The C. elegans glutamate transporters GLT-4 and GLT-5 regulate protein expression, behavior, and lifespan.

Glutamate transporters are important for regulating extracellular glutamate levels, impacting neural function and metabolic homeostasis. This study explores the behavioral, lifespan, and proteomic profiles in Caenorhabditis elegans strains with either glt-4 or glt-5 null mutations, highlighting contrasting phenotypes. Δglt-4 mutants displayed impaired mechanosensory and chemotactic responses, reduced lifespans, and decreased expression levels of ribosomal proteins and chaperonins involved in protein synthesis and folding. In contrast, Δglt-5 mutants displayed heightened chemorepulsion, extended lifespans, and upregulation of mitochondrial pyruvate carriers and cytoskeletal proteins. Proteomic profiling via mass spectrometry identified 53 differentially expressed proteins in Δglt-4 mutants and 45 in Δglt-5 mutants. Δglt-4 mutants showed disruptions in ribonucleoprotein complex organization and translational processes, including downregulation of glycogen phosphorylase and V-type ATPase subunits, while Δglt-5 mutants revealed altered metabolic protein expression, such as increased levels of mitochondrial pyruvate carriers and decreased levels of fibrillarin and ribosomal proteins. Gene ontology enrichment analysis highlighted differential regulation of protein biosynthesis and metabolic pathways between the strains. Overall, these findings underscore the distinct, tissue-specific roles of GLT-4 and GLT-5 in C. elegans, with broader implications for glutamate regulation and systemic physiology. The results also reinforce the utility of C. elegans as a model for studying glutamate transporters' impact on behavior, longevity, and proteostasis.