Using a combination of PCR based cloning and Northern blot analysis we have investigated the tissue expression of cyclic nucleotide-gated (CNG) cation channels in a variety of non-excitable tissues and cells. Partial sequences of all three known CNG channels and of an auxiliary subunit of the rod photoreceptor channel were determined. The expression of CNG channel genes is both tissue and species specific. Southern blot analysis with human genomic DNA revealed specific patterns of hybridization with probes derived from the different CNG channel types indicating that they are encoded by distinct genes. Analysis of human genomic sequences showed that all three genes are derived from a common ancestral gene and might have a similar gene structure. We were not able to identify additional genes encoding CNG channels. The CNG3 channel, which was originally cloned from bovine kidney may be expressed also in bovine cone photoreceptor cells. These data suggest that some of the effects of cGMP in peripheral tissues and cells might involve the activation of CNG channels.