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Cyclic nucleotide-regulated channels (CNG) C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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Cyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems. 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 [9,12], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular cyclic GMP level. This results in a closure of CNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons [17] and the pineal gland [8]. The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include hyperolarisation-activated, cyclic nucleotide-gated channels (HCN), ether-a-go-go and certain plant potassium channels.
The HCN channels are cation channels that are activated by hyperpolarisation at voltages negative to ~-50 mV. The cyclic nucleotides cyclic AMP and cyclic GMP directly bind to the cyclic nucleotide-binding domain of HCN channels and shift their activation curves to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons [7,18]. In native cells, these currents have a variety of names, such as Ih, Iq and If. The four known HCN channels have six transmembrane domains and form tetramers. It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 [1]. High resolution structural studies of CNG and HCN channels has provided insight into the the gating processes of these channels [14-16]. A standardised nomenclature for CNG and HCN channels has been proposed by the NC-IUPHAR Subcommittee on voltage-gated ion channels [11].
Channels and Subunits
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CNGA1
C
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CNGA2
C
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CNGA3
C
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CNGA4
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CNGB1
C
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CNGB3
C
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HCN1
C
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HCN2
C
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HCN3
C
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HCN4
C
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Further reading
* Key recommended reading is highlighted with an asterisk
* Barret DCA, Kaupp UB, Marino J. (2022) The structure of cyclic nucleotide-gated channels in rod and cone photoreceptors. Trends Neurosci, 45 (10): 763-776. [PMID:35934530]
Baruscotti M, Bottelli G, Milanesi R, DiFrancesco JC, DiFrancesco D. (2010) HCN-related channelopathies. Pflugers Arch, 460 (2): 405-15. [PMID:20213494]
Baruscotti M, Bucchi A, Difrancesco D. (2005) Physiology and pharmacology of the cardiac pacemaker ("funny") current. Pharmacol Ther, 107 (1): 59-79. [PMID:15963351]
Biel M, Ludwig A, Zong X, Hofmann F. (1999) Hyperpolarization-activated cation channels: a multi-gene family. Rev Physiol Biochem Pharmacol, 136: 165-81. [PMID:9932486]
Biel M, Michalakis S. (2009) Cyclic nucleotide-gated channels. Handb Exp Pharmacol, (191): 111-36. [PMID:19089328]
Biel M, Schneider A, Wahl C. (2002) Cardiac HCN channels: structure, function, and modulation. Trends Cardiovasc Med, 12 (5): 206-12. [PMID:12161074]
Biel M, Wahl-Schott C, Michalakis S, Zong X. (2009) Hyperpolarization-activated cation channels: from genes to function. Physiol Rev, 89 (3): 847-85. [PMID:19584315]
Bois P, Guinamard R, Chemaly AE, Faivre JF, Bescond J. (2007) Molecular regulation and pharmacology of pacemaker channels. Curr Pharm Des, 13 (23): 2338-49. [PMID:17692005]
Bradley J, Reisert J, Frings S. (2005) Regulation of cyclic nucleotide-gated channels. Curr Opin Neurobiol, 15 (3): 343-9. [PMID:15922582]
Brown RL, Strassmaier T, Brady JD, Karpen JW. (2006) The pharmacology of cyclic nucleotide-gated channels: emerging from the darkness. Curr Pharm Des, 12 (28): 3597-613. [PMID:17073662]
Craven KB, Zagotta WN. (2006) CNG and HCN channels: two peas, one pod. Annu Rev Physiol, 68: 375-401. [PMID:16460277]
Cukkemane A, Seifert R, Kaupp UB. (2011) Cooperative and uncooperative cyclic-nucleotide-gated ion channels. Trends Biochem Sci, 36 (1): 55-64. [PMID:20729090]
DiFrancesco D. (1993) Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol, 55: 455-72. [PMID:7682045]
DiFrancesco D. (2010) The role of the funny current in pacemaker activity. Circ Res, 106 (3): 434-46. [PMID:20167941]
DiFrancesco D, Camm JA. (2004) Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs, 64 (16): 1757-65. [PMID:15301560]
Dunlop J, Vasilyev D, Lu P, Cummons T, Bowlby MR. (2009) Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and pain. Curr Pharm Des, 15 (15): 1767-72. [PMID:19442189]
* Gerhardt MJ, Priglinger SG, Biel M, Michalakis S. (2023) Biology, Pathobiology and Gene Therapy of CNG Channel-Related Retinopathies. Biomedicines, 11 (2). [PMID:36830806]
* Hennis K, Biel M, Fenske S, Wahl-Schott C. (2022) Paradigm shift: new concepts for HCN4 function in cardiac pacemaking. Pflugers Arch, 474 (7): 649-663. [PMID:35556164]
Herrmann S, Schnorr S, Ludwig A. (2015) HCN channels--modulators of cardiac and neuronal excitability. Int J Mol Sci, 16 (1): 1429-47. [PMID:25580535]
James ZM, Zagotta WN. (2018) Structural insights into the mechanisms of CNBD channel function. J Gen Physiol, 150 (2): 225-244. [PMID:29233886]
Kaupp UB, Seifert R. (2001) Molecular diversity of pacemaker ion channels. Annu Rev Physiol, 63: 235-57. [PMID:11181956]
Kaupp UB, Seifert R. (2002) Cyclic nucleotide-gated ion channels. Physiol Rev, 82 (3): 769-824. [PMID:12087135]
Maher MP, Wu NT, Guo HQ, Dubin AE, Chaplan SR, Wickenden AD. (2009) HCN channels as targets for drug discovery. Comb Chem High Throughput Screen, 12 (1): 64-72. [PMID:19149492]
Matulef K, Zagotta WN. (2003) Cyclic nucleotide-gated ion channels. Annu Rev Cell Dev Biol, 19: 23-44. [PMID:14570562]
Mazzolini M, Marchesi A, Giorgetti A, Torre V. (2010) Gating in CNGA1 channels. Pflugers Arch, 459 (4): 547-55. [PMID:19898862]
Meldrum BS, Rogawski MA. (2007) Molecular targets for antiepileptic drug development. Neurotherapeutics, 4 (1): 18-61. [PMID:17199015]
Michalakis S, Becirovic E, Biel M. (2018) Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy. Int J Mol Sci, 19 (3). DOI: 10.3390/ijms19030749 [PMID:29518895]
* Napolitano LMR, Torre V, Marchesi A. (2021) CNG channel structure, function, and gating: a tale of conformational flexibility. Pflugers Arch, 473 (9): 1423-1435. [PMID:34357442]
Pape HC. (1996) Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu Rev Physiol, 58: 299-327. [PMID:8815797]
Podda MV, Grassi C. (2014) New perspectives in cyclic nucleotide-mediated functions in the CNS: the emerging role of cyclic nucleotide-gated (CNG) channels. Pflugers Arch, 466 (7): 1241-57. [PMID:24142069]
* Santoro B, Shah MM. (2020) Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels as Drug Targets for Neurological Disorders. Annu Rev Pharmacol Toxicol, 60: 109-131. [PMID:31914897]
* Sartiani L, Mannaioni G, Masi A, Novella Romanelli M, Cerbai E. (2017) The Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels. Pharmacol Rev, 69 (4): 354-395. [PMID:28878030]
Tardif JC. (2008) Ivabradine: I(f) inhibition in the management of stable angina pectoris and other cardiovascular diseases. Drugs Today, 44 (3): 171-81. [PMID:18536779]
Tsantoulas C, Mooney ER, McNaughton PA. (2016) HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain. Biochem J, 473 (18): 2717-36. [PMID:27621481]
Wahl-Schott C, Biel M. (2009) HCN channels: structure, cellular regulation and physiological function. Cell Mol Life Sci, 66 (3): 470-94. [PMID:18953682]
Wahl-Schott C, Fenske S, Biel M. (2014) HCN channels: new roles in sinoatrial node function. Curr Opin Pharmacol, 15: 83-90. [PMID:24441197]
Yu FH, Catterall WA. (2004) The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE, 2004 (253): re15. [PMID:15467096]
References
1. Altomare C, Terragni B, Brioschi C, Milanesi R, Pagliuca C, Viscomi C, Moroni A, Baruscotti M, DiFrancesco D. (2003) Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node. J Physiol (Lond.), 549 (Pt 2): 347-59. [PMID:12702747]
2. Barret DCA, Schertler GFX, Kaupp UB, Marino J. (2022) The structure of the native CNGA1/CNGB1 CNG channel from bovine retinal rods. Nat Struct Mol Biol, 29 (1): 32-39. [PMID:34969975]
3. BoSmith RE, Briggs I, Sturgess NC. (1993) Inhibitory actions of ZENECA ZD7288 on whole-cell hyperpolarization activated inward current (If) in guinea-pig dissociated sinoatrial node cells. Br J Pharmacol, 110 (1): 343-9. [PMID:7693281]
4. Bucchi A, Baruscotti M, DiFrancesco D. (2002) Current-dependent block of rabbit sino-atrial node I(f) channels by ivabradine. J Gen Physiol, 120 (1): 1-13. [PMID:12084770]
5. Chen TY, Peng YW, Dhallan RS, Ahamed B, Reed RR, Yau KW. (1993) A new subunit of the cyclic nucleotide-gated cation channel in retinal rods. Nature, 362 (6422): 764-7. [PMID:7682292]
6. Del Lungo M, Melchiorre M, Guandalini L, Sartiani L, Mugelli A, Koncz I, Szel T, Varro A, Romanelli MN, Cerbai E. (2012) Novel blockers of hyperpolarization-activated current with isoform selectivity in recombinant cells and native tissue. Br J Pharmacol, 166 (2): 602-16. [PMID:22091830]
7. DiFrancesco D. (1993) Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol, 55: 455-72. [PMID:7682045]
8. Dryer SE, Henderson D. (1991) A cyclic GMP-activated channel in dissociated cells of the chick pineal gland. Nature, 353 (6346): 756-8. [PMID:1719422]
9. Fesenko EE, Kolesnikov SS, Lyubarsky AL. (1985) Induction by cyclic GMP of cationic conductance in plasma membrane of retinal rod outer segment. Nature, 313 (6000): 310-3. [PMID:2578616]
10. Gerstner A, Zong X, Hofmann F, Biel M. (2000) Molecular cloning and functional characterization of a new modulatory cyclic nucleotide-gated channel subunit from mouse retina. J Neurosci, 20 (4): 1324-32. [PMID:10662822]
11. Hofmann F, Biel M, Kaupp UB. (2005) International Union of Pharmacology. LI. Nomenclature and structure-function relationships of cyclic nucleotide-regulated channels. Pharmacol Rev, 57 (4): 455-62. [PMID:16382102]
12. Kaupp UB, Niidome T, Tanabe T, Terada S, Bönigk W, Stühmer W, Cook NJ, Kangawa K, Matsuo H, Hirose T. (1989) Primary structure and functional expression from complementary DNA of the rod photoreceptor cyclic GMP-gated channel. Nature, 342 (6251): 762-6. [PMID:2481236]
13. Knaus A, Zong X, Beetz N, Jahns R, Lohse MJ, Biel M, Hein L. (2007) Direct inhibition of cardiac hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by clonidine. Circulation, 115 (7): 872-80. [PMID:17261653]
14. Lee CH, MacKinnon R. (2017) Structures of the Human HCN1 Hyperpolarization-Activated Channel. Cell, 168 (1-2): 111-120.e11. [PMID:28086084]
15. Lee CH, MacKinnon R. (2019) Voltage Sensor Movements during Hyperpolarization in the HCN Channel. Cell, 179 (7): 1582-1589.e7. [PMID:31787376]
16. Li M, Zhou X, Wang S, Michailidis I, Gong Y, Su D, Li H, Li X, Yang J. (2017) Structure of a eukaryotic cyclic-nucleotide-gated channel. Nature, 542 (7639): 60-65. [PMID:28099415]
17. Nakamura T, Gold GH. (1987) A cyclic nucleotide-gated conductance in olfactory receptor cilia. Nature, 325 (6103): 442-4. [PMID:3027574]
18. Pape HC. (1996) Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu Rev Physiol, 58: 299-327. [PMID:8815797]
19. Peng C, Rich ED, Varnum MD. (2004) Subunit configuration of heteromeric cone cyclic nucleotide-gated channels. Neuron, 42 (3): 401-10. [PMID:15134637]
20. Rosenbaum T, Gordon-Shaag A, Islas LD, Cooper J, Munari M, Gordon SE. (2004) State-dependent block of CNG channels by dequalinium. J Gen Physiol, 123 (3): 295-304. [PMID:14981138]
21. Rosenbaum T, Islas LD, Carlson AE, Gordon SE. (2003) Dequalinium: a novel, high-affinity blocker of CNGA1 channels. J Gen Physiol, 121 (1): 37-47. [PMID:12508052]
22. Stieber J, Stöckl G, Herrmann S, Hassfurth B, Hofmann F. (2005) Functional expression of the human HCN3 channel. J Biol Chem, 280 (41): 34635-43. [PMID:16043489]
23. Stieber J, Wieland K, Stöckl G, Ludwig A, Hofmann F. (2006) Bradycardic and proarrhythmic properties of sinus node inhibitors. Mol Pharmacol, 69 (4): 1328-37. [PMID:16387796]
24. Weitz D, Ficek N, Kremmer E, Bauer PJ, Kaupp UB. (2002) Subunit stoichiometry of the CNG channel of rod photoreceptors. Neuron, 36 (5): 881-9. [PMID:12467591]
25. Zheng J, Trudeau MC, Zagotta WN. (2002) Rod cyclic nucleotide-gated channels have a stoichiometry of three CNGA1 subunits and one CNGB1 subunit. Neuron, 36 (5): 891-6. [PMID:12467592]
26. Zheng J, Zagotta WN. (2004) Stoichiometry and assembly of olfactory cyclic nucleotide-gated channels. Neuron, 42 (3): 411-21. [PMID:15134638]
27. Zheng X, Hu Z, Li H, Yang J. (2022) Structure of the human cone photoreceptor cyclic nucleotide-gated channel. Nat Struct Mol Biol, 29 (1): 40-46. [PMID:34969976]
28. Zhong H, Molday LL, Molday RS, Yau KW. (2002) The heteromeric cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry. Nature, 420 (6912): 193-8. [PMID:12432397]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Martin Biel (Chairperson)
Elvir Becirovic
Verena Hammelmann |
Other contributors:
Stefanie Fenske
Franz Hofmann
U. Benjamin Kaupp |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Mathie AA, Peters JA, Veale EL, Striessnig J, Kelly E, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Ion channels. Br J Pharmacol. 180 Suppl 2:S145-S222.
CNGA1, CNGA2 and CNGA3 express functional channels as homomers. Three additional subunits CNGA4 (Q8IV77), CNGB1 (Q14028) and CNGB3 (Q9NQW8) 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 [2]; Cone: CNGA33/CNGB31 [27] ; Olfactory neurons: CNGA22/CNGA4/CNGB1b [19,24-26,28]. HCN channels are permeable to both Na+ and K+ ions, with a Na+/K+ permeability ratio of about 0.2. Functionally, they differ from each other in terms of time constant of activation with HCN1 the fastest, HCN4 the slowest and HCN2 and HCN3 intermediate. The compounds ZD7288 [3] and ivabradine [4] have proven useful in identifying and studying functional HCN channels in native cells. Zatebradine and cilobradine are also useful blocking agents.