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SOL-1 is a CUB-domain protein required for GLR-1 glutamate receptor function in C. elegans

Abstract

Ionotropic glutamate receptors (iGluRs) mediate most excitatory synaptic signalling between neurons. Binding of the neurotransmitter glutamate causes a conformational change in these receptors that gates open a transmembrane pore through which ions can pass. The gating of iGluRs is crucially dependent on a conserved amino acid that was first identified in the ‘lurcher’ ataxic mouse1. Through a screen for modifiers of iGluR function in a transgenic strain of Caenorhabditis elegans expressing a GLR-1 subunit containing the lurcher mutation, we identify suppressor of lurcher (sol-1). This gene encodes a transmembrane protein that is predicted to contain four extracellular β-barrel-forming domains known as CUB domains2,3. SOL-1 and GLR-1 are colocalized at the cell surface and can be co-immunoprecipitated. By recording from neurons expressing GLR-1, we show that SOL-1 is an accessory protein that is selectively required for glutamate-gated currents. We propose that SOL-1 participates in the gating of non-NMDA (N-methyl-d-aspartate) iGluRs, thereby providing a previously unknown mechanism of regulation for this important class of neurotransmitter receptor.

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Figure 1: Genetic screen for mutations suppressing the hyper-reversal phenotype of lurcher worms.
Figure 2: sol-1(ak63) phenocopies glr-1(ky176).
Figure 3: sol-1(ak63) does not affect GLR-1 expression, localization or membrane insertion.
Figure 4: Non-NMDA-gated currents are eliminated in both glr-1(ky176) and sol-1(ak63) mutants.
Figure 5: SOL-1 is a predicted type I transmembrane protein that interacts with GLR-1.

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Acknowledgements

We thank M. Vetter and members of the Maricq laboratory for comments on the manuscript; L. Jack for generating transgenic strains; C. Walker, N. Strutz, M. Francis and A. Ebens for discussions; C. Rongo and J. Kaplan for the nuIs25 strain; and A. Gottschalk and W. Schafer for help with immunolabelling live worms. Some strains were provided by the Caenorhabditis Genetics Center. This research was supported by the Burroughs Wellcome Foundation, and by a grant from the NIH.

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Correspondence to Andres V. Maricq.

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Supplementary information

Supplementary Figure 1: sol-1 genomic location and organization (JPG 29 kb)

41586_2004_BFnature02244_MOESM2_ESM.jpg

Supplementary Figure 2: Sequence alignment of CUB domains from various CUB domain proteins (modified from 11) and the 4 predicted CUB domains of SOL-1. (JPG 79 kb)

41586_2004_BFnature02244_MOESM3_ESM.jpg

Supplementary Figure 3: Confocal images of GFP (top), anti-GFP antibody staining (middle) and the merged images (bottom) in transgenic sol-1(ak63) worms that expressed GFP::GLR-2 (extracellular GFP) injected with Alexa 594 conjugated rabbit anti-GFP polyclonal sera. (JPG 91 kb)

Supplementary Figure Legends. (DOC 21 kb)

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Zheng, Y., Mellem, J., Brockie, P. et al. SOL-1 is a CUB-domain protein required for GLR-1 glutamate receptor function in C. elegans. Nature 427, 451–457 (2004). https://doi.org/10.1038/nature02244

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