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. 1998 Mar;74(3):1333–1345. doi: 10.1016/S0006-3495(98)77846-4

Functional co-assembly among subunits of cyclic-nucleotide-activated, nonselective cation channels, and across species from nematode to human.

J T Finn 1, D Krautwurst 1, J E Schroeder 1, T Y Chen 1, R R Reed 1, K W Yau 1
PMCID: PMC1299480  PMID: 9512030

Abstract

Cyclic-nucleotide-activated, nonselective cation channels have a central role in sensory transduction. They are most likely tetramers, composed of two subunits (alpha and beta or 1 and 2), with the former, but not the latter, being able to form homomeric cyclic-nucleotide-activated channels. Identified members of this channel family now include, in vertebrates, the rod and cone channels mediating visual transduction and the channel mediating olfactory transduction, each apparently with distinct alpha- and beta-subunits. Homologous channels have also been identified in Drosophila melanogaster and Caenorhabditis elegans. By co-expressing any combination of two alpha-subunits, or alpha- and beta-subunits, of this channel family in HEK 293 cells, we have found that they can all co-assemble functionally with each other, including those from fly and nematode. This finding suggests that the subunit members so far identified form a remarkably homogeneous and conserved group, functionally and evolutionarily, with no subfamilies yet identified. The ability to cross-assemble allows these subunits to potentially generate a diversity of heteromeric channels, each with properties specifically suited to a particular cellular function.

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Selected References

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  1. Ahmad I., Korbmacher C., Segal A. S., Cheung P., Boulpaep E. L., Barnstable C. J. Mouse cortical collecting duct cells show nonselective cation channel activity and express a gene related to the cGMP-gated rod photoreceptor channel. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10262–10266. doi: 10.1073/pnas.89.21.10262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ahmad I., Leinders-Zufall T., Kocsis J. D., Shepherd G. M., Zufall F., Barnstable C. J. Retinal ganglion cells express a cGMP-gated cation conductance activatable by nitric oxide donors. Neuron. 1994 Jan;12(1):155–165. doi: 10.1016/0896-6273(94)90160-0. [DOI] [PubMed] [Google Scholar]
  3. Balasubramanian S., Lynch J. W., Barry P. H. Calcium-dependent modulation of the agonist affinity of the mammalian olfactory cyclic nucleotide-gated channel by calmodulin and a novel endogenous factor. J Membr Biol. 1996 Jul;152(1):13–23. doi: 10.1007/s002329900081. [DOI] [PubMed] [Google Scholar]
  4. Baumann A., Frings S., Godde M., Seifert R., Kaupp U. B. Primary structure and functional expression of a Drosophila cyclic nucleotide-gated channel present in eyes and antennae. EMBO J. 1994 Nov 1;13(21):5040–5050. doi: 10.1002/j.1460-2075.1994.tb06833.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Berghard A., Buck L. B., Liman E. R. Evidence for distinct signaling mechanisms in two mammalian olfactory sense organs. Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2365–2369. doi: 10.1073/pnas.93.6.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Biel M., Altenhofen W., Hullin R., Ludwig J., Freichel M., Flockerzi V., Dascal N., Kaupp U. B., Hofmann F. Primary structure and functional expression of a cyclic nucleotide-gated channel from rabbit aorta. FEBS Lett. 1993 Aug 23;329(1-2):134–138. doi: 10.1016/0014-5793(93)80209-d. [DOI] [PubMed] [Google Scholar]
  7. Biel M., Zong X., Distler M., Bosse E., Klugbauer N., Murakami M., Flockerzi V., Hofmann F. Another member of the cyclic nucleotide-gated channel family, expressed in testis, kidney, and heart. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3505–3509. doi: 10.1073/pnas.91.9.3505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Biel M., Zong X., Ludwig A., Sautter A., Hofmann F. Molecular cloning and expression of the Modulatory subunit of the cyclic nucleotide-gated cation channel. J Biol Chem. 1996 Mar 15;271(11):6349–6355. doi: 10.1074/jbc.271.11.6349. [DOI] [PubMed] [Google Scholar]
  9. Bradley J., Li J., Davidson N., Lester H. A., Zinn K. Heteromeric olfactory cyclic nucleotide-gated channels: a subunit that confers increased sensitivity to cAMP. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8890–8894. doi: 10.1073/pnas.91.19.8890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bradley J., Zhang Y., Bakin R., Lester H. A., Ronnett G. V., Zinn K. Functional expression of the heteromeric "olfactory" cyclic nucleotide-gated channel in the hippocampus: a potential effector of synaptic plasticity in brain neurons. J Neurosci. 1997 Mar 15;17(6):1993–2005. doi: 10.1523/JNEUROSCI.17-06-01993.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bönigk W., Müller F., Middendorff R., Weyand I., Kaupp U. B. Two alternatively spliced forms of the cGMP-gated channel alpha-subunit from cone photoreceptor are expressed in the chick pineal organ. J Neurosci. 1996 Dec 1;16(23):7458–7468. doi: 10.1523/JNEUROSCI.16-23-07458.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chen T. Y., Illing M., Molday L. L., Hsu Y. T., Yau K. W., Molday R. S. Subunit 2 (or beta) of retinal rod cGMP-gated cation channel is a component of the 240-kDa channel-associated protein and mediates Ca(2+)-calmodulin modulation. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11757–11761. doi: 10.1073/pnas.91.24.11757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chen T. Y., Peng Y. W., Dhallan R. S., Ahamed B., Reed R. R., Yau K. W. A new subunit of the cyclic nucleotide-gated cation channel in retinal rods. Nature. 1993 Apr 22;362(6422):764–767. doi: 10.1038/362764a0. [DOI] [PubMed] [Google Scholar]
  14. Chen T. Y., Yau K. W. Direct modulation by Ca(2+)-calmodulin of cyclic nucleotide-activated channel of rat olfactory receptor neurons. Nature. 1994 Apr 7;368(6471):545–548. doi: 10.1038/368545a0. [DOI] [PubMed] [Google Scholar]
  15. Coburn C. M., Bargmann C. I. A putative cyclic nucleotide-gated channel is required for sensory development and function in C. elegans. Neuron. 1996 Oct;17(4):695–706. doi: 10.1016/s0896-6273(00)80201-9. [DOI] [PubMed] [Google Scholar]
  16. Covarrubias M., Wei A. A., Salkoff L. Shaker, Shal, Shab, and Shaw express independent K+ current systems. Neuron. 1991 Nov;7(5):763–773. doi: 10.1016/0896-6273(91)90279-9. [DOI] [PubMed] [Google Scholar]
  17. Delgado R., Hidalgo P., Diaz F., Latorre R., Labarca P. A cyclic AMP-activated K+ channel in Drosophila larval muscle is persistently activated in dunce. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):557–560. doi: 10.1073/pnas.88.2.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Delgado R., Latorre R., Labarca P. Selectivity and gating properties of a cAMP-modulated, K(+)-selective channel from Drosophila larval muscle. FEBS Lett. 1995 Aug 14;370(1-2):113–117. doi: 10.1016/0014-5793(95)00784-7. [DOI] [PubMed] [Google Scholar]
  19. Dhallan R. S., Macke J. P., Eddy R. L., Shows T. B., Reed R. R., Yau K. W., Nathans J. Human rod photoreceptor cGMP-gated channel: amino acid sequence, gene structure, and functional expression. J Neurosci. 1992 Aug;12(8):3248–3256. doi: 10.1523/JNEUROSCI.12-08-03248.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Dhallan R. S., Yau K. W., Schrader K. A., Reed R. R. Primary structure and functional expression of a cyclic nucleotide-activated channel from olfactory neurons. Nature. 1990 Sep 13;347(6289):184–187. doi: 10.1038/347184a0. [DOI] [PubMed] [Google Scholar]
  21. Feng L., Subbaraya I., Yamamoto N., Baehr W., Kraus-Friedmann N. Expression of photoreceptor cyclic nucleotide-gated cation channel alpha subunit (CNGCalpha) in the liver and skeletal muscle. FEBS Lett. 1996 Oct 14;395(1):77–81. doi: 10.1016/0014-5793(96)01011-3. [DOI] [PubMed] [Google Scholar]
  22. Fesenko E. E., Kolesnikov S. S., Lyubarsky A. L. Induction by cyclic GMP of cationic conductance in plasma membrane of retinal rod outer segment. Nature. 1985 Jan 24;313(6000):310–313. doi: 10.1038/313310a0. [DOI] [PubMed] [Google Scholar]
  23. Finn J. T., Grunwald M. E., Yau K. W. Cyclic nucleotide-gated ion channels: an extended family with diverse functions. Annu Rev Physiol. 1996;58:395–426. doi: 10.1146/annurev.ph.58.030196.002143. [DOI] [PubMed] [Google Scholar]
  24. Frings S., Lynch J. W., Lindemann B. Properties of cyclic nucleotide-gated channels mediating olfactory transduction. Activation, selectivity, and blockage. J Gen Physiol. 1992 Jul;100(1):45–67. doi: 10.1085/jgp.100.1.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Frings S., Seifert R., Godde M., Kaupp U. B. Profoundly different calcium permeation and blockage determine the specific function of distinct cyclic nucleotide-gated channels. Neuron. 1995 Jul;15(1):169–179. doi: 10.1016/0896-6273(95)90074-8. [DOI] [PubMed] [Google Scholar]
  26. Gordon S. E., Downing-Park J., Zimmerman A. L. Modulation of the cGMP-gated ion channel in frog rods by calmodulin and an endogenous inhibitory factor. J Physiol. 1995 Aug 1;486(Pt 3):533–546. doi: 10.1113/jphysiol.1995.sp020832. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Gordon S. E., Zagotta W. N. Localization of regions affecting an allosteric transition in cyclic nucleotide-activated channels. Neuron. 1995 Apr;14(4):857–864. doi: 10.1016/0896-6273(95)90229-5. [DOI] [PubMed] [Google Scholar]
  28. Gordon S. E., Zagotta W. N. Subunit interactions in coordination of Ni2+ in cyclic nucleotide-gated channels. Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10222–10226. doi: 10.1073/pnas.92.22.10222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Goulding E. H., Tibbs G. R., Siegelbaum S. A. Molecular mechanism of cyclic-nucleotide-gated channel activation. Nature. 1994 Nov 24;372(6504):369–374. doi: 10.1038/372369a0. [DOI] [PubMed] [Google Scholar]
  30. Hatt H., Ache B. W. Cyclic nucleotide- and inositol phosphate-gated ion channels in lobster olfactory receptor neurons. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6264–6268. doi: 10.1073/pnas.91.14.6264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Haynes L. W., Stotz S. C. Modulation of rod, but not cone, cGMP-gated photoreceptor channels by calcium-calmodulin. Vis Neurosci. 1997 Mar-Apr;14(2):233–239. doi: 10.1017/s0952523800011378. [DOI] [PubMed] [Google Scholar]
  32. Haynes L., Yau K. W. Cyclic GMP-sensitive conductance in outer segment membrane of catfish cones. Nature. 1985 Sep 5;317(6032):61–64. doi: 10.1038/317061a0. [DOI] [PubMed] [Google Scholar]
  33. Heginbotham L., Abramson T., MacKinnon R. A functional connection between the pores of distantly related ion channels as revealed by mutant K+ channels. Science. 1992 Nov 13;258(5085):1152–1155. doi: 10.1126/science.1279807. [DOI] [PubMed] [Google Scholar]
  34. Hsu Y. T., Molday R. S. Modulation of the cGMP-gated channel of rod photoreceptor cells by calmodulin. Nature. 1993 Jan 7;361(6407):76–79. doi: 10.1038/361076a0. [DOI] [PubMed] [Google Scholar]
  35. Isacoff E. Y., Jan Y. N., Jan L. Y. Evidence for the formation of heteromultimeric potassium channels in Xenopus oocytes. Nature. 1990 Jun 7;345(6275):530–534. doi: 10.1038/345530a0. [DOI] [PubMed] [Google Scholar]
  36. Jan L. Y., Jan Y. N. Cloned potassium channels from eukaryotes and prokaryotes. Annu Rev Neurosci. 1997;20:91–123. doi: 10.1146/annurev.neuro.20.1.91. [DOI] [PubMed] [Google Scholar]
  37. Karlson K. H., Ciampolillo-Bates F., McCoy D. E., Kizer N. L., Stanton B. A. Corrigendum to "Cloning of a cGMP-gated cation channel from mouse kidney inner medullary collecting duct" [Biochim. Biophys. Acta 1236 (1995) 197-200]. Biochim Biophys Acta. 1995 Sep 13;1238(2):197–197. doi: 10.1016/0005-2736(95)00131-l. [DOI] [PubMed] [Google Scholar]
  38. Kaupp U. B. Family of cyclic nucleotide gated ion channels. Curr Opin Neurobiol. 1995 Aug;5(4):434–442. doi: 10.1016/0959-4388(95)80002-6. [DOI] [PubMed] [Google Scholar]
  39. Kaupp U. B., Niidome T., Tanabe T., Terada S., Bönigk W., Stühmer W., Cook N. J., Kangawa K., Matsuo H., Hirose T. Primary structure and functional expression from complementary DNA of the rod photoreceptor cyclic GMP-gated channel. Nature. 1989 Dec 14;342(6251):762–766. doi: 10.1038/342762a0. [DOI] [PubMed] [Google Scholar]
  40. Kingston P. A., Zufall F., Barnstable C. J. Rat hippocampal neurons express genes for both rod retinal and olfactory cyclic nucleotide-gated channels: novel targets for cAMP/cGMP function. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10440–10445. doi: 10.1073/pnas.93.19.10440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Kolesnikov S. S., Margolskee R. F. A cyclic-nucleotide-suppressible conductance activated by transducin in taste cells. Nature. 1995 Jul 6;376(6535):85–88. doi: 10.1038/376085a0. [DOI] [PubMed] [Google Scholar]
  42. Komatsu H., Mori I., Rhee J. S., Akaike N., Ohshima Y. Mutations in a cyclic nucleotide-gated channel lead to abnormal thermosensation and chemosensation in C. elegans. Neuron. 1996 Oct;17(4):707–718. doi: 10.1016/s0896-6273(00)80202-0. [DOI] [PubMed] [Google Scholar]
  43. Körschen H. G., Illing M., Seifert R., Sesti F., Williams A., Gotzes S., Colville C., Müller F., Dosé A., Godde M. A 240 kDa protein represents the complete beta subunit of the cyclic nucleotide-gated channel from rod photoreceptor. Neuron. 1995 Sep;15(3):627–636. doi: 10.1016/0896-6273(95)90151-5. [DOI] [PubMed] [Google Scholar]
  44. Labarca P., Santi C., Zapata O., Morales E., Beltr'an C., Li'evano A., Darszon A. A cAMP regulated K+-selective channel from the sea urchin sperm plasma membrane. Dev Biol. 1996 Mar 15;174(2):271–280. doi: 10.1006/dbio.1996.0072. [DOI] [PubMed] [Google Scholar]
  45. Li M., Jan Y. N., Jan L. Y. Specification of subunit assembly by the hydrophilic amino-terminal domain of the Shaker potassium channel. Science. 1992 Aug 28;257(5074):1225–1230. doi: 10.1126/science.1519059. [DOI] [PubMed] [Google Scholar]
  46. Light D. B., Schwiebert E. M., Karlson K. H., Stanton B. A. Atrial natriuretic peptide inhibits a cation channel in renal inner medullary collecting duct cells. Science. 1989 Jan 20;243(4889):383–385. doi: 10.1126/science.2463673. [DOI] [PubMed] [Google Scholar]
  47. Liman E. R., Buck L. B. A second subunit of the olfactory cyclic nucleotide-gated channel confers high sensitivity to cAMP. Neuron. 1994 Sep;13(3):611–621. doi: 10.1016/0896-6273(94)90029-9. [DOI] [PubMed] [Google Scholar]
  48. Liu D. T., Tibbs G. R., Siegelbaum S. A. Subunit stoichiometry of cyclic nucleotide-gated channels and effects of subunit order on channel function. Neuron. 1996 May;16(5):983–990. doi: 10.1016/s0896-6273(00)80121-x. [DOI] [PubMed] [Google Scholar]
  49. Liu M., Chen T. Y., Ahamed B., Li J., Yau K. W. Calcium-calmodulin modulation of the olfactory cyclic nucleotide-gated cation channel. Science. 1994 Nov 25;266(5189):1348–1354. doi: 10.1126/science.266.5189.1348. [DOI] [PubMed] [Google Scholar]
  50. Marshall J., Molloy R., Moss G. W., Howe J. R., Hughes T. E. The jellyfish green fluorescent protein: a new tool for studying ion channel expression and function. Neuron. 1995 Feb;14(2):211–215. doi: 10.1016/0896-6273(95)90279-1. [DOI] [PubMed] [Google Scholar]
  51. Misaka T., Kusakabe Y., Emori Y., Gonoi T., Arai S., Abe K. Taste buds have a cyclic nucleotide-activated channel, CNGgust. J Biol Chem. 1997 Sep 5;272(36):22623–22629. doi: 10.1074/jbc.272.36.22623. [DOI] [PubMed] [Google Scholar]
  52. Nakamura T., Gold G. H. A cyclic nucleotide-gated conductance in olfactory receptor cilia. 1987 Jan 29-Feb 4Nature. 325(6103):442–444. doi: 10.1038/325442a0. [DOI] [PubMed] [Google Scholar]
  53. Perry R. J., McNaughton P. A. Response properties of cones from the retina of the tiger salamander. J Physiol. 1991 Feb;433:561–587. doi: 10.1113/jphysiol.1991.sp018444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Picones A., Korenbrot J. I. Permeability and interaction of Ca2+ with cGMP-gated ion channels differ in retinal rod and cone photoreceptors. Biophys J. 1995 Jul;69(1):120–127. doi: 10.1016/S0006-3495(95)79881-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Ruiz M. L., London B., Nadal-Ginard B. Cloning and characterization of an olfactory cyclic nucleotide-gated channel expressed in mouse heart. J Mol Cell Cardiol. 1996 Jul;28(7):1453–1461. doi: 10.1006/jmcc.1996.0136. [DOI] [PubMed] [Google Scholar]
  56. Ruppersberg J. P., Schröter K. H., Sakmann B., Stocker M., Sewing S., Pongs O. Heteromultimeric channels formed by rat brain potassium-channel proteins. Nature. 1990 Jun 7;345(6275):535–537. doi: 10.1038/345535a0. [DOI] [PubMed] [Google Scholar]
  57. Shen N. V., Pfaffinger P. J. Molecular recognition and assembly sequences involved in the subfamily-specific assembly of voltage-gated K+ channel subunit proteins. Neuron. 1995 Mar;14(3):625–633. doi: 10.1016/0896-6273(95)90319-4. [DOI] [PubMed] [Google Scholar]
  58. Sheng M., Liao Y. J., Jan Y. N., Jan L. Y. Presynaptic A-current based on heteromultimeric K+ channels detected in vivo. Nature. 1993 Sep 2;365(6441):72–75. doi: 10.1038/365072a0. [DOI] [PubMed] [Google Scholar]
  59. Tibbs G. R., Goulding E. H., Siegelbaum S. A. Allosteric activation and tuning of ligand efficacy in cyclic-nucleotide-gated channels. Nature. 1997 Apr 10;386(6625):612–615. doi: 10.1038/386612a0. [DOI] [PubMed] [Google Scholar]
  60. Wang H., Kunkel D. D., Martin T. M., Schwartzkroin P. A., Tempel B. L. Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons. Nature. 1993 Sep 2;365(6441):75–79. doi: 10.1038/365075a0. [DOI] [PubMed] [Google Scholar]
  61. Weyand I., Godde M., Frings S., Weiner J., Müller F., Altenhofen W., Hatt H., Kaupp U. B. Cloning and functional expression of a cyclic-nucleotide-gated channel from mammalian sperm. Nature. 1994 Apr 28;368(6474):859–863. doi: 10.1038/368859a0. [DOI] [PubMed] [Google Scholar]
  62. Xu J., Yu W., Jan Y. N., Jan L. Y., Li M. Assembly of voltage-gated potassium channels. Conserved hydrophilic motifs determine subfamily-specific interactions between the alpha-subunits. J Biol Chem. 1995 Oct 20;270(42):24761–24768. doi: 10.1074/jbc.270.42.24761. [DOI] [PubMed] [Google Scholar]
  63. Yao X., Segal A. S., Welling P., Zhang X., McNicholas C. M., Engel D., Boulpaep E. L., Desir G. V. Primary structure and functional expression of a cGMP-gated potassium channel. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11711–11715. doi: 10.1073/pnas.92.25.11711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Yau K. W., Nakatani K. Light-suppressible, cyclic GMP-sensitive conductance in the plasma membrane of a truncated rod outer segment. Nature. 1985 Sep 19;317(6034):252–255. doi: 10.1038/317252a0. [DOI] [PubMed] [Google Scholar]
  65. Yu W. P., Grunwald M. E., Yau K. W. Molecular cloning, functional expression and chromosomal localization of a human homolog of the cyclic nucleotide-gated ion channel of retinal cone photoreceptors. FEBS Lett. 1996 Sep 16;393(2-3):211–215. doi: 10.1016/0014-5793(96)00889-7. [DOI] [PubMed] [Google Scholar]
  66. Zagotta W. N., Siegelbaum S. A. Structure and function of cyclic nucleotide-gated channels. Annu Rev Neurosci. 1996;19:235–263. doi: 10.1146/annurev.ne.19.030196.001315. [DOI] [PubMed] [Google Scholar]
  67. del Pilar Gomez M., Nasi E. Activation of light-dependent K+ channels in ciliary invertebrate photoreceptors involves cGMP but not the IP3/Ca2+ cascade. Neuron. 1995 Sep;15(3):607–618. doi: 10.1016/0896-6273(95)90149-3. [DOI] [PubMed] [Google Scholar]

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