Exogenous PDE5 Expression Rescues Photoreceptors in

Animals Calcium / metabolism Codon, Nonsense / metabolism Cyclic GMP / metabolism Cyclic Nucleotide Phosphodiesterases, Type 5 Cyclic Nucleotide Phosphodiesterases, Type 6 / genetics Disease Models, Animal Guanosine Monophosphate / metabolism Mice Mice, Inbred C57BL Retina / metabolism Retinal Degeneration / genetics Rhodopsin / genetics
PDE5 PDE6B RD1 mice cGMP retinitis pigmentosa rhodopsin

Journal

Current medicinal chemistry
ISSN: 1875-533X
Titre abrégé: Curr Med Chem
Pays: United Arab Emirates
ID NLM: 9440157

Informations de publication

Date de publication:
2022
Historique:
received: 11 10 2021
revised: 26 12 2021
accepted: 13 01 2022
pubmed: 17 2 2022
medline: 14 10 2022
entrez: 16 2 2022
Statut: ppublish

Résumé

Catalytic hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase 6 (PDE6) is critical in phototransduction signalling in photoreceptors. Mutations in the genes encoding any of the three PDE6 subunits are associated with retinitis pigmentosa, the most common form of inherited retinal diseases. The RD1 mouse carries a naturally occurring nonsense mutation in the Pde6b gene. The RD1 mouse retina rapidly degenerates and fails to form rod photoreceptor outer segments due to the elevated cGMP level and subsequent excessive Ca2+ influx. In this study, we aim to test whether the PDE5 expression, a non-photoreceptor-specific member of the PDE superfamily, rescues photoreceptors in the RD1 retina. Electroporation used the PDE5 expression plasmid to transfect neonatal RD1 mice. The mouse retina degeneration was assessed by retinal sections' stains with DAPI. The expression and localization of phototransduction proteins in photoreceptors were analysed by immunostaining. The expression of proteins in cultured cells was analysed by immunoblotting. The exogenous PDE5 expression, a non-photoreceptor-specific member of the PDE superfamily, prevents photoreceptor degeneration in RD1 mice. Unlike endogenous photoreceptor-specific PDE6 localised in the outer segments of photoreceptors, ectopically- expressed PDE5 was distributed in inner segments and synaptic terminals. PDE5 also promoted the development of the outer segments in RD1 mice. PDE5 co-expression with rhodopsin in cultured cells showed enhanced rhodopsin expression. Lowering the cGMP level in photoreceptors by PDE5 is sufficient to rescue photoreceptors in RD1 retinas. cGMP may also play a role in rhodopsin expression regulation in photoreceptors.

Sections du résumé

BACKGROUND
Catalytic hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase 6 (PDE6) is critical in phototransduction signalling in photoreceptors. Mutations in the genes encoding any of the three PDE6 subunits are associated with retinitis pigmentosa, the most common form of inherited retinal diseases. The RD1 mouse carries a naturally occurring nonsense mutation in the Pde6b gene. The RD1 mouse retina rapidly degenerates and fails to form rod photoreceptor outer segments due to the elevated cGMP level and subsequent excessive Ca2+ influx. In this study, we aim to test whether the PDE5 expression, a non-photoreceptor-specific member of the PDE superfamily, rescues photoreceptors in the RD1 retina.
METHODS
Electroporation used the PDE5 expression plasmid to transfect neonatal RD1 mice. The mouse retina degeneration was assessed by retinal sections' stains with DAPI. The expression and localization of phototransduction proteins in photoreceptors were analysed by immunostaining. The expression of proteins in cultured cells was analysed by immunoblotting.
RESULTS
The exogenous PDE5 expression, a non-photoreceptor-specific member of the PDE superfamily, prevents photoreceptor degeneration in RD1 mice. Unlike endogenous photoreceptor-specific PDE6 localised in the outer segments of photoreceptors, ectopically- expressed PDE5 was distributed in inner segments and synaptic terminals. PDE5 also promoted the development of the outer segments in RD1 mice. PDE5 co-expression with rhodopsin in cultured cells showed enhanced rhodopsin expression.
CONCLUSION
Lowering the cGMP level in photoreceptors by PDE5 is sufficient to rescue photoreceptors in RD1 retinas. cGMP may also play a role in rhodopsin expression regulation in photoreceptors.

Identifiants

DOI: 10.2174/0929867329666220216111952 PMID: 35170405
pubmed: 35170405
pii: CMC-EPUB-120936
doi: 10.2174/0929867329666220216111952
doi:

Substances chimiques

Codon, Nonsense 0
Guanosine Monophosphate 85-32-5
Rhodopsin 9009-81-8
Cyclic Nucleotide Phosphodiesterases, Type 5 EC 3.1.4.35
Cyclic Nucleotide Phosphodiesterases, Type 6 EC 3.1.4.35
Pde5a protein, mouse EC 3.1.4.35
Cyclic GMP H2D2X058MU
Calcium SY7Q814VUP

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

6115-6124

Subventions

Organisme : National Precision Medicine Project
ID : 2016YFC0905200
Organisme : National Natural Science Foundation of China
ID : 81570882, 81770935, 81800830
Organisme : Department of Science and Technology of Sichuan Province, China
ID : 2020YJ0445
Organisme : Key Research and Development and Promotion Project Science and Technology program of Henan Province
ID : 192102310077

Informations de copyright

Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

Auteurs

Tongdan Zou (T)

The Key Laboratory for Human Disease Gene Study of Sichuan Province and Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.

Ting Wang (T)

The Key Laboratory for Human Disease Gene Study of Sichuan Province and Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.

Fangyuan Zhen (F)

Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital, Zhengzhou, China.

Xu He (X)

The Central Laboratory, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.

Shuqian Dong (S)

Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital, Zhengzhou, China.

Houbin Zhang (H)

The Key Laboratory for Human Disease Gene Study of Sichuan Province and Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Facteurs biologiques › Facteurs de la coagulation sanguine › Calcium › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Codon non-sens › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Ribonucléotides › Nucléotides guanyliques › GMP cyclique › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › 3',5'-Cyclic-GMP Phosphodiesterases › Cyclic Nucleotide Phosphodiesterases, Type 5 › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › 3',5'-Cyclic-GMP Phosphodiesterases › Cyclic Nucleotide Phosphodiesterases, Type 6 › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Ribonucléotides › Nucléotides guanyliques › Guanosine monophosphate › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Organes des sens › Oeil › Rétine › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Maladies de l'oeil › Rétinopathies › Dégénérescence de la rétine › Exogenous PDE5 Expression Rescues Photoreceptors in
questionsmedicales.fr › Facteurs biologiques › Pigments biologiques › Pigments rétiniens › Opsines › Opsines des bâtonnets › Rhodopsine › Exogenous PDE5 Expression Rescues Photoreceptors in