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GRLD-1 regulates cell-wide abundance of glutamate receptor through post-transcriptional regulation

Nature Neuroscience volume 13, pages 1489–1495 (2010)Cite this article

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Abstract

AMPA receptors mediate most of the fast postsynaptic response at glutamatergic synapses. The abundance of AMPA receptors in neurons and at postsynaptic membranes is tightly regulated. It has been suggested that changes in synaptic AMPA receptor levels are an important regulatory event in synaptic plasticity and learning and memory. Although the local, synapse-specific regulation of AMPA receptors has been intensely studied, global, cell-wide control is less well understood. Using a forward genetic approach, we identified glutamate receptor level decreased-1 (GRLD-1), a putative RNA-binding protein that was required for efficient production of GLR-1 in the AVE interneurons in the nematode Caenorhabditis elegans. In grld-1 mutants, GLR-1 levels were markedly reduced. Consistently, glutamate-induced currents in AVE were diminished and glr-1–dependent nose-touch avoidance behavior was defective in grld-1 mutants. We propose that this evolutionarily conserved family of proteins controls the abundance of GLR-1 by regulating glr-1 transcript splicing.

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Figure 1: grld-1(wy225) mutants have decreased levels of GLR-1 in AVE.
Figure 2: grld-1 mutants are nose-touch defective and exhibit decreased glutamate-gated currents.
Figure 3: GRLD-1 is a member of the SPEN family.
Figure 4: GRLD-1 acts cell autonomously in AVE.
Figure 5: The GRLD-1 RRMs are sufficient to rescue GLR-1 levels in AVE.
Figure 6: Expression of glr-1 cDNA bypasses the requirement for grld-1.
Figure 7: Expression of grld-1 after initial development can rescue GLR-1 levels.

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Acknowledgements

We thank the International Caenorhabditis Genetic Center for worm strains and the Antebi, Bargmann, Kaplan and Sengupta laboratories for strains and constructs. We also thank Q. Hu, C. Gao, F. Chen and Y. Fu for assistance and members of the Shen laboratory for comments on the manuscript. This work was supported by grants from the Human Frontier Science Foundation, the W.M. Keck Foundation and the Howard Hughes Medical Institute to K.S., the Pew Scholar Award and the US National Institutes of Health to X.Z.S.X. and the National Science Foundation Graduate Research Fellowship Program and the Burt and Deedee McMurtry Stanford Graduate Fellowship to G.J.W.

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  1. Department of Biology, Howard Hughes Medical Institute, Stanford University, California, USA

    George J Wang, Julie E Kim, Géraldine S Maro & Kang Shen

  2. Life Sciences Institute and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA

    Lijun Kang & X Z Shawn Xu

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Contributions

G.J.W. performed most of the experiments. X.Z.S.X. supervised L.K., who carried out the electrophysiological experiments. J.E.K. contributed to the initial screen and transgene development. G.S.M. contributed to the intron experiments. K.S., G.J.W. and G.S.M. analyzed the data and wrote the manuscript.

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Correspondence to Kang Shen.

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Wang, G., Kang, L., Kim, J. et al. GRLD-1 regulates cell-wide abundance of glutamate receptor through post-transcriptional regulation. Nat Neurosci 13, 1489–1495 (2010). https://doi.org/10.1038/nn.2667

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