Cyclic Nucleotide‐gated Ion Channels


Cyclic nucleotide‐gated (CNG) ion channels are activated by cAMP or cGMP, crucial intracellular messenger molecules that regulate a wide variety of physiological activities. In photoreceptors and olfactory neurons, CNG channels play an essential role in transducing sensory stimuli into electrical and chemical responses. CNG channels are also found in other tissues including brain and sperm, where they may contribute to physiological functions including pacemaking, synaptic transmission and chemosensation. The exquisite regulation of different CNG channels by divalent cations, calmodulin, phosphorylation and phospholipids allows these proteins to carry out disparate physiological functions with high precision. Our understanding of the structure of these channels has been greatly enhanced by the recent determination of the structures of domains of related ion channels. The powerful combination of electrophysiology, biochemistry, patch‐clamp fluorometry and X‐ray crystallography has begun to unravel the mystery of how CNG channels are regulated and how the binding of cyclic nucleotides lead to channel opening.

Key concepts

  • Ion channels are membrane proteins that allow ions to diffuse across cellular membranes in a regulated manner.

  • CNG channels are ion channels regulated by the direct binding of cyclic nucleotides.

  • Photoreceptors are retinal cells that contain a high density of ion channels regulated by the binding of cyclic nucleotides.

  • Olfaction is the process of odour sensation, also regulated by the binding of cyclic nucleotides.

  • Permeation describes the ability of ion channels to selectively determine which ions can move through them.

  • Gating is the process by which ion channels open and close to control the flow of ions.

  • Structure/function describes the relationship between the 3D structure of an ion channel and its function.

  • Cyclic nucleotides are small ligands used to control the gating of CNG channels.

Keywords: ion channels; cyclic AMP; cyclic GMP; photoreceptor; olfaction

Figure 1.

Subunit stoichiometry of CNG channels in photoreceptors and olfactory neurons.

Figure 2.

The dark current of photoreceptors. CNG channels that are kept open in the dark by the relatively high concentration of cGMP allowing an inward current, carried by Na+, and to a lesser extent Ca2+. The steady inward current is balanced by a steady outward current through K+ channels in the inner segment, completing the circuit. Ion concentration gradients are maintained by the Na+/Ca2+‐K+ exchanger in the outer segment and the Na+/K+ ATPase active transporter in the inner segment.

Figure 3.

Membrane topology of CNG channels. For simplicity, this figure shows two of the four subunits comprising CNG channels. Similarly to voltage‐gated K+ channels, CNG channels are tetramers where each subunit contains six transmembrane domains, intracellular N‐ and C‐termini, positive charges in the fourth transmembrane domain (S4), and a P‐loop lining the pore of the channel. In addition, CNG channels contain a cyclic nucleotide‐binding domain in the C‐terminus of each subunit, connected to the transmembrane domain by a region called the C‐linker. The P‐loop, lining the pore, is shown in red, and the CNBD is shown in blue with cGMP bound.

Figure 4.

Structures of domains of related ion channels. (a) Structure of the NaK selectivity filter (PDB: 2AHY). Two Na+‐binding sites are shown in purple and one Ca2+‐binding site is shown in green. D66 is important for Ca2+ binding in NaK, as the homologous aspartate in CNG channels. However, D66 does not directly coordinate the Ca2+ ion, as had been previously predicted. Rather, the backbone carbonyl groups from G67 stabilize the Ca2+ ion and D66 indirectly stabilizes the positioning of G67. (b) Structure of the cytoplasmic domain from a single subunit of HCN2 channels (PDB: 1Q5O). The C‐linker, shown at the top, contains six α‐helices separated by short loops. The cyclic nucleotide‐binding domain contains four α‐helices with a β‐roll separating the first two α‐helices. cAMP is shown bound between the β‐roll and the final α‐helix, called the C helix. Although only one subunit is shown, this domain folds as a stable tetramer with intersubunit contacts between the C‐linkers. (c) Structure of the P‐loop and S6 of MlotiK1 (PDB: 3BEH). Residues spacefilled in blue represent residues blocking the permeation pathway in the structure. Residues spacefilled in red represent residues in the selectivity filter accessible to cysteine modification in closed CNG channels.

Figure 5.

Model of CNG channel gating. Cartoon illustrating conformational changes in response to ligand binding and channel opening. Although CNG channels are tetrameric proteins with 4‐fold symmetry, only 2 subunits are illustrated for simplicity. In the closed, unliganded state, salt bridges hold the C‐linkers of multiple subunits together. The C helices (blue cylinders) from multiple subunits are in close proximity in the closed state. Cyclic nucleotides initially bind by interacting with residues in the β‐roll of the cyclic nucleotide‐binding domain. This triggers a conformational change leading to channel opening. This conformational change involves a relative movement of the C helices away from each other and towards the β‐rolls, and destabilization of the tetramerization of the C‐linkers. The details of this model remain to be determined.



Baylor DA, Lamb TD and Yau KW (1979) The membrane current of single rod outer segments. Journal of Physiology 288: 589–611.

Biskup C, Kusch J, Schulz E et al. (2007) Relating ligand binding to activation gating in CNGA2 channels. Nature 446(7134): 440–443.

Contreras JE, Srikumar D and Holmgren M (2008) Gating at the selectivity filter in cyclic nucleotide‐gated channels. Proceedings of the National Academy of Sciences of the USA 105(9): 3310–3314.

Fesenko EE, Kolesnikov SS and Lyubarsky AL (1985) Induction by cyclic GMP of cationic conductance in plasma membrane of retinal rod outer segment. Nature 313(6000): 310–313.

Flynn GE and Zagotta WN (2001) Conformational changes in S6 coupled to the opening of cyclic nucleotide‐gated channels. Neuron 30(3): 689–698.

Kurahashi T and Menini A (1997) Mechanism of odorant adaptation in the olfactory receptor cell. Nature 385(6618): 725–729.

Nakamura T and Gold GH (1987) A cyclic nucleotide‐gated conductance in olfactory receptor cilia. Nature 325(6103): 442–444.

Savchenko A, Barnes S and Kramer RH (1997) Cyclic‐nucleotide‐gated channels mediate synaptic feedback by nitric oxide. Nature 390(6661): 694–698.

Shi N, Ye S, Alam A, Chen L and Jiang Y (2006) Atomic structure of a Na+‐ and K+‐conducting channel. Nature 440(7083): 570–574.

Song Y, Cygnar KD, Sagdullaev B et al. (2008) Olfactory CNG channel desensitization by Ca2+/CaM via the B1b subunit affects response termination but not sensitivity to recurring stimulation. Neuron 58(3): 374–386.

Zagotta WN, Olivier NB, Black KD et al. (2003) Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature 425(6954): 200–205.

Further Reading

Barnstable CJ, Wei JY and Han MH (2004) Modulation of synaptic function by cGMP and cGMP‐gated cation channels. Neurochemistry Internationals 45(6): 875–884.

Biel M and Michalakis S (2007) Function and dysfunction of CNG channels: insights from channelopathies and mouse models. Molecular Neurobiology 35(3): 266–277.

Bradley J, Reisert J and Frings S (2005) Regulation of cyclic nucleotide‐gated channels. Current Opinion in Neurobiology 15(3): 343–349.

Brown RL, Strassmaier T, Brady JD and Karpen JW (2006) The pharmacology of cyclic nucleotide‐gated channels: emerging from the darkness. Current Pharmaceutical Design 12(28): 3597–3613.

Craven KB and Zagotta WN (2006) CNG and HCN channels: two peas, one pod. Annual Review of Physiology 68: 375–401.

Dowling JE (1987) The Retina: An Approachable Part of the Brain. Cambridge, MA: Belknap Press.

Kaupp UB and Seifert R (2002) Cyclic nucleotide‐gated ion channels. Physiological Review 82(3): 769–824.

Matulef K and Zagotta WN (2003) Cyclic nucleotide‐gated ion channels. Annual Review of Cell and Developmental Biology 19: 23–44.

Pifferi S, Boccaccio A and Menini A (2006) Cyclic nucleotide‐gated ion channels in sensory transduction. FEBS Letter 22; 580(12): 2853–2859.

Trudeau MC and Zagotta WN (2003) Calcium/calmodulin modulation of olfactory and rod cyclic nucleotide‐gated ion channels. Journal of Biological Chemistry 278(21): 18705–18708.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Zheng, Jie, and Matulef, Kimberly(Mar 2009) Cyclic Nucleotide‐gated Ion Channels. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000091.pub2]