Skip to main content

Mouse Models to Study GCAP Functions In Intact Photoreceptors

  • Chapter
Photoreceptors and Calcium

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 514))

Abstract

In photoreceptor cells cGMP is the second messenger that transduces light into an electrical response. Regulation of cGMP synthesis by Ca2+is one of the key mechanisms by which Caz+exerts negative feedback to the phototransduction cascade in the process of light adaptation.This Ca2+feedback to retinal guanylyl cyclases (Ret-GCs) is conferred by the guanylate cyclase-activating proteins (GCAPs). Mutations in GCAP1 that disrupt the Ca2+regulation of Ret-GCs in vitro have been associated with severe human vision disorders. This chapter focuses on recent data obtained from biochemical and electrophysiological studies of GCAP I /GCAP2 knockout mice and other GCAP transgenic mice, addressing:

1. the quantitative aspects of the Ca2+-feedback to Ret-GCs in regulating the light sensitivity and adaptation in intact rods;

2. functional differences between GCAPI and GCAP2 in intact rod photore-ceptors; and

3. whether GCAP mutants with impaired Ca2+ binding lead to retinal disease in vivo by constitutive activation ofRet-GCs and elevation of intracellular cOMP, as predicted from in vitro studies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Koch KW, Stryer L. Highly cooperative feedback control of retinal rod guanylate cyclase by calcium ions. Nature 1988; 334:64–66.

    Article  PubMed  CAS  Google Scholar 

  2. Koutalos Y, Nakatani K, Tamura T et al. Characterization of guanylate cyclase activity in single retinal rod outer segments. J Gen Physiol 1995; 106:863–890.

    Article  PubMed  CAS  Google Scholar 

  3. Koutalos Y, Yau KW. Regulation of sensitivity in vertebrate rod photoreceptors by calcium. Trends Neurosci 1996; 19:73–81.

    Article  PubMed  CAS  Google Scholar 

  4. Gorczyca WA, Polans AS, Surgucheva IG et al. Guanylyl cyclase activating protein. A calcium-sensitive regulator of phototransduction. J Biol Chem 1995; 270:22029–22036.

    Article  PubMed  CAS  Google Scholar 

  5. Dizhoor AM, Olshevskaya EV, Henzel WJ et al. Cloning, sequencing, and expression of a 24-kDa Ca(2+)-binding protein activating photoreceptor guanylyl cyclase. J Biol Chem 1995; 270:25200–25206.

    Article  PubMed  CAS  Google Scholar 

  6. Palczewski K, Subbaraya I, Gorczyca WA et al. Molecular cloning and characterization of retinal photoreceptor guanylyl cyclase-activating protein. Neuron 1994; 13:395–404.

    Article  PubMed  CAS  Google Scholar 

  7. Shyjan AW, de Sauvage FJ, Gillett NA et al. Molecular cloning of a retina-specific membrane guanylyl cyclase. Neuron 1992; 9:727–737.

    Article  PubMed  CAS  Google Scholar 

  8. Lowe DG, Dizhoor AM, Liu K et al. Cloning and expression of a second photoreceptor-specific membrane retinal guanylyl cyclase (RetGC), RetGC-2. Proc Natl Acad Sci USA 1995; 92:5535–5539.

    Article  PubMed  CAS  Google Scholar 

  9. Liu X, Seno K, Nishizawa Y et al. Ultrastructural localization of retinal guanylate cyclase in human and monkey retinas. Exp Eye Res 1994; 59:761–768.

    Article  PubMed  CAS  Google Scholar 

  10. Dizhoor AM, Lowe DG, Olshevskaya EV et al. The human photoreceptor membrane guanylyl cyclase, RetGC, is present in outer segments and is regulated by calcium and a soluble activator. Neuron 1994; 12:1345–1352.

    Article  PubMed  CAS  Google Scholar 

  11. Koch KW. Purification and identification of photoreceptor guanylate cyclase. J Biol Chem 1991; 266:8634–8637.

    PubMed  CAS  Google Scholar 

  12. Hallett MA, Delaat JL, Arikawa K et al. Distribution of guanylate cyclase within photoreceptor outer segments. J Cell Sci 1996; 109:1803–1812.

    PubMed  CAS  Google Scholar 

  13. Perrault I, Rozet JM, Calvas P et al. Retinal-specific guanylate cyclase gene mutations in Leber’s congenital amaurosis. Nat Genet 1996; 14:461–464.

    Article  PubMed  CAS  Google Scholar 

  14. Yang RB, Garbera DL. Two eye guanylyl cyclases are expressed in the same photoreceptor cells and form homomers in preference to heteromers. J Biol Chem 1997; 272:13738–13742.

    Article  PubMed  CAS  Google Scholar 

  15. Yang RB, Robinson SW, Xiong WH et al. Disruption of a retinal guanylyl cyclase gene leads to cone-specific dystrophy and paradoxical rod behavior. J Neurosci 1999; 19:5889–5897.

    PubMed  CAS  Google Scholar 

  16. Haeseleer F, Sokal I, Li N et al. Molecular characterization of a third member of the guanylyl cyclase-activating protein subfamily. J Biol Chem 1999; 274:6526–6535.

    Article  PubMed  CAS  Google Scholar 

  17. Howes K, Bronson JD, Dang YL et al. Gene array and expression of mouse retina guanylate cyclase activating proteins 1 and 2. Invest Ophthalmol Vis Sci 1998; 39:867–875.

    PubMed  CAS  Google Scholar 

  18. Otto-Bruc A, Fariss RN, Haeseleer F et al. Localization of guanylate cyclase-activating protein 2 in mammalian retinas. Proc Natl Acad Sci USA 1997; 94:4727–4732.

    Article  PubMed  CAS  Google Scholar 

  19. Cuenca N, Lopez S, Howes K et al. The localization of guanylyl cyclase-activating proteins in the mammalian retina. Invest Ophthalmol Vis Sci 1998; 39:1243–1250.

    PubMed  CAS  Google Scholar 

  20. Kachi S, Nishizawa Y, Olshevskaya E et al. Detailed localization of photoreceptor guanylate cyclase activating protein-1 and -2 in mammalian retinas using light and electron microscopy. Exp Eye Res 1999; 68:465–473.

    Article  PubMed  CAS  Google Scholar 

  21. Imanishi Y, Li N, Sowa ME et al. Characterization of retinal guanylate cyclase-activating protein 3 (GCAP3) from zebrafish to man. Eur J Neurosci 2002; 15:63–78.

    Article  PubMed  Google Scholar 

  22. Duda T, Goraczniak R, Surgucheva I et al. Calcium Modulation of Bovine Photoreceptor Guanylate Cyclase. Biochemistry 1996; 35:8478–8482.

    Article  PubMed  CAS  Google Scholar 

  23. Dizhoor AM, Hurley JB. Inactivation of EF-hands makes GCAP-2 (p24) a constitutive activator of photoreceptor guanylyl cyclase by preventing a Ca2+-induced “activator-to-inhibitor” transition. J Biol Chem 1996; 271:19346–19350.

    Article  PubMed  CAS  Google Scholar 

  24. Laura RP, Dizhoor AM, Hurley JB. The membrane guanylyl cyclase, retinal guanylyl cyclase-1, is activated through its intracellular domain. J Biol Chem 1996; 271:11646–11651.

    Article  PubMed  CAS  Google Scholar 

  25. Laura RP, Hurley JB. The kinase homology domain of retinal guanylyl cyclases 1 and 2 specifies the affinity and cooperativity of interaction with guanylyl cyclase activating protein-2. Biochemistry 1998; 37:11264–11271.

    Article  PubMed  CAS  Google Scholar 

  26. Krylov DM, Niemi GA, Dizhoor AM et al. Mapping sites in Guanylyl Cyclase Activating Protein-I required for regulation of photoreceptor membrane Guanylyl Cyclases. J Biol Chem 1999; 274:10833–10839.

    Article  PubMed  CAS  Google Scholar 

  27. Krylov DM, Hurley JB. Identification of proximate regions in a complex of retinal guanylyl cyclase I and guanylyl cyclase-activating protein-I by a novel mass spectrometry-based method. J Biol Chem 2001; 276:30648–30654.

    Article  PubMed  CAS  Google Scholar 

  28. Olshevskaya EV, Boikov S, Ermilov A et al. Mapping functional domains of the guanylate cyclase regulator protein, GCAP2. J Biol Chem 1999; 274:10823–10832.

    Article  PubMed  CAS  Google Scholar 

  29. Rudnicka-Nawrot M, Surgucheva I, Hulmes JD et al. Changes in biological activity and folding of guanylate cyclase-activating protein I as a function of calcium. Biochemistry 1998; 37:248–257.

    Article  PubMed  CAS  Google Scholar 

  30. Dizhoor AM, Boikov SG, Olshevskaya EV. Constitutive activation of photoreceptor guanylate cyclase by Y99C mutant of GCAP-1. Possible role in causing human autosomal dominant cone degeneration. J Biol Chem 1998; 273:17311–17314.

    Article  PubMed  CAS  Google Scholar 

  31. Ramamurthy V, Tucker C, Wilkie SE et al. Interactions within the coiled-coil domain of RetGC-I guanylyl cyclase are optimized for regulation rather than for high affinity. J Biol Chem 2001; 276:26218–26229.

    Article  PubMed  CAS  Google Scholar 

  32. Olshevskaya EV, Ermilov AN, Dizhoor AM. Dimerization of guanylyl cyclase-activating protein and a mechanism of photoreceptor guanylyl cyclase activation. J Biol Chem 1999; 274:25583–25587.

    Article  PubMed  CAS  Google Scholar 

  33. Yu H, Olshevskaya E, Duda T et al. Activation of retinal guanylyl cyclase-1 by Ca2+-binding proteins involves its dimerization. J Biol Chem 1999; 274:15547-I5555.

    Article  PubMed  CAS  Google Scholar 

  34. Payne AM, Downes SM, Bessant DAR et al. A mutation in guanylate cyclase activator IA (GUCA 1 A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1. Hum Mol Genet 1998; 7:273–277.

    Article  PubMed  CAS  Google Scholar 

  35. Downes SM, Holder GE, Fitzke FW et al. Autosomal dominant cone and cone-rod dystrophy with mutations in the guanylate cyclase activator 1 A gene-encoding guanylate cyclase activating protein-1. Arch Ophthalmol 2001; 119:96–105.

    Article  PubMed  CAS  Google Scholar 

  36. Wilkie SE, Newbold RJ, Decry E et al. Functional characterization of missense mutations at codon 838 in retinal guanylate cyclase correlates with disease severity in patients with autosomal dominant cone-rod dystrophy. Hum Mol Genet 2000; 9:3065–3073.

    Article  PubMed  CAS  Google Scholar 

  37. Wilkie SE, Li Y, Deery EC et al. Identification and functional consequences of a new mutation (E155G) in the gene for GCAPI that causes autosomal dominant cone dystrophy. Am J Hum Genet 2001; 69:471–480.

    Article  PubMed  CAS  Google Scholar 

  38. Sokal I, Li N, Surgucheva I et al. GCAP1(Y99C) mutant is constitutively active in autosomal dominant cone dystrophy. Mol Cell 1998; 2:129–133.

    Article  PubMed  CAS  Google Scholar 

  39. Surguchov A, Bronson JD, Banerjee P et al. The human GCAPI and GCAP2 genes are arranged in a tail-to-tail array on the short arm of chromosome 6 (p2I.I). Genomics 1997; 39:312–322.

    Article  PubMed  CAS  Google Scholar 

  40. Baylor DA, Lamb TD, Yau KW. Responses of retinal rods to single photons. J Physiol (Lond) 1979; 288:613–634.

    CAS  Google Scholar 

  41. Leskov IB, Klenchin VA, Handy JW et al. The gain of rod phototransduction: reconciliation of biochemical and electrophysiological measurements. Neuron 2000; 27:525–537.

    Article  PubMed  CAS  Google Scholar 

  42. Matthews HR, Murphy RL, Fain GL et al. Photoreceptor light adaptation is mediated by cytoplasmic calcium concentration. Nature 1988; 334:67–69.

    Article  PubMed  CAS  Google Scholar 

  43. Nakatani K, Yau KW. Calcium and light adaptation in retinal rods and cones. Nature 1988; 334:69–71.

    Article  PubMed  CAS  Google Scholar 

  44. Pepperberg DR, Cornwall MC, Kahlert M et al. Light-dependent delay in the falling phase of the retinal rod photoresponse. Vis Neurosci 1992; 8:9–18.

    Article  PubMed  CAS  Google Scholar 

  45. Rispoli G, Sather WA, Detwiler PB. Visual transduction in dialysed detached rod outer segments from lizard retina. J Physiol (Lond) 1993; 465:513–537.

    CAS  Google Scholar 

  46. Koutalos Y, Nakatani K, Yau KW. The cGMP-phosphodiesterase and its contribution to sensitivity regulation in retinal rods. J Gen Physiol 1995; 106:891–921.

    Article  PubMed  CAS  Google Scholar 

  47. Matthews HR. Actions of Ca2+ on an early stage in phototransduction revealed by the dynamic fall in Ca2+ concentration during the bright flash response. J Gen Physiol 1997; 109:141–146.

    Article  PubMed  CAS  Google Scholar 

  48. Kawamura S, and Murakami M. Calcium-dependent regulation of cyclic GMP phosphodiesterase by a protein from frog retinal rods. Nature 1991; 349:420–423.

    Article  PubMed  CAS  Google Scholar 

  49. Kawamura S. Rhodopsin phosphorylation as a mechanism of cyclic GMP phosphodiesterase regulation by S-modulin. Nature 1993; 362:855–857.

    Article  PubMed  CAS  Google Scholar 

  50. Klenchin VA, Calvert PD, Bownds MD. Inhibition of rhodopsin kinase by recoverin. Further evidence for a negative feedback system in phototransduction. J Biol Chem 1995; 270:16147–16152.

    Article  PubMed  CAS  Google Scholar 

  51. Hsu YT, Molday RS. Modulation of the cGMP-gated channel of rod photoreceptor cells by calmodulin. Nature 1993; 361:76–79.

    Article  PubMed  CAS  Google Scholar 

  52. 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; 269:29765–29770.

    PubMed  CAS  Google Scholar 

  53. Nakatani K, Koutalos Y, and Yau KW. Ca2+ modulation of the cGMP-gated channel of bullfrog retinal rod photoreceptors. J Physiol (Lond) 1995; 484:69–76.

    CAS  Google Scholar 

  54. Lolley RN, Racz E. Calcium modulation of cGMP synthesis in rat visual cells. Vision Res 1982; 22:1481–1486.

    Article  PubMed  CAS  Google Scholar 

  55. Kawamura S, Murakami M. Regulation of cGMP levels by guanylate cyclase in truncated frog rod outer segments. J Gen Physiol 1989; 94:649–668.

    Article  PubMed  CAS  Google Scholar 

  56. Hu G, Jang GF, Cowan CW et al. Phosphorylation of RGS9-I by an endogenous protein kinase in rod outer segments. J Biol Chem 2001; 276:22287–22295.

    Article  PubMed  CAS  Google Scholar 

  57. Mendez A, Burns ME, Sokal I et al. Role of guanylate cyclase-activating proteins (GCAPs) in setting the flash sensitivity of rod photoreceptors. Proc Nati Acad Sci USA 2001; 98:9948–9953.

    Article  CAS  Google Scholar 

  58. 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; 394:529–572.

    CAS  Google Scholar 

  59. Karpen JW, Zimmerman AL, Stryer L et al. Gating kinetics of the cyclic-GMP-activated channel of retinal rods: flash photolysis and voltage jump studies. Proc Natl Acad Sci USA 1988; 85:1287–1291.

    Article  PubMed  CAS  Google Scholar 

  60. Dizhoor AM, Hurley JB. Regulation of photoreceptor membrane guanylyl cyclases by guanylyl cyclase activator proteins. Methods 1999; 19:521–531.

    Article  PubMed  CAS  Google Scholar 

  61. Lamb TD, Matthews HR, Torre V. Incorporation of calcium buffers into salamander retinal rods: a rejection of the calcium hypothesis of phototransduction. J Physiol (Lond) 1986; 372:315–349.

    CAS  Google Scholar 

  62. Matthews HR, Torre V, Lamb TD. Effects on the photoresponse of calcium buffers and cyclic GMP incorporated into the cytoplasm of retinal rods. Nature 1985; 313:582–585.

    Article  PubMed  CAS  Google Scholar 

  63. Nikonov S, Engheta N, Pugh EN Jr. Kinetics of recovery of the dark-adapted salamander rod photoresponse. J Gen Physiol 1998; 111:7–37.

    Article  PubMed  CAS  Google Scholar 

  64. Korschen HG, Beyermann M, Muller F et al. Interaction of glutamic-acid-rich proteins with the cGMP signalling pathway in rod photoreceptors. Nature 1999; 400:761–766.

    Article  PubMed  CAS  Google Scholar 

  65. Sokal I, Otto-Bruc AE, Surgucheva I et al. Conformational changes in guanylyl cyclase-activating protein 1 (GCAP1) and its tryptophan mutants as a function of calcium concentration. J Biol Chem 1999; 274:19829–19837.

    Article  PubMed  CAS  Google Scholar 

  66. Chen J, Makino CL, Peachey NS et al. Mechanisms of rhodopsin inactivation in vivo as revealed by a COOH-terminal truncation mutant. Science 1995; 267:374–377.

    Article  PubMed  CAS  Google Scholar 

  67. Chen CK, Bums ME, Spencer M et al. Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase. Proc Natl Acad Sci USA 1999; 96:3718–3722.

    Article  PubMed  CAS  Google Scholar 

  68. Mendez A, Burns ME, Roca A et al. Rapid and reproducible deactivation of rhodopsin requires multiple phosphorylation sites. Neuron 2000; 28:153–164.

    Article  PubMed  CAS  Google Scholar 

  69. Kelsell RE, Gregory-Evans, K, Payne AM et al. Mutations in the retinal guanylate cyclase (RetGC-1) gene in dominant cone-rod dystrophy. Hum Mol Genet 1998; 7:1179–1184.

    Article  PubMed  CAS  Google Scholar 

  70. Semple-Rowland SL, Lee NR, Van Hooser JP et al. A null mutation in the photoreceptor guanylate cyclase gene causes the retinal degeneration chicken phenotype. Proc Natl Acad Sci USA 1998; 95:1271–1276.

    Article  PubMed  CAS  Google Scholar 

  71. Suber ML, Pittler SJ, Qin N et al. Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene. Proc Natl Acad Sci USA 1993; 90:3968–3972.

    Article  PubMed  CAS  Google Scholar 

  72. Bowes C, Li T, Frankel WN et al. Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase. Proc Natl Acad Sci USA 1993; 90:2955–2959.

    Article  PubMed  CAS  Google Scholar 

  73. Tsang SH, Burns ME, Calvert PD et al. Role for the target enzyme in deactivation of photoreceptor G protein in vivo. Science 1998; 282:117–121.

    Article  PubMed  CAS  Google Scholar 

  74. Sokal I, Li N, Verlinde C et al. Caz+-binding proteins in the retina: from discovery to etiology of human disease. Biochim Biophys Acta 2000; 1498:233–251.

    Article  PubMed  CAS  Google Scholar 

  75. Newbold RJ, Deery EC, Walker CE et al. The destabilization of human GCAPI by a pro-line to leucine mutation might cause cone-rod dystrophy. Hum Mol Genet 2001; 10:47–54.

    Article  PubMed  CAS  Google Scholar 

  76. Pittler SB, Baehr W. Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse. Proc Natl Acad Sci USA 1991; 88:8322–8326.

    Article  PubMed  CAS  Google Scholar 

  77. Farber DB, Lolley RN. Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina. Science 1974; 186:449–451.

    Article  PubMed  CAS  Google Scholar 

  78. Farber DB. From mice to men: the cyclic GMP phosphodiesterase gene in vision and disease. The Proctor Lecture. Invest Ophthalmol Vis Sci 1995; 36:263–275.

    PubMed  CAS  Google Scholar 

  79. Fain GL, Lisman JE. Light, Ca2+, and Photoreceptor Death: New Evidence for the Equivalent-Light Hypothesis from Arrestin Knockout Mice. Invest Ophthalmol Vis Sci 1999; 40:2770–2772.

    PubMed  CAS  Google Scholar 

  80. Palczewski K, Polans AS, Baehr W et al. Ca(2+)-binding proteins in the retina: structure, function, and the etiology of human visual diseases. Bioessays 2000; 22:337–350.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2002 Springer Science+Business Media New York

About this chapter

Cite this chapter

Mendez, A., Chen, J. (2002). Mouse Models to Study GCAP Functions In Intact Photoreceptors. In: Baehr, W., Palczewski, K. (eds) Photoreceptors and Calcium. Advances in Experimental Medicine and Biology, vol 514. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0121-3_22

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-0121-3_22

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-4933-4

  • Online ISBN: 978-1-4615-0121-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics