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Mutation of a glutamate receptor motif reveals its role in gating and δ2 receptor channel properties

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.

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Figure 1: The mutation of δ2 receptors in lurcher mice.
Figure 2: Current–voltage (I–V) relationship of cells expressing mutant glutamate receptors.
Figure 3: Effects of antagonists and modulators on lurcher mutant receptors.
Figure 4: Ca2+ permeability of δ2Lc channels.
Figure 5: Properties of δ2Lc channels in Purkinje cells.
Figure 6: Ligand-induced currents in lurcher mutant receptors.
Figure 7: Noise analysis of glutamate-induced currents mediated by lurcher NMDA receptors.
Figure 8: Dose–response relationships of lurcher mutant receptors.

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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.

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Correspondence to Michisuke Yuzaki.

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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

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