Cargando…
Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina
Retinal guanylate cyclase (RetGC) and guanylate cyclase activating proteins (GCAPs) play an important role during the light response in photoreceptor cells. Mutations in these proteins are linked to distinct forms of blindness. RetGC and GCAPs exert their role at the ciliary outer segment where phot...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811540/ https://www.ncbi.nlm.nih.gov/pubmed/29440717 http://dx.doi.org/10.1038/s41598-018-20893-1 |
_version_ | 1783299879916797952 |
---|---|
author | López-Begines, Santiago Plana-Bonamaisó, Anna Méndez, Ana |
author_facet | López-Begines, Santiago Plana-Bonamaisó, Anna Méndez, Ana |
author_sort | López-Begines, Santiago |
collection | PubMed |
description | Retinal guanylate cyclase (RetGC) and guanylate cyclase activating proteins (GCAPs) play an important role during the light response in photoreceptor cells. Mutations in these proteins are linked to distinct forms of blindness. RetGC and GCAPs exert their role at the ciliary outer segment where phototransduction takes place. We investigated the mechanisms governing GCAP1 and GCAP2 distribution to rod outer segments by expressing selected GCAP1 and GCAP2 mutants as transient transgenes in the rods of GCAP1/2 double knockout mice. We show that precluding GCAP1 direct binding to RetGC (K23D/GCAP1) prevented its distribution to rod outer segments, while preventing GCAP1 activation of RetGC post-binding (W94A/GCAP1) did not. We infer that GCAP1 translocation to the outer segment strongly depends on GCAP1 binding affinity for RetGC, which points to GCAP1 requirement to bind to RetGC to be transported. We gain further insight into the distinctive regulatory steps of GCAP2 distribution, by showing that a phosphomimic at position 201 is sufficient to retain GCAP2 at proximal compartments; and that the bovine equivalent to blindness-causative mutation G157R/GCAP2 results in enhanced phosphorylation in vitro and significant retention at the inner segment in vivo, as likely contributing factors to the pathophysiology. |
format | Online Article Text |
id | pubmed-5811540 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58115402018-02-16 Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina López-Begines, Santiago Plana-Bonamaisó, Anna Méndez, Ana Sci Rep Article Retinal guanylate cyclase (RetGC) and guanylate cyclase activating proteins (GCAPs) play an important role during the light response in photoreceptor cells. Mutations in these proteins are linked to distinct forms of blindness. RetGC and GCAPs exert their role at the ciliary outer segment where phototransduction takes place. We investigated the mechanisms governing GCAP1 and GCAP2 distribution to rod outer segments by expressing selected GCAP1 and GCAP2 mutants as transient transgenes in the rods of GCAP1/2 double knockout mice. We show that precluding GCAP1 direct binding to RetGC (K23D/GCAP1) prevented its distribution to rod outer segments, while preventing GCAP1 activation of RetGC post-binding (W94A/GCAP1) did not. We infer that GCAP1 translocation to the outer segment strongly depends on GCAP1 binding affinity for RetGC, which points to GCAP1 requirement to bind to RetGC to be transported. We gain further insight into the distinctive regulatory steps of GCAP2 distribution, by showing that a phosphomimic at position 201 is sufficient to retain GCAP2 at proximal compartments; and that the bovine equivalent to blindness-causative mutation G157R/GCAP2 results in enhanced phosphorylation in vitro and significant retention at the inner segment in vivo, as likely contributing factors to the pathophysiology. Nature Publishing Group UK 2018-02-13 /pmc/articles/PMC5811540/ /pubmed/29440717 http://dx.doi.org/10.1038/s41598-018-20893-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article López-Begines, Santiago Plana-Bonamaisó, Anna Méndez, Ana Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina |
title | Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina |
title_full | Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina |
title_fullStr | Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina |
title_full_unstemmed | Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina |
title_short | Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina |
title_sort | molecular determinants of guanylate cyclase activating protein subcellular distribution in photoreceptor cells of the retina |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811540/ https://www.ncbi.nlm.nih.gov/pubmed/29440717 http://dx.doi.org/10.1038/s41598-018-20893-1 |
work_keys_str_mv | AT lopezbeginessantiago moleculardeterminantsofguanylatecyclaseactivatingproteinsubcellulardistributioninphotoreceptorcellsoftheretina AT planabonamaisoanna moleculardeterminantsofguanylatecyclaseactivatingproteinsubcellulardistributioninphotoreceptorcellsoftheretina AT mendezana moleculardeterminantsofguanylatecyclaseactivatingproteinsubcellulardistributioninphotoreceptorcellsoftheretina |