| Ligand-gated ion channels, such as the nicotinic acetylcholine receptor, are multimeric protein complexes whose function depends on the correct ordered assembly of individual subunits. Assembly of individual subunits occurs in the endoplasmic reticulum prior to trafficking of mature receptors to the plasma membrane. Trafficking of mature receptors is regulated to ensure that only assembled subunits are transported to the plasma membrane, while unassembled subunits remain in the endoplasmic reticulum. However, the molecules and mechanisms that regulate nicotinic acetylcholine receptor formation are not well understood.; Forward genetic analysis provides an unbiased method to identify molecules that are involved in a given process. The nematode Caenorhabditis elegans has been established as a genetic model system that is well-suited toward the discovery of genes involved in nervous system development and function. Mobilization of the Drosophila transposon Mos1 in the germ line of C. elegans can disrupt genes, resulting in visible phenotypes. Mos1 insertions represent unique sequence tags that can be used to rapidly assign function to a specific gene, alleviating traditional genetic mapping.; Mos1-mediated mutagenesis was used to isolate and clone unc-74, which is required for the formation of a specific nicotinic acetylcholine receptor. unc-74 encodes a transmembrane thioredoxin that functions cell-autonomously in the endoplasmic reticulum to promote formation of nicotinic acetylcholine receptors. The promotion of receptor formation is through a novel mechanism that is independent of redox chemistry. Homologues of UNC-74 are found in other metazoans, suggesting a conserved functional role in the formation of specific nicotinic acetylcholine receptors. |
