blocking effect of 1-naphthyl acetyl spermine on Ca2+-permeable AMPA receptors in cultured rat hippocampal neurons. Neurosci. Res. 29, 27–36 ( 1997).
Blaschke, M. et al. A single amino acid determines the subunit-specific spider toxin block of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor channels. Proc. Natl. Acad. Sci. USA 90, 6528–6532 (1993).
Partin, K. M., Bowie, D. & Mayer, M. L. Structural determinants of allosteric regulation in alternatively spliced AMPA receptors. Neuron 14, 833–843 (1995).
Mayer, M. L. & Westbrook, G. L. Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurones . J. Physiol. (Lond.) 394, 501– 527 (1987).
Iino, M., Ozawa, S. & Tsuzuki, K. Permeation of calcium through excitatory amino acid receptor channels in cultured rat hippocampal neurones. J. Physiol. (Lond.) 424, 151–165 ( 1990).
Burnashev, N., Monyer, H., Seeburg, P. H. & Sakmann, B. Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 8, 189– 198 (1992).
Burnashev, N., Villarroel, A. & Sakmann, B. Dimensions and ion selectivity of recombinant AMPA and kainate receptor channels and their dependence on Q/R site residues. J. Physiol. (Lond.) 496, 165–173 (1996).
Clements, J. D., Feltz, A., Sahara, Y. & Westbrook, G. L. Activation kinetics of AMPA receptor channels reveal the number of functional agonist binding sites. J. Neurosci. 18, 119– 127 (1998).
Clements, J. D. & Westbrook, G. L. Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-D-aspartate receptor. Neuron 7, 605– 613 (1991).
Johansen, T. H., Chaudhary, A. & Verdoorn, T. A. Interactions among GYKI-52466, cyclothiazide, and aniracetam at recombinant AMPA and kainate receptors. Mol. Pharmacol. 48, 946–955 ( 1995).
Yamada, K. A. & Turetsky, D. M. Allosteric interactions between cyclothiazide and AMPA/kainate receptor antagonists. Br. J. Pharmacol. 117, 1663–1672 ( 1996).
Lester, R. A. & Jahr, C. E. NMDA channel behavior depends on agonist affinity. J. Neurosci. 12, 635– 643 (1992).
Partin, K. M., Fleck, M. W. & Mayer, M. L. AMPA receptor flip/flop mutants affecting deactivation, desensitization, and modulation by cyclothiazide, aniracetam, and thiocyanate . J. Neurosci. 16, 6634– 6647 (1996).
Patneau, D. K. & Mayer, M. L. Structure-activity relationships for amino acid transmitter candidates acting at N-methyl-D-aspartate and quisqualate receptors. J. Neurosci. 10, 2385–2399 (1990).
Geiger, J. R. et al. Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS. Neuron 15, 193– 204 (1995).
Kohler, M., Burnashev, N., Sakmann, B. & Seeburg, P. H. Determinants of Ca2+ permeability in both TM1 and TM2 of high affinity kainate receptor channels: diversity by RNA editing. Neuron 10, 491–500 (1993).
Linden, D. J. & Connor, J. A. Long-term synaptic depression . Annu. Rev. Neurosci. 18, 319– 357 (1995).
Wang, Y., Small, D. L., Stanimirovic, D. B., Morley, P. & Durkin, J. P. AMPA receptor-mediated regulation of a Gi-protein in cortical neurons. Nature 389, 502–504 (1997).
Hayashi, T., Umemori, H., Mishina, M. & Yamamoto, T. The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn. Nature 397, 72–76 ( 1999).
Sprengel, R. et al. Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell 92, 279–289 (1998).
Armstrong, N., Sun, Y., Chen, G. Q. & Gouaux, E. Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 395, 913–917 ( 1998).
Stern-Bach, Y. et al. Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins . Neuron 13, 1345–1357 (1994).
Krupp, J. J., Vissel, B., Heinemann, S. F. & Westbrook, G. L. N-terminal domains in the NR2 subunit control desensitization of NMDA receptors . Neuron 20, 317–327 (1998).
Wo, Z. G. & Oswald, R. E. Unraveling the modular design of glutamate-gated ion channels. Trends Neurosci. 18 , 161–168 (1995).
Doyle, D. A. et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77 (1998).
Holmgren, M., Shin, K. S. & Yellen, G. The activation gate of a voltage-gated K+ channel can be trapped in the open state by an intersubunit metal bridge. Neuron 21, 617–621 ( 1998).
Zukin, R. S. & Bennett, M. V. Alternatively spliced isoforms of the NMDARI receptor subunit. Trends Neurosci. 18 , 306–313 (1995).
Ho, S. N., Hunt, H. D., Horton, R. M., Pullen, J. K. & Pease, L. R. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 77, 51–59 (1989).
Yuzaki, M., Forrest, D., Curran, T. & Connor, J. A. Selective activation of calcium permeability by aspartate in Purkinje cells. Science 273, 1112–1114 ( 1996).
Yuzaki, M. et al. Functional NMDA receptors are transiently active and support the survival of Purkinje cells in culture. J. Neurosci. 16, 4651–4661 (1996).
Ozawa, S. & Yuzaki, M. Patch-clamp studies of chloride channels activated by gamma-aminobutyric acid in cultured hippocampal neurones of the rat. Neurosci. Res. 1, 275– 293 (1984).
Acknowledgements
We thank J. Boulter for the δ2, NR1a and NR2A cDNAs, P. H. Seeburg for the GluR1 cDNA, R. Dingledine for the GluR6 cDNA, T. Nakajima for NASP, D. Goldwitz for lurcher mice, J. Zuo and J. Treadaway for determining the genotype of lurcher mice and J. Miyazaki for the pCAGGS vector. We also thank S. Hestrin and T. Curran for reading the manuscript. This work was supported by the NIH grant NS36925, Cancer Center Support CORE Grant CA 21765 and by the American Lebanese Syrian Associated Charities.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kohda, K., Wang, Y. & Yuzaki, M. Mutation of a glutamate receptor motif reveals its role in gating and δ2 receptor channel properties. Nat Neurosci 3, 315–322 (2000). https://doi.org/10.1038/73877
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/73877
This article is cited by
-
GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons
Molecular Psychiatry (2018)
-
Phylogenetic analysis of ionotropic L-glutamate receptor genes in the Bilateria, with special notes on Aplysia californica
BMC Evolutionary Biology (2017)
-
Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating
Scientific Reports (2017)
-
Chemical labelling for visualizing native AMPA receptors in live neurons
Nature Communications (2017)
-
Tousled-like kinase mediated a new type of cell death pathway in Drosophila
Cell Death & Differentiation (2016)