Aims: The GIRK channel signalling cascade is composed of the G-protein coupled receptor (GPCR), the heterotrimeric G-protein subunits, RGS, and the Kir 3.x/3.x channel. This signalling pathway is rapid and selective. The efficacy and selectivity can be partly explained by the fact that GPCR dimers and the G protein heterotrimer are present at the cell membrane in the resting state in a pentameric complex (Nobles, M., Benians, A. & Tinker A. 2005. Proc Natl Acad Sci USA 102,18706-11). Another contribution to this efficacy/specificity might be the location of the GIRK signalling pathway in membrane microdomains such as rafts and caveolae. Methods: To explore the potential function of caveolar domains we constructed a YFP tagged variant of caveolin-2 (YFP-Cav2) and receptor chimaeras with YFP-Cav2 and GPCR: A1 adenosine and M2 muscarinic receptors. We have expressed these chimaeras into HEKs cell line expressing Kir 3.1/3.4. Using single cell electrophysiology, we analysed the activation kinetics of GIRK current using a rapid and localized drug-perfusion system. GIRK current activation consists of an initial lag phase followed by exponential rise to peak (lag + TTP). The activation and deactivation phases of the current kinetics can be fitted by single exponentials where tis the time constant. Results: The current activation showed slower kinetics when activated through the caveolae- targeted A1 or M2 receptors. This was reflected by an increase in the lag + TTP for the M2 and A1 receptors (P<0.001), along with a large increase in tac for M2 and A1 receptors (P<0.001). We also observed a reduction in the desensitisation of the current during agonist application (P<0.001 for M2 and P<0.01 for A1). Finally, the tdeactivation, after agonist withdraw was reduced (P<0.01 for M2, NS for A1). Conclusion: The localisation in caveolae domains of the GPCR involved in the GIRK signal transduction cascade substantially slows the speed of signalling.