Cyclic nucleotide-regulated channels
More information on this family may be found on the IUPHAR-DB family and introduction pages.
Cyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems. A standardised nomenclature for CNG channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels [7].
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 [6,8], 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 [9] and the pineal gland [5]. 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.
Hyperpolarisation-activated, cyclic nucleotide-gated (HCN)
The hyperpolarisation-activated, cyclic nucleotide-gated (HCN) channels are cation channels that are activated by hyperpolarisation at voltages negative to ~-50 mV. The cyclic nucleotides cAMP and cGMP directly activate the channels and shift the activation curves of HCN channels to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons [4,10]. 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]. A standardised nomenclature for HCN channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels [7].
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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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]
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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]
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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]
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]
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]
Pape, HC. (1996) Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu. Rev. Physiol., 58: 299-327. [PMID:8815797]
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]
Wahl-Schott, C; Biel, M. (2009) HCN channels: structure, cellular regulation and physiological function. Cell. Mol. Life Sci., 66 (3): 470-94. [PMID:18953682]
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]
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. 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]
3. 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]
4. DiFrancesco, D. (1993) Pacemaker mechanisms in cardiac tissue. Annu. Rev. Physiol., 55: 455-72. [PMID:7682045]
5. 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]
6. 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]
7. 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]
8. 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]
9. Nakamura, T; Gold, GH. (1987) A cyclic nucleotide-gated conductance in olfactory receptor cilia. Nature, 325 (6103): 442-4. [PMID:3027574]
10. Pape, HC. (1996) Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu. Rev. Physiol., 58: 299-327. [PMID:8815797]
11. Peng, C; Rich, ED; Varnum, MD. (2004) Subunit configuration of heteromeric cone cyclic nucleotide-gated channels. Neuron, 42 (3): 401-10. [PMID:15134637]
12. 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]
13. 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]
14. Zheng, J; Zagotta, WN. (2004) Stoichiometry and assembly of olfactory cyclic nucleotide-gated channels. Neuron, 42 (3): 411-21. [PMID:15134638]
15. 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]
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CNGA1, CNGA2 and CNGA3 express functional channels as homomers. Three additional subunits CNGA4 (ENSG00000132259), CNGB1 (ENSG00000070729) and CNGB3 (ENSG00000170289) 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 [11-15].
Hyperpolarisation-activated, cyclic nucleotide-gated (HCN)
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 [2] and ivabradine [3] have proven useful in identifying and studying functional HCN channels in native cells. zatebradine and cilobradine are also useful blocking agents.