AbstractThe neuron‐specific G protein‐coupled receptor interacting scaffold protein (GISP) is a multidomain, brain‐specific protein derived from the A‐kinase anchoring protein‐9 gene. We originally isolated GISP as an interacting partner for the GABAB receptor subunit GABAB1. Here, we show that the protein tumour susceptibility gene 101 (TSG101), an integral component of the endosomal sorting machinery that targets membrane proteins for lysosomal degradation, also interacts with GISP. TSG101 co‐immunoprecipitates with GISP from adult rat brain, and using GST pull‐downs, we identified that the eighth coiled‐coiled region of GISP is critical for TSG101 association. Intriguingly, although there is no direct interaction between GISP and the GABAB2 subunit, their co‐expression in HEK293 cells increases levels of GABAB2. GISP also inhibits TSG101‐dependent GABAB2 down‐regulation in human embryonic kidney 293 cells whereas over‐expression of a mutant GISP lacking the TSG101 binding domain has no effect on GABAB2 degradation. These data suggest that GISP can function as a negative regulator of TSG101‐dependent lysosomal degradation of transmembrane proteins in neurons to promote receptor stability.