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The Journal of Neuroscience, September 15, 2004, 24(37):8135-8140; doi:10.1523/JNEUROSCI.2587-04.2004

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Neuronal Toxicity in Caenorhabditis elegans from an Editing Site Mutant in Glutamate Receptor Channels

Rachel Aronoff,¹ Jerry E. Mellem,² Andres Villu Maricq,² Rolf Sprengel,¹ and Peter H. Seeburg¹

¹Max Planck Institute for Medical Research, 69120 Heidelberg, Germany, and ²University of Utah, Salt Lake City, Utah 84112-0840

Ionotropic glutamate receptors (iGluRs) in Caenorhabditis elegans are predicted to have high permeability for Ca²⁺ because of glutamine (Q) residues in the pore loop. This contrasts to the low Ca²⁺ permeability of similar iGluRs in principal neurons of mammals, because of an edited arginine (R) at the critical pore position in at least one channel subunit. Here, we introduced the R residue into the pore loop of a glutamate receptor subunit, GLR-2, in C. elegans. GLR-2(R) participated in channel formation, as revealed by decreased rectification of kainate-evoked currents in electrophysiological recordings when GLR-2(R) and the wild-type GLR-2(Q) were coexpressed in worms. Notably, the transgenic worms exhibited, at low penetrance, strong phenotypic impairments including uncoordination, neuronal degeneration, developmental arrest, and lethality. Penetrance of adverse phenotypes could be enhanced by transgenic expression of an optimal GLR-2(Q)/(R) ratio, implicating channel activity as the cause. In direct support, a mutation in eat-4, which prevents glutamatergic transmission, suppressed adverse phenotypes. Suppression was also achieved by mutation in calreticulin, which is necessary for maintainance of intracellular Ca²⁺ stores in the endoplasmic reticulum. Thus, synaptically activated GLR-2(R)-containing iGluR channels appear to trigger inappropriate, neurotoxic Ca²⁺ release from intracellular stores.

Key words: glutamatergic synaptic transmission; necrotic-like cell death; transgenic expression; iGluR; intracellular calcium; phenotypic rescue

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Received March 11, 2004; accepted July 13, 2004.

This article has been cited by other articles:

				A. Schmid, G. Qin, C. Wichmann, R. J. Kittel, S. Mertel, W. Fouquet, M. Schmidt, M. Heckmann, and S. J. Sigrist Non-NMDA-Type Glutamate Receptors Are Essential for Maturation But Not for Initial Assembly of Synapses at Drosophila Neuromuscular Junctions. J. Neurosci., November 1, 2006; 26(44): 11267 - 11277. [Abstract] [Full Text] [PDF]

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