Cyclic nucleotide-gated channels

Overview: Cyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems. A standardized nomenclature for CNG channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels (see Hofmann et al., 2005).

CNG channels are voltage-independent cation channels formed as tetramers. Each subunit has 6TM, with the pore-forming domain between TM5 and TM6. CNG channels were first found in rod photoreceptors (Fesenko et al., 1985; Kaupp et al., 1989), where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular cGMP level. This results in a closure of CNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons (Nakamura and Gold, 1987) and the pineal gland (Dryer and Henderson, 1991). The cyclic nucleotides bind to a domain in the C-terminus of the subunit protein: other channels directly binding cyclic nucleotides include HCN, eag and certain plant potassium channels.

Nomenclature	CNGA1	CNGA2	CNGA3
Other names	CNG1, CNGα1, RCNC1	CNG2, CNGα3, OCNC1	CNG3, CNGα2, CCNC1
Ensembl ID	ENSG00000198515	ENSG00000183862	ENSG00000144191
Activators	Intracellular cyclic nucleotides: cGMP (EC50∼ 30 µM)>>cAMP	Intracellular cyclic nucleotides: cGMP ∼ cAMP (EC50∼ 1 µM)	Intracellular cyclic nucleotides: cGMP (EC50∼ 30 µM)>>cAMP
Inhibitors	L-cis diltiazem	–	L-cis diltiazem
Functional characteristics	γ= 25–30 pS PCa/PNa=3.1	γ= 35 pS PCa/PNa= 6.8	γ= 40 pS PCa/PNa= 10.9

CNGA1, CNGA2 and CNGA3 express functional channels as homomers. Three additional subunits CNGA4 (Genbank protein AAH40277), CNGB1 (Q14028) and CNGB3 (NP_061971) do not, and are referred to as auxiliary subunits. The subunit composition of the native channels is believed to be as follows. Rod: CNGA1₃/CNGB1a; Cone: CNGA3₂/CNGB3₂; Olfactory neurons: CNGA2₂/CNGA4/CNGB1b (Weitz et al., 2002; Zheng et al., 2002; Zhong et al., 2002; Peng et al., 2004; Zheng and Zagotta, 2004).

Further Reading

Biel M, Michalakis S (2009). Cyclic nucleotide-gated channels. Handb Exp Pharmacol191: 111–136.

Bradley J, Reisert J, Frings S (2005). Regulation of cyclic nucleotide-gated channels. Curr Opin Neurobiol15: 343–349.

Brown RL, Strassmaier T, Brady JD, Karpen JW (2006). The pharmacology of cyclic nucleotide-gated channels: emerging from the darkness. Curr Pharm Des12: 3597–3613.

Craven KB, Zagotta WN (2006). CNG and HCN channels: two peas, one pod. Annu Rev Physiol68: 375–401.

Hofmann F, Biel M, Kaup UB (2005). International Union of Pharmacology. LI. Nomenclature and structure-function relationships of cyclic nucleotide-regulated channels. Pharmacol Rev57: 455–462.

Kaupp UB, Seifert R (2002). Cyclic nucleotide-gated ion channels. Physiol Rev82: 769–824.

Matulef K, Zagotta WN (2003). Cyclic nucleotide-gated ion channels. Annu Rev Cell Dev Biol19: 23–44.

Yu FH, Catterall WA (2004). The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE2004 (253): re15.