Advertisement

Tuning Outer Segment Ca2+Homeostasis to Phototransduction in Rods and Cones

  • Juan I. Korenbrot
  • Tatiana I. Rebrik
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 514)

Abstract

Cone photoreceptors respond to light with less sensitivity, faster kinetics and adapt over a much wider range of intensities than do rods. These differences can be explained, in part, by the quantitative differences in the molecular processes that regulate the cytoplasmic free Ca2+concentration in the outer segment of both receptor types. Ca2+concentration is regulated through the kinetic balance between the ions’ influx and efflux and the action of intracellular buffers. Influx is passive and mediated by the cyclic-GMP gated ion channels. In cones, Ca2+ions carry about 35% of the ionic current flowing through the channels in darkness. In rods, in contrast, this fraction is about 20%. We present a kinetic rate model of the ion channels that helps explain the differences in their Ca2+fractional flux. In cones, but not in rods, the cGMP-sensitivity of the cyclic GMP-gated ion channels changes with Ca2+at the concentrations expected in dark-adapted photoreceptors. Ca2+efflux is active and mediated by a Na+and K+dependent exchanger. The rate of Ca2+clearance mediated by the exchanger in cones, regardless of the absolute size of their outer segment is of the order of tens of milliseconds. In rod outer segments, and again independently of their size, Ca2+clearance rate is of the order of hundreds of milliseconds to seconds. We investigate the functional consequences of these differences in Ca2+homeostasis using computational models of the phototransduction signal in rods and cones. Consistent with experimental observation, differences in Ca2+homeostasis can make the cone’s flash response faster and less sensitive to light than that of rods. In the simulations, however, changing Ca2+homeostasis is not sufficient to recreate authentic cone responses. Accelerating the rate of inactivation (but NOT activation) of the enzymes of the transduction cascade, in addition, to changes in Ca2+homeostasis are needed to explain the differences between rod and cone photosignals.

The large gain and precise kinetic control of the electrical photoresponse of rod and cone retinal receptors suggested a long time back that phototransduction is mediated by cytoplasmic second messengers that, in turn, control membrane ionic conductance.1 The unquestionable identification of cyclic GMP as the phototransduction messenger, however, did not come until the mid 1980’s with the discovery that the light-regulated membrane conductance in both rods and cones is gated by this nucleotide2-4 and is, in fact, an ion channel.5-7The cyclic nucleotide gated (CNG) channels, now we know, are not just the compliant targets of light-dependent change in cytoplasmic cGMP, but actively participate in the regulation transduction through Ca2+feedback signals.

The precise magnitude and time course of the concentration changes of cGMP and Ca2+in either rods or cones remains controversial. It is clear, however, that whereas cGMP directly controls the opening and closing of the plasma membrane channels, Ca2+controls the light-sensitivity and kinetics of the transduction signal.8,9The modulatory role of Ca2+is particularly apparent in the process of light adaptation: in light-adapted rods or cones, the transduction signal generated by a given flash is lower in sensitivity and faster in time course than in dark-adapted cells. Light adaptation is compromised if Ca2+concentration changes are attenuated by cytoplasmic Ca2+buffers8,10,11 and does not occur if Ca2+concentration changes are prevented by manipulation of the solution bathing the cells.12-14Several Ca2+-dependent biochemical reactions have been identified in photoreceptors, among them:

1.ATP-dependent deactivation.15,16

2.Rhodopsin phosphorylation, through the action of recoverin (S-modulin).17-19

3.Catalytic activity of guanylyl cyclase2-22through the action of GCAP proteins.23,24,25

4.cGMP-sensitivity of the CNG channels26-29,30

A challenge in contemporary phototransduction research is to understand the details of these reactions and their role in the control of the phototransduction signal.

Transduction signals in cone photoreceptors are faster, lower in light sensitivity, and more robust in their adaptation features than those in rods (for review see refs. 31;32). A detailed molecular explanation for these differences is not at hand. However, biochemical and electrophysiological33 studies indicate that the elements in the light-activated pathway that hydrolyzes cGMP are quantitatively similar in their function in rods and cones and unlikely to account for the functional differences. Also, within the limited exploration completed todate, the Ca2+-dependence of guanylyl cyclase34 and visual pigment phosphorylation19 do not differ in rods and cones. On the other hand, data accumulated over the past few years indicate that cytoplasmic Ca2+homeostasis, while controlled through essentially identical mecha-nisms it is quantitatively very different in its features in the two photoreceptor types. Both Ca2+influx through CNG channels and the rate of Ca2+clearance from the outer segment differ between the two receptor cells. Also, the Ca2+-dependent modulation of cGMP sensitivity is larger in extent in cones than in rods. Most significantly, the concentration range of this Ca2+dependence overlaps the physiological range of light-dependent changes in cytoplasmic Ca2+level in cones, but not in rods. We briefly review some of the evidence that supports these assertions and we then provide a quantitative analysis of the possible significance of these known differences. We conclude that while differences in Ca2+homeostasis contribute importantly to explaining the differences between the two receptor types, they are alone not sufficient to explain the differences in the photoreceptor’s response. It is likely that Ca2+-independent inactivation of the transduction cascade enzymes is more rapid in cones than in rods.

Keywords

Outer Segment Striped Bass Cone Photoreceptor Tiger Salamander Cyclic Nucleotide Gate Channel 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hagins WA. The visual process: Excitatory mechanisms in the primary receptor cells. Annu Rev Biophys Bioeng 1972; 1:131–58.PubMedCrossRefGoogle Scholar
  2. 2.
    Fesenko EE, Kolesnikov SS, Lyubarski AL. Induction by cyclic GMP of cationic conductance in plasma membrane of retinal rod outer segments. Nature 1985; 313:310–13.Google Scholar
  3. 3.
    Koch KW, Kaupp UB. Cyclic GMP directly regulates a cation conductance in membranes of bovine rods by a cooperative mechanism. J Biol Chem 1985; 260:6788–800.PubMedGoogle Scholar
  4. 4.
    Matthews G. Comparison of the light-sensitive and cyclic GMP-sensitive conductances of the rod photoreceptor: noise characteristics. J Neurosci 1986; 6:2521–6.PubMedGoogle Scholar
  5. 5.
    Zimmerman AL, Baylor DA. Cyclic GMP-sensitive conductance of retinal rods consists of aqueous pores. Nature 1986; 321:70–2.PubMedCrossRefGoogle Scholar
  6. 6.
    Bodoia RD, Detwiler PB. Patch-clamp recordings of the light-sensitive dark noise in retinal rods from the lizard and frog. J Physiol 1985; 367:183–216.PubMedGoogle Scholar
  7. 7.
    Haynes LW, Kay AR, Yau KW. Single cyclic GMP-activated channel activity in excised patches of rod outer segment membrane. Nature 1986; 321:66–70.PubMedCrossRefGoogle Scholar
  8. 8.
    Korenbrot JI, Miller DL. Calcium ions act as modulators of intracellular information flow in retinal rod phototransduction. Neurosci Res Suppl 1986; 4:511–34.CrossRefGoogle Scholar
  9. 9.
    Torre V, Matthews HR, Lamb TD. Role of calcium in regulating the cyclic GMP cascade of phototransduction in retinal rods. Proc Natl Acad Sci USA 1986; 83:7109–13.PubMedCrossRefGoogle Scholar
  10. 10.
    Lamb TD, Matthews HR, Torre V. Incorporation of calcium buffers into salamander retinal rods: a rejection of the calcium hypothesis of phototransduction. J Physiol 1986; 372:315–49.PubMedGoogle Scholar
  11. 11.
    Matthews HR. Incorporation of chelator into guinea-pig rods shows that calcium mediates mammalian photoreceptor light adaptation. J Physiol 1991; 436:93–105.PubMedGoogle Scholar
  12. 12.
    Nakatani K, Yau KW. Calcium and light adaptation in retinal rods and cones. Nature 1988; 334:69–71.PubMedCrossRefGoogle Scholar
  13. 13.
    Fain GL, Lamb TD, Matthews HR et al. Cytoplasmic calcium as the messenger for light adaptation in salamander rods. J Physiol 1989; 416:215–43.PubMedGoogle Scholar
  14. 14.
    Matthews HR, Fain GL, Murphy RL et al. Light adaptation in cone photoreceptors of the salamander: a role for cytoplasmic calcium. J Physiol (Lond) 1990; 420:447–69.Google Scholar
  15. 15.
    Lagnado L, Baylor DA. Calcium controls light-triggered formation of catalytically active rhodopsin. Nature 1994; 367:273–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Sagoo MS, Lagnado L. G-protein deactivation is rate-limiting for shut-off of the phototransduction cascade. Nature 1997; 389:392–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Kawamura S. Rhodopsin phosphorylation as a mechanism of cyclic GMP phosphodiesterase regulation by S-modulin. Nature 1993; 362:855–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Chen CK, Inglese J, Lefkowitz RJ et al. Ca2+-dependent interaction of recoverin with rhodopsin kinase. J Biol Chem 1995; 270:18060–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Kawamura S, Kuwata O, Yamada M et al. Photoreceptor protein s26, a cone homologue of S-modulin in frog retina. J Biol Chem 1996; 271:21359–64.PubMedCrossRefGoogle Scholar
  20. 20.
    Lolley RN, Racz E. Calcium modulation of cyclic GMP synthesis in rat visual cells. Vision Res 1982; 22:1481–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Pepe IM, Boero A, Vergani L et al. Effect of light and calcium on cyclic GMP synthesis in rod outer segments of toad retina. Biochim Biophys Acta 1986; 889:271–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Koch KW, Stryer L. Highly cooperative feedback control of retinal rod guanylate cyclase by calcium ions. Nature 1988; 334:64–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Dizhoor AM, Olshevskaya EV, Henzel WJ et al. Cloning, sequencing, and expression of a 24-kDa Ca2+-binding protein activating photoreceptor guanylyl cyclase. J Biol Chem 1995; 270:25200–6PubMedCrossRefGoogle Scholar
  24. 24.
    Palczewski K, Subbaraya I, Gorczyca WA et al. Molecular cloning and characterization of retinal photoreceptor guanylyl cyclase-activating protein. Neuron 1994; 13:395–404.PubMedCrossRefGoogle Scholar
  25. 25.
    Gorczyca WA, Polans AS, Surgucheva I et al. Guanylyl cyclase activating protein (GCAP): a calcium sensitive regulator of phototransduction. J Biol Chem 1995; 270:22029–22036.PubMedCrossRefGoogle Scholar
  26. 26.
    Hsu YT, Molday RS. Interaction of calmodulin with the cyclic GMP-gated channel of rod photoreceptor cells. Modulation of activity, affinity purification, and localization. J Biol Chem 1994; 269:29765–70.PubMedGoogle Scholar
  27. 27.
    Bauer PJ. Cyclic GMP-gated channels of bovine rod photoreceptors: affinity, density and stoichiometry of Ca2+-calmodulin binding sites. J Physiol (Lond) 1996; 494:675–85.Google Scholar
  28. 28.
    Gordon SE, Downing-Park J, Zimmerman AL. Modulation of the cGMP-gated ion channel in frog rods by calmodulin and an endogenous inhibitory factor. J Physiol (Lond) 1995; 486:533–46.Google Scholar
  29. 29.
    Hackos DH, Korenbrot JI. Calcium modulation of ligand affinity in the cyclic GMP-gated ion channels of cone photoreceptors. J Gen Physiol 1997; 110:515–28.PubMedCrossRefGoogle Scholar
  30. 30.
    Rebrik TI, Korenbrot JI. In intact cone photoreceptors, a Ca2+-dependent, diffusible factor modulates the cGMP-gated ion channels differently than in rods. J Gen Physiol 1998; 112:537–48.PubMedCrossRefGoogle Scholar
  31. 31.
    McNaughton PA. Light response of vertebrate photoreceptors. Physiol Rev 1990; 70:847–83.PubMedGoogle Scholar
  32. 32.
    Burns ME, Baylor DA. Activation, deactivation, and adaptation in vertebrate photoreceptor cells. Annu Rev Neurosci 2001; 24:779–805.PubMedCrossRefGoogle Scholar
  33. 33.
    Hestrin S, Korenbrot JI. Activation kinetics of retinal cones and rods: response to intense flashes of light. J Neurosci 1990; 10:1967–73.PubMedGoogle Scholar
  34. 34.
    Miller JL, Korenbrot JI. Differences in calcium homeostasis between retinal rod and cone photoreceptors revealed by the effects of voltage on the cgmp-gated conductance in intact cells. J Gen Physiol 1994; 104:909–40.PubMedCrossRefGoogle Scholar
  35. 35.
    Hodgkin AL, McNaughton PA, Nunn BJ. The ionic selectivity and calcium dependence of the light-sensitive pathway in toad rods. J Physiol (Lond) 1985; 358:447–68.Google Scholar
  36. 36.
    Cervetto L, Menini A, Rispoli G et al. The modulation of the ionic selectivity of the light-sensitive current in isolated rods of the tiger salamander. J Physiol (Lond) 1988; 406:181–98.Google Scholar
  37. 37.
    Wells GB, Tanaka JC. Ion selectivity predictions from a two-site permeation model for the cyclic nucleotide-gated channel of retinal rod cells. Biophys J 1997; 72:127–40.PubMedCrossRefGoogle Scholar
  38. 38.
    Zimmerman AL, Baylor DA. Cation interactions within the cyclic GMP-activated channel of retinal rods from the tiger salamander. J Physiol (Lond) 1992; 449:759–83.Google Scholar
  39. 39.
    Ohyama T, Picones A, Korenbrot JI. Voltage-dependence of Ion Permeation in Cyclic GMP-gated ion channels is optimized for cell function in rod and cone photoreceptors. J Gen Physiol 2002; 119:341–54.PubMedCrossRefGoogle Scholar
  40. 40.
    Picones A, Korenbrot JI. Permeability and interaction of Ca2+ with cGMP-gated ion channels differ in retinal rod and cone photoreceptors. Biophys J 1995; 69:120–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Hackos DH, Korenbrot JI. Divalent cation selectivity is a function of gating in native and recombinant cyclic nucleotide-gated ion channels from retinal photoreceptors [see comments]. J Gen Physiol 1999; 113:799–818.PubMedCrossRefGoogle Scholar
  42. 42.
    Frings S, Seifert R, Godde M et al. Profoundly different calcium permeation and blockage determine the specific function of distinct cyclic nucleotide-gated channels. Neuron 1995; 15:169–79.PubMedCrossRefGoogle Scholar
  43. 43.
    Nakatani K, Yau KW. Calcium and magnesium fluxes across the plasma membrane of the toad rod outer segment. J Physiol (Lond) 1988; 395:695–729.Google Scholar
  44. 44.
    Lagnado L, Cervetto L, McNaughton PA. Calcium homeostasis in the outer segments of retinal rods from the tiger salamander. J Physiol (Lond) 1992; 455:111–42.Google Scholar
  45. 45.
    Gray-Keller MP, Detwiler PB. The calcium feedback signal in the phototransduction cascade of vertebrate rods. Neuron 1994; 13:849–61.PubMedCrossRefGoogle Scholar
  46. 46.
    Younger JP, McCarthy ST, Owen WG. Light-dependent control of calcium in intact rods of the bullfrog Rana catesbeiana. J Neurophysiol 1996; 75:354–66.PubMedGoogle Scholar
  47. 47.
    Dzeja C, Hagen V, Kaupp UB et al. Ca2+permeation in cyclic nucleotide-gated channels. EMBO J 1999; 18:131–44.PubMedCrossRefGoogle Scholar
  48. 48.
    Frings S, Hackos DH, Dzeja C et al. Determination of fractional Calcium ion current in cyclic nucleotide-gated channels. Methods Enzymol 2000; 315:797–817.PubMedCrossRefGoogle Scholar
  49. 49.
    Ohyama T, Hackos DH, Frings S et al. Fraction of the dark current carried by Ca(2+) through cGMP-gated ion channels of intact rod and cone photoreceptors. J Gen Physiol 2000; 116:735–54.PubMedCrossRefGoogle Scholar
  50. 50.
    Zagotta WN, Siegelbaum SA. Structure and function of cyclic nucleotide-gated channels. Annu Rev Neurosci 1996; 19:235–63.PubMedCrossRefGoogle Scholar
  51. 51.
    Yau, K-W and Chen, T-Y. Cyclic nucleotide-gated channels. In R. Alan North Ligand-and voltage-gated channels, 307–337. Boca Raton: CRC Press, 1995.Google Scholar
  52. 52.
    Seifert R, Eismann E, Ludwig J et al. Molecular determinants of a Ca2+-binding site in the pore of cyclic nucleotide-gated channels: S5/S6 segments control affinity of intrapore glutamates. EMBO J 1999; 18:119–30.PubMedCrossRefGoogle Scholar
  53. 53.
    Zwolinski BJ, Eyring H, Reese CE. Diffusion and Membrane Permeability. J. Phys Colloid Chem 1949; 53:1426–53.CrossRefGoogle Scholar
  54. 54.
    Hille B. Ionic selectivity, saturation, and block in sodium channels. A four-barrier model. J Gen Physiol 1975; 66:535–60.PubMedCrossRefGoogle Scholar
  55. 55.
    Andersen OS. Perspectives on ion permeation. J Gen Physiol 1999; 113:763–4.PubMedCrossRefGoogle Scholar
  56. 56.
    Zimmerman AL, Baylor DA. Cation interactions within the cyclic GMP-activated channel of retinal rods from the tiger salamander. J Physiol (Lond) 1992; 449:759–83.Google Scholar
  57. 57.
    Wells GB, Tanaka JC. Ion selectivity predictions from a two-site permeation model for the cyclic nucleotide-gated channel of retinal rod cells. Biophys J 1997; 72:127–40.PubMedCrossRefGoogle Scholar
  58. 58.
    Picones A, Korenbrot JI. Permeability and interaction of Ca2+with cGMP-gated ion channels differ in retinal rod and cone photoreceptors. Biophys J 1995; 69:120–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Yau KW, Nakatani K. Light-induced reduction of cytoplasmic free calcium in retinal rod outer segment. Nature 1985; 313:579–82.PubMedCrossRefGoogle Scholar
  60. 60.
    Miller DL, Korenbrot JI. Kinetics of light-dependent Ca fluxes across the plasma membrane of rod outer segments. A dynamic model of the regulation of the cytoplasmic Ca concentration. J Gen Physiol 1987; 90:397–425.PubMedCrossRefGoogle Scholar
  61. 61.
    McNaughton PA, Cervetto L, Nunn BJ. Measurement of the intracellular free calcium concentration in salamander rods. Nature 1986; 322:261–3.PubMedCrossRefGoogle Scholar
  62. 62.
    Bauer PJ, Drechsler M. Association of cyclic GMP-gated channels and Na(+)-Ca(2+)-K+exchangers in bovine retinal rod outer segment plasma membranes. J Physiol 1992; 451:109–31.PubMedGoogle Scholar
  63. 63.
    Korenbrot JI, Miller DL. Cytoplasmic free calcium concentration in dark-adapted retinal rod outer segments. Vision Res 1989; 29:939–48.PubMedCrossRefGoogle Scholar
  64. 64.
    McCarthy ST, Younger JP, Owen WG. Free calcium concentrations in bullfrog rods determined in the presence of multiple forms of Fura-2. Biophys J 1994; 67:2076–89.PubMedCrossRefGoogle Scholar
  65. 65.
    Sampath AP, Matthews HR, Cornwall MC et al. Light-dependent changes in outer segment free-Ca2+ concentration in salamander cone photoreceptors. J Gen Physiol 1999; 113:267–77.PubMedCrossRefGoogle Scholar
  66. 66.
    McCarthy ST, Younger JP, Owen WG. Dynamic, spatially nonuniform calcium regulation in frog rods exposed to light. J Neurophysiol 1996; 76:1991–2004.PubMedGoogle Scholar
  67. 67.
    Cobbs WH, Pugh EN Jr. Kinetics and components of the flash photocurrent of isolated retinal rods of the larval salamander, Ambystoma tigrinum. J Physiol (Lond) 1987; 394:529–72.Google Scholar
  68. 68.
    Nakatani K, Yau KW. Sodium-dependent calcium extrusion and sensitivity regulation in retinal cones of the salamander. J Physiol (Lond) 1989; 409:525–48.Google Scholar
  69. 69.
    Yau KW, Nakatani K. Light-suppressible, cyclic GMP-sensitive conductance in the plasma membrane of a truncated rod outer segment. Nature 1985; 317:252–5.PubMedCrossRefGoogle Scholar
  70. 70.
    Perry RJ, McNaughton PA. Response properties of cones from the retina of the tiger salamander JT. J Physiol (Lond) 1991; 433:561–87.Google Scholar
  71. 71.
    Nakatani K, Koutalos Y, Yau KW. Ca2+modulation of the cGMP-gated channel of bullfrog retinal rod photoreceptors. J Physiol (Lond) 1995; 484 (Pt 1):69–76.Google Scholar
  72. 72.
    Sagoo MS, Lagnado L. The action of cytoplasmic calcium on the cGMP-activated channel in salamander rod photoreceptors. J Physiol (Lond) 1996; 497:309–19.Google Scholar
  73. 73.
    Rebrik TI, Kotelnikova EA, Korenbrot JI. Time course and Ca(2+) dependence of sensitivity modulation in cyclic GMP-gated currents of intact cone photoreceptors. J Gen Physiol 2000; 116:521–34.PubMedCrossRefGoogle Scholar
  74. 74.
    Haynes LW, Stotz SC. Modulation of rod, but not cone, cGMP-gated photoreceptor channel by calcium-calmodulin. Vis Neurosci 1997; 14:233–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Forti S, Menini A, Rispoli G et al. Kinetics of phototransduction in retinal rods of the newt Triturus cristatus. J Physiol (Lond) 1989; 419:265–95.Google Scholar
  76. 76.
    Torre V, Forti S, Menini A et al. Model of phototransduction in retinal rods. Cold Spring Harb Symp Quant Biol 1990; 55:563–73.PubMedCrossRefGoogle Scholar
  77. 77.
    Sneyd J, Tranchina D. Phototransduction in cones: an inverse problem in enzyme kinetics. Bull Math Biol 1989; 51:749–84.PubMedGoogle Scholar
  78. 78.
    Tranchina D, Sneyd J, Cadenas ID. Light adaptation in turtle cones. Testing and analysis of a model for phototransduction. Biophys J 1991; 60:217–37.PubMedCrossRefGoogle Scholar
  79. 79.
    Nikonov S, Engheta N, Pugh EN Jr. Kinetics of recovery of the dark-adapted salamander rod photoresponse. J Gen Physiol 1998; 111:7–37.PubMedCrossRefGoogle Scholar
  80. 80.
    Tamura T, Nakatani K, Yau KW. Calcium feedback and sensitivity regulation in primate rods. J Gen Physiol 1991; 98:95–130.PubMedCrossRefGoogle Scholar
  81. 81.
    Hamer RD. Computational analysis of vertebrate phototransduction: combined quantitative and qualitative modeling of dark-and light-adapted responses in amphibian rods. Vis Neurosci 2000; 17:679–99.PubMedCrossRefGoogle Scholar
  82. 82.
    Duda T, Goraczniak R, Surgucheva I et al. Calcium modulation of bovine photoreceptor guanylate cyclase. Biochemistry 1996; 35:8478–82.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Juan I. Korenbrot
    • 1
  • Tatiana I. Rebrik
    • 1
  1. 1.Department of Physiology School of MedicineUniversity of California at San FranciscoSan FranciscoUSA

Personalised recommendations