Regulation of ion channel activity has been suggested to be vitally important in the responses of the carotid body and pulmonary vasculature to hypoxia. In 2004, Kemp and colleagues (Williams et al., 2004) reported that high conductance Ca²⁺ activated K⁺ (maxiK) channels were O₂ sensitive because they were tightly coupled to heme oxygenase-2 (HO-2), an enzyme that generates carbon monoxide (CO) in an O₂ dependent manner during the catabolism of heme. CO enhanced maxiK channel activity, and under hypoxia channel activity declined due to the suppression of CO production. With this mechanism in mind, we have investigated whether other O₂ sensitive channels might employ the same mechanism i.e. be regulated by CO in an O₂ dependent manner. L-type Ca²⁺ channels are also known to be O₂ sensitive (Franco-Obregon et al., 1995), an effect which may contribute to hypoxic relaxation of systemic smooth muscle cells. We reported that this sensitivity to O₂ only occurred when the channels expressed a splice insert in the cytoplasmic C-terminal domain of the α subunit (Fearon et al., 2000). We recently found both native L-type Ca²⁺ channels and recombinant α_1C channels expressed in the absence of auxiliary subunits to be inhibited by CO (Scragg et al., 2008), an effect which is opposite of that predicted by the HO-2 / CO model reported for maxiK channels (Williams et al., 2004). Interestingly, however, the inhibitory effect of CO was attributable to increased production of mitochondrial reactive oxygen species (an effect which is also considered central to many cellular responses to hypoxia (Bell et al., 2005)). Furthermore, CO sensitivity (like O₂ sensitivity) required the presence of a spliced insert in the cytoplasmic C-terminal domain. Indeed, three key cysteine residues within the splice insert were found to be essential for CO sensitivity (Scragg et al., 2008). Kv2.1 is a voltage-gated K⁺ channel which has been suggested to be inhibited by hypoxia in pulmonary smooth muscle cells (Patel et al., 1997). This effect, which is enhanced when the channel is co-expressed with the “silent” subunit Kv9.3, may contribute to hypoxic pulmonary vasoconstriction. In ongoing studies, we have found that Kv2.1 (when expressed in HEK 293 cells) is also inhibited by CO. Such an effect is also observed in native Kv2.1 channels recorded in hippocampal neurones. Thus, hypoxic inhibition of Kv2.1 through suppression of HO-2 derived CO production cannot account for hypoxic inhibition of the channel. Our findings to date suggest that suppression of CO production by heme oxygenases is unlikely to represent a universal mechanism to account for the inhibitory actions of hypoxia on ion channels. However, the regulation of channels by CO is a potentially important phenomenon which is currently largely unexplored. Given the widespread distribution of constitutively active HO-2, and the ability of many cells to express the stress-inducible isoform, HO-1 (Kim et al., 2006), the physiological significance of ion channel regulation by CO is worthy of further investigation.