TRPC5, a member of the Transient Receptor Potential (TRP) channel family, is widely expressed with roles in neuro and vascular physiology. We recently discovered the capability of TRPC5 but not TRPM2 to sense important lipid signalling molecules such as lysophosphatidylcholine (LPC) (Flemming et al. 2006). LPC activates TREK1 potassium channels too, an effect which is thought to be through deformation of the lipid bilayer (Maingret et al. 2000). TREK1 is also activated by anaesthetics (Patel et al. 1999). We therefore explored the effect of anaesthetics on TRPC5. Tetracycline inducible TRPC5- or TRPM2-expressing HEK293 cell lines were used. Cells were studied using real-time 96-well plate assays with the fura-2 calcium indicator dye and whole-cell patch clamp. TRPC5 activation by gadolinium, carbachol or LPC was inhibited by halothane or chloroform. TRPC5 was activated by isoflurane, whereas sevoflurane had no effect. Chloroform, halothane and isoflurane were relatively ineffective at the common clinical concentrations (1, 0.2 and 0.27 mM respectively). Propofol inhibited TRPC5 activation by gadolinium or carbachol but not LPC. The effect of propofol was not through its anti-oxidant property because the inhibition was mimicked by di-isopropylbenzene, an analogue that lacks the hydroxyl group. In patch-clamp experiments, propofol evoked large activation followed by sustained inhibition of TRPC5, suggesting it has a dual effect. Activation of TRPM2 by hydrogen peroxide was not affected by any of the anaesthetics. The data show striking effects of anaesthetics on TRPC5. Effects occurred at relatively high concentrations and may reflect, in part, sensitivity of TRPC5 to biophysical properties of the lipid bilayer.