AbstractSynaptic transmission depends on the regulated surface expression of neurotransmitter receptors, but many of the cellular processes required to achieve this remain poorly understood. To better define specific mechanisms for the GABABreceptor (GABABR) trafficking, we screened for proteins that bind to the carboxy‐terminus of the GABAB1subunit. We report the identification and characterization of a novel 130‐kDa protein, GPCR interacting scaffolding protein (GISP), that interacts directly with the GABAB1subunit via a coiled‐coil domain. GISP co‐fractionates with GABABR and with the postsynaptic density and co‐immunoprecipitates with GABAB1and GABAB2from rat brain. In cultured hippocampal neurons, GISP displays a punctate dendritic distribution and has an overlapping localization with GABABRs. When co‐expressed with GABABRs in human embryonic kidney cells, GISP promotes GABABR surface expression and enhances both baclofen‐evoked extracellular signal‐regulated kinase (ERK) phosphorylation and G‐protein inwardly rectifying potassium channel (GIRK) currents. These results suggest that GISP is involved in the forward trafficking and stabilization of functional GABABRs.