Neuronal Toxicity inCaenorhabditis elegansfrom an Editing Site Mutant in Glutamate Receptor Channels

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Abstract
Ionotropic glutamate receptors (iGluRs) inCaenorhabditis elegansare 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, inC. 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 ineat-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.