Lipid raft domains have attracted much recent attention as platforms for plasma membrane signalling complexes. In particular, evidence is emerging that shows them to be key regulators of G protein coupled receptor function. The G protein coupled gamma-aminobutyric acid receptor B (GABA(B) receptor) co-isolates with lipid raft domains from rat brain cerebellum. In the present study, we show that the GABA(B1a.2) receptor was also present in lipid raft domains when expressed ectopically in a Chinese hamster ovary cell line. Lipid raft-associated receptor was functionally active, displaying a concentration-dependent increase in GTPgammaS binding in response to the receptor agonist GABA. Compared with whole cell membranes, lipid raft-associated receptor displayed an increased EC50 and a reduced magnitude of response to GABA. We conclude that lipid raft association is an intrinsic property of the GABA(B1a.2) receptor and is not cell-type specific. In addition, localisation to lipid raft domains may provide a mechanism to inhibit receptor function. (C) 2004 Elsevier Inc. All rights reserved.