# Photoreceptor Phosphodiesterase Regulation

> **NIH NIH R01** · UNIVERSITY OF NEW HAMPSHIRE · 2024 · $374,248

## Abstract

PROJECT SUMMARY/ABSTRACT
Photoreceptor phosphodiesterase (PDE6) is the central enzyme of the visual signaling pathway. Precise
regulation of its activation and deactivation is essential for the speed, sensitivity, and recovery of rod and cone
photoreceptors to illumination. Inherited mutations in rod and cone PDE6 genes have been linked in a variety
of retinal diseases, including retinitis pigmentosa, congenital stationary night blindness, and cone dystrophy.
Next-generation sequencing is identifying a growing number of mutations in PDE6 genes, the large majority of
which remain of uncertain clinical significance. Even less is known about the molecular etiology of retinal
disease-causing mutations. Rod PDE6 consists of two catalytic subunits whose activity is inhibited in the dark-
adapted state by binding of two identical γ-subunits (Pγ). Upon light-induced activation of the visual signaling
pathway, PDE6 activity is stimulated by binding of the heterotrimeric G-protein, transducin. The lifetime of light-
activated PDE6 is precisely controlled by the rate at which the transducin hydrolyzes its bound GTP, a process
controlled by RGS9-1 (Regulator of G-protein Signaling9-1). While the proteins involved in regulation of PDE6
during phototransduction have been identified, the molecular sequence of events in which PDE6 dynamically
interacts with its binding partners--as well as its allosteric regulation--during PDE6 activation and deactivation
remain poorly understood. Until we understand the mechanistic basis of PDE6 regulation during normal
phototransduction, we will be hampered in developing therapeutic interventions for those diseases arising from
defects in PDE6 or its binding partners that result in retinal degenerative diseases and visual disorders.
The overall objective of this application is to understand the sequence of events accompanying PDE6
activation by transducin and its subsequent inactivation by RGS9-1 and other proteins during recovery of
PDE6 to its dark-adapted state. Our experimental plan is based on the hypothesis that the inhibitory Pγ subunit
of PDE6 is the “master regulator” responsible for mediating multiple allosteric interactions that occur within the
PDE6 catalytic dimer, as well as with the transducin α-subunit and RGS9-1. We propose two specific aims that
will (1) delineate the sequence of binding interactions between transducin α-subunits and PDE6 catalytic and
inhibitory Pγ subunits to provide a comprehensive model of rod PDE6 activation, and (2) determine the
molecular architecture of the PDE6 inactivation complex upon RGS9-1 binding and the structural
rearrangements of the Pγ subunit that accelerate termination of activated PDE6. The outcomes of this
research advance the goals of the Retinal Diseases Program at the National Eye Institute by enhancing our
ability to predict the pathogenicity of mutations in phototransduction proteins, thereby enabling development of
personalized therapeutic interventions for retinal...

## Key facts

- **NIH application ID:** 10872137
- **Project number:** 5R01EY033403-03
- **Recipient organization:** UNIVERSITY OF NEW HAMPSHIRE
- **Principal Investigator:** Rick H Cote
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $374,248
- **Award type:** 5
- **Project period:** 2022-09-30 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872137

## Citation

> US National Institutes of Health, RePORTER application 10872137, Photoreceptor Phosphodiesterase Regulation (5R01EY033403-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10872137. Licensed CC0.

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