Abstract

Rod and cone photoreceptors of the vertebrate retina utilize cGMP as the primary

intracellular messenger for the visual signaling pathway that converts a light stimulus into an electrical response. cGMP metabolism in the signal-transducing photoreceptor outer segment reflects the balance of cGMP synthesis (catalyzed by guanylyl cyclase) and degradation (catalyzed by the photoreceptor phosphodiesterase, PDE6). Upon light stimulation, rapid activation of PDE6 by the heterotrimeric G-protein (transducin) triggers a dramatic drop in cGMP levels that lead to cell hyperpolarization. Following cessation of the light stimulus, the lifetime of activated PDE6 is also precisely regulated by additional processes. This review summarizes recent advances in the structural characterization of the rod and cone PDE6 catalytic and regulatory subunits in the context of previous biochemical studies of the enzymological properties and allosteric regulation of PDE6. Emphasis is given to recent advances in understanding the structural and conformational changes underlying the mechanism by which the activated transducin α-subunit binds to—and relieves inhibition of—PDE6 catalysis that is controlled by its intrinsically disordered, inhibitory γ-subunit. The role of the regulator of G-protein signaling 9-1 (RGS9-1) in regulating the lifetime of the transducin-PDE6 is also briefly covered. The therapeutic potential of pharmacological compounds acting as inhibitors or activators targeting PDE6 is discussed in the context of inherited retinal diseases resulting from mutations in rod and cone PDE6 genes as well as other inherited defects that arise from excessive cGMP accumulation in retinal photoreceptor cells.

Department

Molecular, Cellular and Biomedical Sciences

Publication Date

2021

Grant/Award Number and Agency

National Eye Institute (NIH) R01 EY005798; National Institute of General Medical Sciences (NIH) P20 GM113131

Journal Title

Pflugers Archives European Journal of Physiology

Publisher

Springer

Digital Object Identifier (DOI)

10.1007/s00424-021-02562-x

Document Type

Article

Rights

The accepted manuscript version, by industry standard called the “Author’s Accepted Manuscript” (“AAM”) is the version accepted for publication in a journal following peer review but prior to copyediting and typesetting that can be made available under the following conditions: (i) Author retains the right to make an AAM of the Article available on their own personal, self-maintained website immediately on acceptance, (ii) Author retains the right to make an AAM of the Article available for public release on any of the following 12 months after first publication ("Embargo Period"): their employer’s internal website; their institutional and/or funder repositories; AAMs may also be deposited in such repositories immediately on acceptance, provided that they are not made publicly available until after the Embargo Period. An acknowledgement in the following form should be included, together with a link to the published version on the publisher’s website: “This is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: http://dx.doi.org/[insert DOI]”.

Comments

This is a post-peer-review, pre-copyedit version of an article published in Pflugers Archives European Journal of Physiology. The final authenticated version is available online at: http://dx.doi.org/10.1007/s00424-021-02562-x.

Available for download on Tuesday, October 25, 2022

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