Cyclic nucleotide-gated channels (CNGs) were first discovered by the observation that cGMP directly activates a current in retinal rods. Soon after, the first CNG channel was cloned. cAMP and cGMP, both activators of CNG channels do so by binding to a specific site on the channels. Indeed, it takes more than one molecule (probably 4) to fully open the tetrameric channel. Mammalian cells express six different isoforms of cyclic nucleotide-gated cation channels which fall into two separate subfamilies: the first, CNGA1-4 represents the principal subunits, those able to form functional channels (except for CNGA4). The second subfamily includes two subunits, namely, CNGB1 and CNGB3. These proteins act as auxiliary subunits and thus cannot form channel-like structures on their own.