Mammalian homologues of Drosophila TRP proteins form non-selective cation channels in the lipid bilayer of many cell types. The TRP channel family is divided into 6 subfamilies based upon sequence similarity and comprises 28 members (Nilius et al 2007). One member of the canonical subfamily, TRPC5, is expressed in a range of tissues including parts of the brain and blood vessels. It is implicated in hippocampal growth cone extension and vascular smooth muscle injury response. Similar to other members of the TRP family, TRPC5 is presumed to have six membrane spanning domains and the amino acid residues between fifth (S5) and sixth (S6) segments are likely to be involved in the formation of the ion pore. TRPC5 functions as a plasma membrane channel, with mixed cation permeability and forms homo- or hetero-multimers with TRPC1 or TRPC4 subunits (Beech 2007). TRPC5 responds to a multiplicity of activation signals including G protein coupled receptor agonists, lipids and lanthanides (Beech 2007). A glutamate residue in the predicted extracellular region between S5 and S6, i.e. in the turret structure of the channel, is essential for activation by lanthanides (Jung et al 2003). Amino acid sequence alignment of TRPC1, 4 and 5 channels revealed the presence of two conserved cysteine residues in close proximity to this glutamate. We hypothesised that these cysteine residues may be functionally important. Such cysteine residues may form a disulphide bridge or be free and thus modified by reducing agents or S-nitrosylation respectively. We tested these possibilities by over-expressing TRPC5 channels in human embryonic kidney cells and using electrophysiological and calcium imaging techniques. Also, we explored the effect of mutating the residues. We find that reducing agents have a marked stimulatory effect on TRPC5 and act from extracellular side of the membrane. Mutation of either cysteine residue (to alanine) led to large constitutive currents, which were not stimulated by dithiothreitol (a reducing agent) or lanthanides, but were inhibited by 2-aminoethoxydiphenyl borate. Dithiothreitol did not activate TRP channels that lack a cysteine pair in this position (TRPC6 and TRPM2). The nitric oxide donor SNAP had a weak stimulatory effect on TRPC5. The data suggest an inhibitory disulphide bridge can exist in the turret of TRPC5 conferring the possibility of regulation by redox potential.