Abstract
The photoreceptor phosphodiesterase (PDE6) is a member of large family of Class I phosphodiesterases responsible for hydrolyzing the second messengers cAMP and cGMP. PDE6 consists of two catalytic subunits and two inhibitory subunits that form a tetrameric protein. PDE6 is a peripheral membrane protein that is localized to the signal-transducing compartment of rod and cone photoreceptors. As the central effector enzyme of the G-protein coupled visual transduction pathway, activation of PDE6 catalysis causes a rapid decrease in cGMP levels that results in closure of cGMP-gated ion channels in the photoreceptor plasma membrane. Because of its importance in the phototransduction pathway, mutations in PDE6 genes result in various retinal diseases that currently lack therapeutic treatment strategies due to inadequate knowledge of the structure, function, and regulation of this enzyme. This review focuses on recent progress in understanding the structure of the regulatory and catalytic domains of the PDE6 holoenzyme, the central role of the multi-functional inhibitory γ-subunit, the mechanism of activation by the heterotrimeric G protein, transducin, and future directions for pharmacological interventions to treat retinal degenerative diseases arising from mutations in the PDE6 genes.
Keywords
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- AIPL1:
-
Aryl hydrocarbon receptor-interacting protein-like 1
- GAF:
-
Regulatory ligand-binding domain occurring in cGMP-binding phosphodiesterases, cyanobacterial Adenylyl cyclases and transcription factor FhlA
- Gα:
-
α-subunit of transducin
- Gα*:
-
activated transducin α-subunit containing GTP, GTPγS, or GDP-AlF4−
- Gαβγ:
-
Transducin heterotrimer
- MD:
-
Molecular dynamics
- PDE:
-
3′,5′-cyclic nucleotide phosphodiesterase
- PDE6:
-
Phosphodiesterase-6
- Pα:
-
Rod PDE6 α-subunit
- Pαβ:
-
Rod PDE6 catalytic heterodimer
- Pβ:
-
Rod PDE6 β-subunit
- Pγ:
-
PDE6 inhibitory γ-subunit
- RGS9-1:
-
Regulator of G-protein Signaling9-1
- XL-MS:
-
Chemical cross-linking/mass spectrometry
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Acknowledgements
This work is supported by the National Eye Institute (R01 EY05798) and by the National Institute of General Medical Sciences (P20 GM113131) of the National Institutes of Health.
Conflicts of Interest
The authors declare no competing financial or non-financial interests in any material discussed in this work.
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Cote, R.H., Gupta, R., Irwin, M.J., Wang, X. (2021). Photoreceptor Phosphodiesterase (PDE6): Structure, Regulatory Mechanisms, and Implications for Treatment of Retinal Diseases. In: Atassi, M.Z. (eds) Protein Reviews. Advances in Experimental Medicine and Biology(), vol 1371. Springer, Cham. https://doi.org/10.1007/5584_2021_649
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