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Cyclic-nucleotide-gated channels mediate synaptic feedback by nitric oxide

Nature volume 390, pages 694–698 (1997)Cite this article

Abstract

Cyclic-nucleotide-gated (CNG) channels in outer segments of vertebrate photoreceptors generate electrical signals in response to changes in cyclic GMP concentration during phototransduction1. CNG channels also allow the influx of Ca2+, which is essential for photoreceptor adaptation2. In cone photoreceptors, cGMP triggers an increase in membrane capacitance indicative of exocytosis, suggesting that CNG channels are also involved in synaptic function3. Here we examine whether CNG channels reside in cone terminals and whether they regulate neurotransmitter release, specifically in response to nitric oxide (NO), a retrograde transmitter that increases cGMP synthesis and potentiates synaptic transmission in the brain4,5,6. Using intact retina, we show that endogenous NO modulates synapses between cones and horizontal cells. In experiments on isolated cones, we show directly that CNG channels occur in clusters and are indirectly activated by S-nitrosocysteine (SNC), an NO donor. Furthermore, both SNC and pCPT–cGMP, a membrane-permeant analogue of cGMP, trigger the release of transmitter from the cone terminals. The NO-induced transmitter release is suppressed by guanylate cyclase inhibitors and prevented by direct activation of CNG channels, indicating that their activation is required for NO to elicit release. These results expand our view of CNG channel function to include the regulation of synaptic transmission and mediation of the presynaptic effects of NO.

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Figure 1: Responses of cone terminals to pCPT–cGMP.
Figure 2: Steady-state I–V curves of the pCPT–cGMP-activated and voltage-gated Ca2+currents.
Figure 3: CNG channels in cone terminals.
Figure 4: Modulation of cone synapses by NO.
Figure 5: Biosensor measurements of transmitter release from cone terminals.

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References

  1. Yau, K.-W. & Baylor, D. A. Cyclic GMP-activated conductance of retinal photoreceptor cells. Annu. Rev. Neurosci. 12, 289–327 (1989).

    Article  CAS  PubMed  Google Scholar 

  2. Koutalos, Y. & Yau, K.-W. Regulation of sensitivity in vertebrate rod photoreceptors by calcium. Trends Neurosci. 19, 73–81 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Rieke, F. & Schwartz, E. A. AcGMP-gated current can control exocytosis at cone synapses. Neuron 13, 863–873 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Garthwaite, J., Charles, S. J. & Chess-Williaams, R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336, 385–388 (1988).

    Article  CAS  PubMed  ADS  Google Scholar 

  5. O'Dell, T. J., Hawkins, R. D., Kandel, E. R. & Arancio, O. Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger. Proc. Natl Acad. Sci. USA 88, 11285–11289 (1991).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  6. Schuman, E. M. & Madison, D. V. Nitric oxide and synaptic function. Annu. Rev. Neurosci. 17, 153–183 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Maricq, A. V. & Korenbrot, J. I. Calcium and calcium-dependent chloride currents generate action potentials in solitary cone photoreceptors. Neuron 1, 503–515 (1988).

    Article  CAS  PubMed  Google Scholar 

  8. Wilkinson, M. F. & Barnes, S. The dihydropyridine-sensitive calcium channel subtypes in cone photoreceptors. J. Gen. Physiol. 107, 621–630 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Zimmerman, A. L., Yamanaka, G., Eckstein, F., Baylor, D. A. & Stryer, L. Interaction of hydrolysis-resistant analogs of cyclic GMP with the phosphodiesterase and light-sensitive channel of retinal rod outer segments. Proc. Natl Acad. Sci. USA 82, 8813–8817 (1985).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  10. Watanabe, S.-I. & Matthews, G. Regional distribution of cGMP-activated ion channels in the plasma membrane of the rod photoreceptor. J. Neurosci. 8, 2334–2337 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liepe, B. A., Stone, C., Koistinaho, J. & Copenhagen, D. R. Nitric oxide synthase in Muller cells and neurons of salamander and fish retina. J. Neurosci. 14, 7641–7654 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kurenny, D. R. et al.Modulation of ion channels in rod photoreceptors by nitric oxide. Neuron 13, 315–324 (1995).

    Article  Google Scholar 

  13. Koch, K. W., Lambrecht, H. G., Haberecht, M., Redburn, D. & Schmidt, H. H. Functional coupling of a Ca2+/calmodulin-dependent nitric oxide synthase and a soluble guanylyl cyclase in vertebrate photoreceptor cells. EMBO J. 13, 3312–3320 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baylor, D. A., Fuortes, M. G. F. & O'Bryan, P. M. Receptive fields of single cones in the retina of the turtle. J. Physiol. (Lond.) 214, 265–294 (1971).

    Article  CAS  PubMed  Google Scholar 

  15. Piccolino, M., Neyton, J. & Gerschenfeldd, H. M. Centre-surround antagonism in small-field luminosity horizontal cells of turtle retina. J. Neurophysiol. 45, 363–375 (1981).

    Article  CAS  PubMed  Google Scholar 

  16. Wu, S. M. Synaptic transmission in the outer retina. Annu. Rev. Physiol. 56, 141–168 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Garthwaite, J. et al.Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Mol. Pharmacol. 48, 184–188 (1995).

    CAS  PubMed  Google Scholar 

  18. Broillet, M.-C. & Firestein, S. Direct activation of the olfactory cyclic nucleotide-gated channel through modification of sulfhydryl groups by NO compounds. Neuron 16, 377–385 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Copenhagen, D. R. & Jahr, C. E. Release of endogenous excitatory amino acids from turtle photoreceptors. Nature 341, 536–539 (1989).

    Article  CAS  PubMed  ADS  Google Scholar 

  20. Tachibana, M. & Okada, T. Release of endogenous excitatory amino acids from ON-type bipolar cells isolated from the goldfish retina. J. Neurosci. 11, 2199–2208 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mulsch, A., Busse, R., Liebau, S. & Forstermann, U. LY83583 interferes with the release of endothelium-derived relaxing factor and inhibits soluble guanylate cyclase. J. Pharmacol. Exp. Ther. 247, 282–288 (1988).

    Google Scholar 

  22. Barnes, S. & Hille, B. Ionic channels of the inner segment of tiger salamander cone photoreceptors. J. Gen. Physiol. 94, 719–743 (1989).

    Article  CAS  PubMed  Google Scholar 

  23. Normann, R. A. & Perlman, I. Signal transmission from red cones to horizontal cells in the turtle retina. J. Physiol. (Lond.) 286, 509–524 (1979).

    Article  CAS  PubMed  Google Scholar 

  24. Meffert, M. K., Premack, B. A. & Schulman, H. Nitric oxide stimulates Ca2+-independent synaptic vesicle release. Neuron 12, 1235–1244 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Arancio, O., Kandel, E. R. & Hawkins, R. D. Activity-dependent long-term enhancement of transmitter release by presynaptic 3′,5′-cyclic GMP in cultured hippocampal neurons. Nature 376, 74–80 (1995).

    Article  CAS  PubMed  ADS  Google Scholar 

  26. 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. USA 93, 10440–10445 (1996).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  27. Bradley, J. et al.Functional expression of the heteromeric “olfactory” cyclic nucleotide-gated channel in the hippocampus: a potential effector of synaptic plasticity in brain neurons. J. Neurosci. 17, 1993–2005 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Finn, J. T., Grunwald, M. E. & Yau, K.-W. Cyclic nucleotide-gated ion channels: an extended family with diverse functions. Annu. Rev. Physiol. 58, 395–426 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Horn, R. Estimating the number of channels in patch recordings. Biophys. J. 60, 433–439 (1991).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  30. Dixon, D. B. & Copenhagen, D. R. Metabotropic glutamate receptor-mediated suppression of an inward rectifier current is linked via a cGMP cascade. J. Neurosci. (1997) (in the press).

  31. Barnes, S. & Deschenes, M. C. Contribution of Ca and Ca-activated Cl channels to regenerative depolarization and membrane bistability of cone photoreceptors. J. Neurophysiol. 68, 745–755 (1992).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank D. Eng for help with preliminary experiments; S. Nawy and R. Bookman for comments; and D. Dixon for advice on horizontal cell culture. This work was supported by grants from the NIH and the American Heart Association (R.H.K.), and the MRC Canada and the AHFMR (S.B.).

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  1. Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, 33101, Florida, USA

    Alexei Savchenko & Richard H. Kramer

  2. Neuroscience Research Group, University of Calgary, Calgary, T2N 4N1, Alberta, Canada

    Steven Barnes

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Correspondence to Richard H. Kramer.

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Savchenko, A., Barnes, S. & Kramer, R. Cyclic-nucleotide-gated channels mediate synaptic feedback by nitric oxide. Nature 390, 694–698 (1997). https://doi.org/10.1038/37803

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