Mammalian tandem pore domain K+ channels (K2P channels) give rise to background currents and control excitability within various tissues (Mathie, 2007). Within the central nervous system, TREK channels appear to serve important roles, for example in the manifestation of depression (Heurteaux et al., 2006). TREK channels are known to be regulated by a number of specific neurotransmitters (Mathie, 2007; Heurteaux et al., 2006). Here we report the effects of “atypical”, gaseous neurotransmitters (Baranano et al., 2001) carbon monoxide (CO) and nitric oxide (NO) on the recombinant human TREK-1 channel stably expressed in HEK 293 cells. Whole cell patch clamp recordings were made from HEK293 cells expressing the hTREK-1. Bath application of the CO donor CORM2 (30μM) evoked a reversible activation of the channel (e.g. by 24.6 ± 6.1% at +60mV; mean ± s.e.m., P<0.05, Student’s paired t test, n=7), but at 100μM led to an inhibition of the channel (by 14.6 ± 3.7%, P0.05, n=5). To determine the mechanism behind the CORM2 effect we examined the role of cGMP. Pre-incubation (2h) of RP-8-Br-PET-cGMPs (100nM), had no effect on TREK currents but abolished the CORM2 (30μM) induced activation, suggesting the involvement of cGMP. Parallel experiments examined the effect of SIN-1 (a NO donor) on the hTREK-1 channel. Similar to CORM2, SIN-1 activated the channel at 10μM (51.9 ± 3.4% at +60mV, P<0.05, n=5). The NO effect was blocked by pre-incubation of the same cGMP inhibitor, also indicating a role for cGMP. These data suggest a novel modulation of the TREK-1 channel via CO that is cGMP dependent and may be mechanistically similar to NO-mediated TREK regulation.