Distinct Endosomal Sorting Complexes Required for Transport Components Differentially Regulate Glutamate and Gamma-Aminobutyric Acid Receptor Surface Expression

Endosomal sorting complexes required for transport (ESCRT) regulate membrane protein trafficking through coordinated cargo selection and endosomal processing, yet their contribution to neurotransmitter receptor sorting remains to be defined. Here, we examined how modulation of distinct complex components influences the surface expression of excitatory and inhibitory neurotransmitter receptors. Using surface biotinylation and imaging approaches in heterologous cells and primary neurons, we altered tumour susceptibility gene 101 (TSG101), a core complex I component, and vacuolar protein sorting-associated protein 4A (VPS4a), an ATPase required for complex III disassembly. Reduction of tumour susceptibility gene 101 increased receptor association with early endosomes and enhanced receptor surface localisation, whereas disruption of VPS4A promoted receptor accumulation within late endosomal compartments and impaired degradative progression. Inhibitory receptor subtypes displayed variable sensitivity. Together, these findings demonstrate that endosomal sorting complex components regulate receptor surface expression through stage-specific trafficking mechanisms associated with altered receptor recycling and degradative processing. Graphical abstractDistinct ESCRT components regulate neurotransmitter receptor trafficking through stage-specific control of the endosomal pathway. ESCRT-I disruption promotes early endosomal retention and recycling, whereas ESCRT-III impairment causes late endosomal accumulation and reduced degradation, together increasing receptor surface expression (created using Biorender). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/732891v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1fe66b9org.highwire.dtl.DTLVardef@10a29d7org.highwire.dtl.DTLVardef@4109c4org.highwire.dtl.DTLVardef@1e84f19_HPS_FORMAT_FIGEXP M_FIG C_FIG