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http://hdl.handle.net/2445/59144
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DC Field | Value | Language |
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dc.contributor.author | Hoyo, N.L. | - |
dc.contributor.author | López Begines, Santiago | - |
dc.contributor.author | Rosa López, José Luis | - |
dc.contributor.author | Chen, Jeannie | - |
dc.contributor.author | Méndez Zunzunegui, Ana | - |
dc.date.accessioned | 2014-10-28T15:05:43Z | - |
dc.date.available | 2014-10-28T15:05:43Z | - |
dc.date.issued | 2014 | - |
dc.identifier.issn | 1553-7390 | - |
dc.identifier.uri | http://hdl.handle.net/2445/59144 | - |
dc.description.abstract | The neuronal calcium sensor proteins GCAPs (guanylate cyclase activating proteins) switch between Ca2+-free and Ca2+-bound conformational states and confer calcium sensitivity to guanylate cyclase at retinal photoreceptor cells. They play a fundamental role in light adaptation by coupling the rate of cGMP synthesis to the intracellular concentration of calcium. Mutations in GCAPs lead to blindness. The importance of functional EF-hands in GCAP1 for photoreceptor cell integrity has been well established. Mutations in GCAP1 that diminish its Ca2+ binding affinity lead to cell damage by causing unabated cGMP synthesis and accumulation of toxic levels of free cGMP and Ca2+. We here investigate the relevance of GCAP2 functional EF-hands for photoreceptor cell integrity. By characterizing transgenic mice expressing a mutant form of GCAP2 with all EF-hands inactivated (EF(-)GCAP2), we show that GCAP2 locked in its Ca2+-free conformation leads to a rapid retinal degeneration that is not due to unabated cGMP synthesis. We unveil that when locked in its Ca2+-free conformation in vivo, GCAP2 is phosphorylated at Ser201 and results in phospho-dependent binding to the chaperone 14-3-3 and retention at the inner segment and proximal cell compartments. Accumulation of phosphorylated EF(-)GCAP2 at the inner segment results in severe toxicity. We show that in wildtype mice under physiological conditions, 50% of GCAP2 is phosphorylated correlating with the 50% of the protein being retained at the inner segment. Raising mice under constant light exposure, however, drastically increases the retention of GCAP2 in its Ca2+-free form at the inner segment. This study identifies a new mechanism governing GCAP2 subcellular distribution in vivo, closely related to disease. It also identifies a pathway by which a sustained reduction in intracellular free Ca2+ could result in photoreceptor damage, relevant for light damage and for those genetic disorders resulting in 'equivalent-light'' scenarios. | - |
dc.format.extent | 20 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Public Library of Science (PLoS) | - |
dc.relation.isformatof | Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.pgen.1004480 | - |
dc.relation.ispartof | PLoS Genetics, 2014, vol. 10, num. 7 | - |
dc.relation.uri | http://dx.doi.org/10.1371/journal.pgen.1004480 | - |
dc.rights | cc-by (c) Hoyo, N.L. et al., 2014 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es | - |
dc.source | Articles publicats en revistes (Ciències Fisiològiques) | - |
dc.subject.classification | Fotoreceptors | - |
dc.subject.classification | Transformació genètica | - |
dc.subject.classification | Ratolins (Animals de laboratori) | - |
dc.subject.other | Photoreceptors | - |
dc.subject.other | Genetic transformation | - |
dc.subject.other | Mice (Laboratory animals) | - |
dc.title | Functional EF-hands in neuronal calcium sensor GCAP2 determine its phosphorylation state and subcellular distribution in vivo, and are essential for photoreceptor cell integrity | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 643494 | - |
dc.date.updated | 2014-10-28T15:05:46Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 25058152 | - |
Appears in Collections: | Articles publicats en revistes (Ciències Fisiològiques) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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File | Description | Size | Format | |
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643494.pdf | 12.15 MB | Adobe PDF | View/Open |
This item is licensed under a Creative Commons License