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A key role for cyclic nucleotide gated (CNG) channels in cGMP-related retinitis pigmentosa

Paquet-Durand, Francois; Beck, Susanne; Michalakis, Stylianos; Goldmann, Tobias; Huber, Gesine; Muehlfriedel, Regine; Trifunovic, Dragana; Fischer, M. Dominik; Fahl, Edda and Duetsch, Gabriele, et al. (2011) In Human Molecular Genetics 20(5). p.941-947
Abstract
The rd1 natural mutant is one of the first and probably the most commonly studied mouse model for retinitis pigmentosa (RP), a severe and frequently blinding human retinal degeneration. In several decades of research, the link between the increase in photoreceptor cGMP levels and the extremely rapid cell death gave rise to a number of hypotheses. Here, we provide clear evidence that the presence of cyclic nucleotide gated (CNG) channels in the outer segment membrane is the key to rod photoreceptor loss. In Cngb1(-/-) x rd1 double mutants devoid of regular CNG channels, cGMP levels are still pathologically high, but rod photoreceptor viability and outer segment morphology are greatly improved. Importantly, cone photoreceptors, the basis for... (More)
The rd1 natural mutant is one of the first and probably the most commonly studied mouse model for retinitis pigmentosa (RP), a severe and frequently blinding human retinal degeneration. In several decades of research, the link between the increase in photoreceptor cGMP levels and the extremely rapid cell death gave rise to a number of hypotheses. Here, we provide clear evidence that the presence of cyclic nucleotide gated (CNG) channels in the outer segment membrane is the key to rod photoreceptor loss. In Cngb1(-/-) x rd1 double mutants devoid of regular CNG channels, cGMP levels are still pathologically high, but rod photoreceptor viability and outer segment morphology are greatly improved. Importantly, cone photoreceptors, the basis for high-resolution daylight and colour vision, survived and remained functional for extended periods of time. These findings strongly support the hypothesis of deleterious calcium (Ca2+)-influx as the cause of rapid rod cell death and highlight the importance of CNG channels in this process. Furthermore, our findings suggest that targeting rod CNG channels, rather than general Ca2+-channel blockade, is a most promising symptomatic approach to treat otherwise incurable forms of cGMP-related RP. (Less)
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publication status
published
subject
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Human Molecular Genetics
volume
20
issue
5
pages
941 - 947
publisher
Oxford University Press
external identifiers
  • wos:000286993500008
  • scopus:79551602686
ISSN
0964-6906
DOI
10.1093/hmg/ddq539
language
English
LU publication?
yes
id
bede3bd4-5195-4313-98a3-94e5497dcd6b (old id 1882536)
date added to LUP
2011-04-01 08:39:21
date last changed
2017-09-24 03:18:07
@article{bede3bd4-5195-4313-98a3-94e5497dcd6b,
  abstract     = {The rd1 natural mutant is one of the first and probably the most commonly studied mouse model for retinitis pigmentosa (RP), a severe and frequently blinding human retinal degeneration. In several decades of research, the link between the increase in photoreceptor cGMP levels and the extremely rapid cell death gave rise to a number of hypotheses. Here, we provide clear evidence that the presence of cyclic nucleotide gated (CNG) channels in the outer segment membrane is the key to rod photoreceptor loss. In Cngb1(-/-) x rd1 double mutants devoid of regular CNG channels, cGMP levels are still pathologically high, but rod photoreceptor viability and outer segment morphology are greatly improved. Importantly, cone photoreceptors, the basis for high-resolution daylight and colour vision, survived and remained functional for extended periods of time. These findings strongly support the hypothesis of deleterious calcium (Ca2+)-influx as the cause of rapid rod cell death and highlight the importance of CNG channels in this process. Furthermore, our findings suggest that targeting rod CNG channels, rather than general Ca2+-channel blockade, is a most promising symptomatic approach to treat otherwise incurable forms of cGMP-related RP.},
  author       = {Paquet-Durand, Francois and Beck, Susanne and Michalakis, Stylianos and Goldmann, Tobias and Huber, Gesine and Muehlfriedel, Regine and Trifunovic, Dragana and Fischer, M. Dominik and Fahl, Edda and Duetsch, Gabriele and Becirovic, Elvir and Wolfrum, Uwe and van Veen, Theo and Biel, Martin and Tanimoto, Naoyuki and Seeliger, Mathias W.},
  issn         = {0964-6906},
  language     = {eng},
  number       = {5},
  pages        = {941--947},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {A key role for cyclic nucleotide gated (CNG) channels in cGMP-related retinitis pigmentosa},
  url          = {http://dx.doi.org/10.1093/hmg/ddq539},
  volume       = {20},
  year         = {2011},
}