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Differential modification of phosducin protein in degenerating rd1 ret is associated with constitutively active CaMKII in rod outer segments.

Hauck, Stefanie M ; Ekström, Per LU ; Ahuja Jensen, Poonam LU ; Suppman, Sabine ; Paquet-Durand, Francois LU ; van Veen, Theo LU and Ueffing, Marius (2006) In Molecular & Cellular Proteomics 5(2). p.324-336
Abstract
Retinitis pigmentosa comprises a heterogeneous group of incurable progressive blinding diseases with unknown pathogenic mechanisms. The retinal degeneration 1 (rd1) mouse is a retinitis pigmentosa model that carries a mutation in a rod photoreceptor-specific phosphodiesterase gene, leading to rapid degeneration of these cells. Elucidation of the molecular differences between rd1 and healthy retinae is crucial for explaining this degeneration and could assist in suggesting novel therapies. Here we used high resolution proteomics to compare the proteomes of the rd1 mouse retina and its congenic, wildtype counterpart at postnatal day 11 when photoreceptor death is profound. Over 3000 protein spots were consistently resolved by two-dimensional... (More)
Retinitis pigmentosa comprises a heterogeneous group of incurable progressive blinding diseases with unknown pathogenic mechanisms. The retinal degeneration 1 (rd1) mouse is a retinitis pigmentosa model that carries a mutation in a rod photoreceptor-specific phosphodiesterase gene, leading to rapid degeneration of these cells. Elucidation of the molecular differences between rd1 and healthy retinae is crucial for explaining this degeneration and could assist in suggesting novel therapies. Here we used high resolution proteomics to compare the proteomes of the rd1 mouse retina and its congenic, wildtype counterpart at postnatal day 11 when photoreceptor death is profound. Over 3000 protein spots were consistently resolved by two-dimensional gel electrophoresis and subjected to a rigorous filtering procedure involving computer-based spot analyses. Five proteins were accepted as being differentially expressed in the rd1 model and subsequently identified by mass spectrometry. The difference in one such protein, phosducin, related to an altered modification pattern in the rd1 retina rather than to changed expression levels. Additional experiments showed phosducin in healthy retinae to be highly phosphorylated in the dark- but not in the light-adapted phase. In contrast, rd1 phosducin was highly phosphorylated irrespective of light status, indicating a dysfunctional rd1 light/dark response. The increased rd1 phosducin phosphorylation coincided with increased activation of calcium/calmodulin-activated protein kinase II, which is known to utilize phosducin as a substrate. Given the increased rod calcium levels present in the rd1 mutation, calcium-evoked overactivation of this kinase may be an early and long sought for step in events leading to photoreceptor degeneration in the rd1 mouse. (Less)
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type
Contribution to journal
publication status
published
subject
in
Molecular & Cellular Proteomics
volume
5
issue
2
pages
324 - 336
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • wos:000235516200011
  • pmid:16253986
  • scopus:33644678324
ISSN
1535-9484
DOI
10.1074/mcp.M500217-MCP200
language
English
LU publication?
yes
id
f274a4bd-ea08-42e8-ba23-5d9d0551ae1c (old id 145113)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16253986
date added to LUP
2016-04-01 12:34:46
date last changed
2021-10-06 03:03:32
@article{f274a4bd-ea08-42e8-ba23-5d9d0551ae1c,
  abstract     = {Retinitis pigmentosa comprises a heterogeneous group of incurable progressive blinding diseases with unknown pathogenic mechanisms. The retinal degeneration 1 (rd1) mouse is a retinitis pigmentosa model that carries a mutation in a rod photoreceptor-specific phosphodiesterase gene, leading to rapid degeneration of these cells. Elucidation of the molecular differences between rd1 and healthy retinae is crucial for explaining this degeneration and could assist in suggesting novel therapies. Here we used high resolution proteomics to compare the proteomes of the rd1 mouse retina and its congenic, wildtype counterpart at postnatal day 11 when photoreceptor death is profound. Over 3000 protein spots were consistently resolved by two-dimensional gel electrophoresis and subjected to a rigorous filtering procedure involving computer-based spot analyses. Five proteins were accepted as being differentially expressed in the rd1 model and subsequently identified by mass spectrometry. The difference in one such protein, phosducin, related to an altered modification pattern in the rd1 retina rather than to changed expression levels. Additional experiments showed phosducin in healthy retinae to be highly phosphorylated in the dark- but not in the light-adapted phase. In contrast, rd1 phosducin was highly phosphorylated irrespective of light status, indicating a dysfunctional rd1 light/dark response. The increased rd1 phosducin phosphorylation coincided with increased activation of calcium/calmodulin-activated protein kinase II, which is known to utilize phosducin as a substrate. Given the increased rod calcium levels present in the rd1 mutation, calcium-evoked overactivation of this kinase may be an early and long sought for step in events leading to photoreceptor degeneration in the rd1 mouse.},
  author       = {Hauck, Stefanie M and Ekström, Per and Ahuja Jensen, Poonam and Suppman, Sabine and Paquet-Durand, Francois and van Veen, Theo and Ueffing, Marius},
  issn         = {1535-9484},
  language     = {eng},
  number       = {2},
  pages        = {324--336},
  publisher    = {American Society for Biochemistry and Molecular Biology},
  series       = {Molecular & Cellular Proteomics},
  title        = {Differential modification of phosducin protein in degenerating rd1 ret is associated with constitutively active CaMKII in rod outer segments.},
  url          = {http://dx.doi.org/10.1074/mcp.M500217-MCP200},
  doi          = {10.1074/mcp.M500217-MCP200},
  volume       = {5},
  year         = {2006},
}