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Conserved SOL-1 proteins regulate ionotropic glutamate receptor desensitization.

ABSTRACT: The neurotransmitter glutamate mediates excitatory synaptic transmission by activating ionotropic glutamate receptors (iGluRs). In Caenorhabditis elegans, the GLR-1 receptor subunit is required for glutamate-gated current in a subset of interneurons that control avoidance behaviors. Current mediated by GLR-1-containing iGluRs depends on SOL-1, a transmembrane CUB-domain protein that immunoprecipitates with GLR-1. We have found that reconstitution of glutamate-gated current in heterologous cells depends on three proteins, STG-1 (a C. elegans stargazin-like protein), SOL-1, and GLR-1. Here, we use genetic and pharmacological perturbations along with rapid perfusion electrophysiological techniques to demonstrate that SOL-1 functions to slow the rate and limit the extent of receptor desensitization as well as to enhance the recovery from desensitization. We have also identified a SOL-1 homologue from Drosophila and show that Dro SOL1 has a conserved function in promoting C. elegans glutamate-gated currents. SOL-1 homologues may play critical roles in regulating glutamatergic neurotransmission in more complex nervous systems.

SUBMITTER: Walker CS

PROVIDER: S-EPMC1502309 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Conserved SOL-1 proteins regulate ionotropic glutamate receptor desensitization.

Walker Craig S CS Francis Michael M MM Brockie Penelope J PJ Madsen David M DM Zheng Yi Y Maricq Andres V AV

Proceedings of the National Academy of Sciences of the United States of America 20060703 28

The neurotransmitter glutamate mediates excitatory synaptic transmission by activating ionotropic glutamate receptors (iGluRs). In Caenorhabditis elegans, the GLR-1 receptor subunit is required for glutamate-gated current in a subset of interneurons that control avoidance behaviors. Current mediated by GLR-1-containing iGluRs depends on SOL-1, a transmembrane CUB-domain protein that immunoprecipitates with GLR-1. We have found that reconstitution of glutamate-gated current in heterologous cells ...[more]

PMID: 16818875

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Project description:AMPA and NMDA receptors are glutamate-gated ion channels that mediate fast excitatory synaptic transmission throughout the nervous system. In the continual presence of glutamate, AMPA and NMDA receptors containing the GluN2A or GluN2B subunit enter into a nonconducting, desensitized state that can impact synaptic responses and glutamate-mediated excitotoxicity. The process of desensitization is dramatically different between subtypes, but the basis for these differences is unknown. We generated an extensive sequence alignment of ionotropic glutamate receptors (iGluRs) from diverse animal phyla and identified a highly conserved motif, which we termed the "hydrophobic box," located at the extracellular interface of transmembrane helices. A single position in the hydrophobic box differed between mammalian AMPA and NMDA receptors. Surprisingly, we find that an NMDAR-to-AMPAR exchange mutation at this position in the rat GluN2A or GluN2B subunit had a dramatic and highly specific effect on NMDAR desensitization, making it AMPAR-like. In contrast, a reverse exchange mutation in AMPARs had minimal effects on desensitization. These experiments highlight differences in desensitization between iGluR subtypes and the highly specific contribution of the GluN2 subunit to this process.Rapid communication between cells in the nervous system depends on ion channels that are directly activated by neurotransmitter molecules. Here, we studied ionotropic glutamate receptors (iGluRs), which are ion channels activated by the neurotransmitter glutamate. By comparing the sequences of a vast number of iGluR proteins from diverse animal species, assisted by available structural information, we identified a highly conserved motif. We showed that a single amino acid difference in this motif between mammalian iGluR subtypes has dramatic effects on receptor function. These results have implications in both the evolution of synaptic function, as well as the role of iGluRs in health and disease.

Dataset Information

Conserved SOL-1 proteins regulate ionotropic glutamate receptor desensitization.

Publications

Conserved SOL-1 proteins regulate ionotropic glutamate receptor desensitization.

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