A Model of the Light Dependent Regulation of Retinal Rod Phosphodiesterase, Guanylate Cyclase and the Cation Flux

  • M. W. Bitensky
  • D. Torney
  • A. Yamazaki
  • M. M. Whalen
  • J. S. George
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 221)


In the 1880’s Kuhn dissected dark adapted eyes and observed that the retina’s red/purple “visual pigment”, changed rapidly to a pale yellow upon illumination. Years later, George Wald and Ruth Hubbard chemically characterized the rod visual pigment as consisting of opsin and 11-cis retinal (Wald, 1968). They demonstrated that the photoisomerization of rhodopsin was driven by a photon induced change in the configuration of 11-cis retinal (to all-trans), which was accompanied by conformational changes in the protein opsin. Subsequently, Wald, Yoshizawa and others were able to identify a series of spectral intermediates that appeared in rapid succession following the illumination of rhodopsin. The early intermediates could only be captured by stabilization at low temperatures or ultrafast spectroscopy. The major opsin photoconformers are called batho, hypso, meta I, meta II and meta III rhodopsin (Wald 1968; Birge, 1981). The meta II conformation was subsequently found to be enzymatically active (see below).


Outer Segment Guanylate Cyclase Light Response Disk Membrane Guanylate Cyclase Activity 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bastian, B. L. and Fain, G. L., The Effects of Sodium Replacement on the Responses of Toad Roads, J. Physiol. (London) 330:331–347 (1982).Google Scholar
  2. Birge, R. R., Photophysics of Light Transduction in Rhodopsin and Bacterio-rhodopsin, Ann. Rev. Biophys. Bioeng. 10:315–354 (1981).CrossRefGoogle Scholar
  3. Bitensky, M. W., Gorman, R. E. and Miller, W. H., Adenyl Cyclase as a Link Between Photon Capture and Changes in Membrane Permeability and Frog Photoreceptors, Proc. Natl. Acad. Sci. USA 68:561–562 (1971).CrossRefGoogle Scholar
  4. Bitensky, M. W., Wheeler, M. A., Rasenick, M. M., Yamazaki, A., Stein, P. J., Halliday, K. R. and Wheeler, G. L., Functional Exchange of Components Between Light-activated Phosphosiesterase and Hormone-activated Adenylate Cyclase, Proc. Natl. Acad. Sci. USA 79:3408–3412 (1982).CrossRefGoogle Scholar
  5. Bitensky, M. W. and Yamazaki, A., Inhibition of Testis Adenylate Cyclase by Rod PDE Inhibitor, in preparation.Google Scholar
  6. Bownds, M. D., Biochemical Steps in Visual Transduction: Roles for Nucleotides and Calcium Ions, Photochem. Photobiol. 32:487–490 (1980).CrossRefGoogle Scholar
  7. Brown, J. E., Coles, J. A. and Pinto, L. H., Effect of Injections of Calcium and EGTA into the Outer Segments of Retinal Rods of Bufo Marinus, J. Physiol. (London) 269:707–722 (1977).Google Scholar
  8. Burnside, M. B., Possible Roles of Microtubules and Actin-Filaments in Retinal Pigmented Epithelium, Exp. Eye Res. 23:257–275 (1978).CrossRefGoogle Scholar
  9. Cerrone, R. A., Codina, J., Kilpatrick, B. F., Staniszewski, C., Gershik, P., Somers, R. L., Spiegel, A. M., Birnbaumer, L., Caron, M. G. and Lefkowitz, R. J., Transducin and the Inhibitory Nucleotide Regulatory Protein Inhibit the Stimulatory Nucleotide Regulation Protein Mediated Stimulation of Adenylate Cyclase in Phospholipid Vesicle Systems, Bio-chem. 24:4499–4503 (1985).Google Scholar
  10. Cervetto, L., McNaughton, P. A. and Nunn, B. J., Calcium Current and Aequo-rin Signals in Isolated Salamander Rods, Biophys. J. 49:281a (1986).CrossRefGoogle Scholar
  11. Cohen, A. I., Hall, I. A. and Ferrendelli, J. A., Calcium and Cyclic Nucleotide Regulation in Incubated Mouse Retinas, J. Gen. Physiol. 71:595–610 (1978).CrossRefGoogle Scholar
  12. Fesenko, E. E., Kolesnikov, S. S. and Lyubarsky, A. L., Induction by Cyclic GMP of Cationic Conductance in Plasma Membrane of Retinal Rod Outer Segments, Nature (London) 313:310–313 (1985).CrossRefGoogle Scholar
  13. Foster, K. W., Saranak, J., Patel, N., Zarilli, G., Okabe, M., Kline, T. and Nakanishi, K. A., Rhodopsin is the Functional Photoreceptor for Photoaxis in the Unicellular Eukaryote Chlamydomonas, Nature 311:756–759 (1984).CrossRefGoogle Scholar
  14. Fung, B. K.-K. and Stryer, L., Photolyzed Rhodopsin Catalyzes the Exchange of GTP for Bound GTP in Retinal Rod Outer segments, Proc. Natl. Acad. Sci. USA 77:2500–2504 (1980).CrossRefGoogle Scholar
  15. George, J. S. and Hagins, W. A., Control of Ca2+ in Rod Outer Segment Disks by Light and Cyclic GMP, Nature (London) 303:344–348 (1983).CrossRefGoogle Scholar
  16. Gold, G. H., Photoreceptor Coupling — Its Mechanism and Consequences, Curr. Top. Membr. Transp. 15:59–89 (1981).CrossRefGoogle Scholar
  17. Gold, G. H. and Korenbrot, J. I., Light-Induced Calcium Release by Intact Retinal Rods, Proc. Natl. Acad. Sci. USA 77:5557–5561 (1980).CrossRefGoogle Scholar
  18. Goldberg, N. D., Ames III, A., Gander, J. E. and Walseth, T. F., Magnitude of Increase in cGMP Metabolic Flux Determined by 18O Incorporation into Nucleotide-phosphoryls Corresponds with Intensity of Photic Stimulation, J. Biol. Chem. 258:9213–9219 (1983).Google Scholar
  19. Hagins, W. A., The Visual Process: Excitatory Mechanisms in the Primary Receptor Cells, Ann. Rev. Biophys. Bioengr. 1:131–158 (1972).CrossRefGoogle Scholar
  20. Hagins, W. A. and Yoshikami, S., A Role for Ca2+ in Excitation of Retinal Rods and Cones, Exp. Eye Res. 18:299–305 (1975).CrossRefGoogle Scholar
  21. Hagins, W. A. and Yoshikami, S., in: Vertebrate Photoreception, H. B. Barlow and P. Fatt, eds. Academic, New York (1977).Google Scholar
  22. Hagins, W. A., Penn, R. D. and Yoshikami, S., Dark Current and Photocurrent in Retinal Rods, Biophys. J. 10:380–412 (1970).CrossRefGoogle Scholar
  23. Hartline, H. K., Wagner, H. G. and MacNichol, E. F., The Peripheral Origin of Nervous Activity in the Visual System, Cold Spring Harbor Symp. Quant. Biol. 17:125–142 (1952).CrossRefGoogle Scholar
  24. Hecht, S., Schlaer, S. and Pirenne, M. H., Energy, Quanta and Vision, J. Gen. Physiol. 25:819–840 (1942).CrossRefGoogle Scholar
  25. Kakiuchi, S. and Rall, T. W., The Influence of Chemical Agents on the Accumulation of Adenesine, 3′,5′-Phosphate in Slices of Rabbit Cerebellum, Mol. Pharmacol. 4:367–388 (1968).Google Scholar
  26. Kanaho, Y., Tasi, S. C., Adamik, R., Hewlitt, E. L., Mass, J. and Vaughan, M., Rhodopsin-Enhanced GTPase Activity of the Inhibitory GTP Binding Protein of Adenylate Cyclase, J. Biol. Chem. 259:7378–7381 (1985).Google Scholar
  27. Keirns, J. J., Miki, N., Bitensky, M. W. and Keirns, M., A Link Between Rhodopsin and Disc Membrane Cyclic Nucleotide Phosphodiesterase Action Spectrum and Sensitivity to Illumination, Biochemistry 4:2760–2766 (1975).CrossRefGoogle Scholar
  28. Kuffler, S. W. and Nichols, J. G., From Neuron to Brain (Sinauer Associates, Sunderland, Mass, 1976).Google Scholar
  29. Lamb, T. D., McNaughton, P. A. and Yau, K.-W., Spatial Spread of Activation and Background Desensitization in Toad Rod Outer Segments, J. Physiol. (London) 319:463–496 (1981).Google Scholar
  30. Liebman, P. A. and Pugh, E. N., Current Topics in Membrane and Transport, 15:157–170 (1981).CrossRefGoogle Scholar
  31. Lipton, S. A., Rasmussen, H. and Dowling, J. E., Electrical and Adaptive Properties in Rod Photoreceptors in Bufo Marinus II, J. Gen. Physiol. 70:771–791 (1977).CrossRefGoogle Scholar
  32. Mathews, H. R., Torre, V. and Lamb, T. D., Effects on the Photoresponse of Calcium Buffers and Cyclic GMP incorporated into Cytoplasm of Retinal Rods, Nature 313:582–585.Google Scholar
  33. Matthews, G. and Baylor, D. A., The Photocurrent and Dark Current of Retinal Rods, Curr. Top. Membr. Transp. 15:3–18 (1981).CrossRefGoogle Scholar
  34. Miki, N., Baraban, J. M., Keirns, J. J., Boyce, J. J. and Bitensky, M. W., Purification and Properties of Light-activated Cyclic Nucleotide Phosphodiesterase of Rod Outer Segments, Biol. Chem. 250:6320–6327 (1975).Google Scholar
  35. Miller, D. L. and Korenbrot, J., Light-activated GTPase in Vertebrate Photoreceptors: Regulation of Light-activated Phosphodiesterase, Biophys. J. 49:281a (1986).CrossRefGoogle Scholar
  36. Miller, W. H. and Nicol, G. D., Molecular Mechanisms of Visual Transduction, Curr. Top. Membr. Transp. 15:417–437 (1981).CrossRefGoogle Scholar
  37. Miller, W. H. and Nicol, G. D., Evidence that Cyclic GMP Regulates Membrane Potential in Photoreceptors, Nature (London) 280:64–66 (1979).CrossRefGoogle Scholar
  38. Nakatani, K. and Yau, K.-W., cGMP Opens the Light-sensitive Conductance in Retinal Rods, Nature 313:379–392 (1985).Google Scholar
  39. Nicol, G. D. and Miller, W. H., Cyclic GMP — Injected into Retinal Rod Outer Segments Increases Latency and Amplitude of Response to Illumination, Proc. Natl. Acad. Sci. USA 75:5217–5220 (1978).CrossRefGoogle Scholar
  40. Pannbacker, R. G., Control of Guanylate Cyclase Activity in Rod Outer Segments, Science 182:1138–1140 (1973).CrossRefGoogle Scholar
  41. Papermaster, D. S., Schneider, B. G., Zorn, M. A. and Kraechenbuhl, J. P., Immunocytochemical Localization of a Large Intrinsic Membrane Protein to the Incisures and Margins of Frog Outer Segment Discs, J. Cell. Biol. 79:415–425 (1978).CrossRefGoogle Scholar
  42. Papermaster, D. S., Schneider, B. G., Sorn, M. A. and Kraenchbuhl, J. P., Immunocytochemical Localization of Opsin in Outer Segments and Golgi Zones of Frog Photoreceptor Cells. An Electron Microscopic Analysis of Cross-linked Albumin-embedded Retinas, J. Cell. Biol. 77:196–210 (1978).CrossRefGoogle Scholar
  43. Pober, J. S. and Bitensky, M. W., Light-regulated Enzymes of Vertebrate Retinal Rods, Adv. Cyclic. Nucleotides. Res. 11:265–301 (1979).Google Scholar
  44. Puckett, K. L., Aronson, E. T. and Goldin, S. M., ATP-dependent Calcium Uptake Activity Associated with a Disk Membrane Fraction Isolated from Bovine Retinal Rod Outer Segments, Biochemistry 24:390–400 (1985).CrossRefGoogle Scholar
  45. Schmidt, S. Y., Phosphatidylinositol Synthesis and Phosphorylation are Enhanced by Light in Rat Retinas, J. Biol. Chem. 256:6863–6868 (1983).Google Scholar
  46. Schroder, W. H. and Fain, G. L., Light-dependent Calcium Release from Photoreceptors Measured by Laser Micromass Analysis, Nature 309:268–270 (1984).CrossRefGoogle Scholar
  47. Shinozawa, T., Uchida, S., Martin, E., Cafisco, D., Hubbell, W. and Bitensky, M. W., Additional Component Required for Activity and Reconstitution of Light-activated Vertebrate Photoreceptor GTPase, Proc. Natl. Acad. Sci. USA 77:1408–1411 (1980).CrossRefGoogle Scholar
  48. Shinozawa, T., Sen, I., Wheeler, G. L. and Bitsensky, M. W., Predictive Value of the Analogy Between Hormone-sensitive Adenylate Cyclase and Light-sensitive Photoreceptor cGMP Phosphodiesterase: A Specific Role for a Light-sensitive GTPase as a Component in the Activation Sequence, J. Supramolec. Struct. 10:185–190 (1979).CrossRefGoogle Scholar
  49. Smith, H. G. and Bauer, P. J., Light-induced Permeability Change in Sonicated Bovine Disks: Aresenazo III and Flow System Measurements, Biochemistry 18:5067–5073 (1979).CrossRefGoogle Scholar
  50. Sterling, P., Microcircuitry of the Cat Retina, Ann. Rev. Neurosci. 6:149–185 (1983).CrossRefGoogle Scholar
  51. Stryer, L., Hurley, J. B. and Fung, B. K.-K., Transducin: An Amplifier Protein in Vision, Trends in Biochem. Sci. 6:245–247 (1981).CrossRefGoogle Scholar
  52. Tomita, T., Electrical Activity of Vertebrate Photoreceptors, Quant. Rev. Biophys. 3:179–222 (1970).CrossRefGoogle Scholar
  53. Torney, D. C. and Bitensky, M. W., Computer Simulation of the Light Response of Vertebrate Rods, Biophys. J. 49:31a (1986).CrossRefGoogle Scholar
  54. Uchida, S., Wheeler, G. L., Yamazaki, A. and Bitensky, M. W., A GTP-protein Activator of Phosphodiesterase which forms in Response to Bleached Rhodopsin, J. Cyclic Nucleotide Res. 7:95–104 (1981).Google Scholar
  55. Wald, G., Molecular Basis of Visual Excitation, Nature (London) 219:800–807 (1968).CrossRefGoogle Scholar
  56. Waloga, G. and Anderson, R. E., Effects of Inositol-1, 4, 5-trisphosphate Injections into Salamander Rods, Biochem. Biophys. Res. Comm. 126:59–62 (1985).CrossRefGoogle Scholar
  57. Wheeler, G. L. and Bitensky, M. W., A Light-activated GTPase in Vertebrate Photoreceptors: Regulation of Light-activated Phosphodiesterase, Proc. Natl. Acad. Sci. USA 74:4238–4242 (1977).CrossRefGoogle Scholar
  58. Wheeler, G. L., Matuo, Y. and Bitensky, M. W., Light-activated GTPase in Vertebrate Photoreceptors, Nature (London) 269:822 (1977).CrossRefGoogle Scholar
  59. Wilden, U., Hall, S. W. and Kuhn, H., ’PDE Activation by Phosphorylated Rodopsin is Quenched when Rhodopsin is Phosphorylated and Binds Intrinsic 48-kDa Protein of Rod Outer Segment, Proc. Natl. Acad. Sci. USA 83: 1174–1178 (1986).CrossRefGoogle Scholar
  60. Yamazaki, A., Stein, P. J., Chernoff, N. and Bitensky, M. W., Activation Mechanism of Rod Outer Segment Cyclic GMP Phosphodiesterase: Release of Inhibitor by the GDP/GTP Binding Protein, J. Biol. Chem. 258:8188–8194 (1983).Google Scholar
  61. Yamazaki, A., Sen, I., Casnelli, J., Greengard, P. and Bitensky, M. W., Cyclic GMP-specific, High Affinity, Non-catalytic Binding Sites on Light-Activated Phosphodiesterase, J. Biol. Chem. 255:11619–11624 (1980).Google Scholar
  62. Yamazaki, A., Bartucca, F., Ting, A. and Bitensky, M. W., Reciprocal Effects of an Inhibitory factor on Catalytic Activity and Noncatalytic cGMP Binding Sites of Rod Phosphodiesterase, Proc. Natl. Acad. Sci. USA 79:3702–3706 (1982).CrossRefGoogle Scholar
  63. Yau, K.-W. and Nakatani, K., Light-suppressible, Cyclic GMP-sensitive Conductance in the Plasma Membrane of a Truncated Rod Outer Segment, Nature (London) 317:252–255 (1985).CrossRefGoogle Scholar
  64. Yau, K.-W. and Nakatani, K., Light-induced Reduction of Cytoplasmic Free Calcium in Retinal Rod Outer Segment, Nature (London) 313:579–582 (1985).CrossRefGoogle Scholar
  65. Yau, K.-W., McNaughton, P. A. and Hodgkin, A., Effect of Ions on the Light-sensitive Current in Retinal Rods, Nature (London) 292:502–505 (1981).CrossRefGoogle Scholar
  66. Yee, R. and Liebman, P. A., Light-activated Phosphodiesterase of the Rod Outer Segment: Kinetics and Parameters of Activation and Deactivation, J. Biol. Chem. 253:8902–8909 (1983).Google Scholar
  67. Yoshikami, S. and Hagins, W. A., Control of the Dark Current in Vertebrate Rods and Cones in: Biochemistry and Physiology of Visual Pigments, pp 245–255, H. Langer, ed., Springer-Verlag, New York (1973).CrossRefGoogle Scholar
  68. Yoshikami, S., George J. S. and Hagins, W. A., Light-induced Calcium Fluxes from Outer Segment Layer of Vertebrate Retinas, Nature (London) 286: 395–398 (1980).CrossRefGoogle Scholar
  69. Young, R. W., Visual Cells and Concept of Renewal, Invest. Ophthalmol. 15: 700–725 (1976).Google Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • M. W. Bitensky
    • 1
  • D. Torney
    • 1
  • A. Yamazaki
    • 1
  • M. M. Whalen
    • 1
  • J. S. George
    • 1
  1. 1.Los Alamos National LaboratoryLos AlamosUSA

Personalised recommendations