# Regulation of Cyclic GMP Synthesis in Photoreceptors

> **NIH NIH R01** · DREXEL UNIVERSITY · 2024 · $514,093

## Abstract

PROJECT SUMMARY
Cyclic cGMP (cGMP) enables phototransduction in vertebrate rods and cones. The cGMP synthesis by retinal
guanylyl (guanylate) cyclase (RetGC), one of the most essential processes in the photoreceptor physiology, is
controlled by calcium, guanylyl cyclase activating proteins (GCAPs), and retinal degeneration 3 (RD3) protein.
The abnormalities in cGMP signaling cause photoreceptor dysfunction and death. Among them, deficiency in
RetGC activity and regulation leads to a variety of recessive and dominant forms of congenital blindness. The
basic principles of the RetGC regulation and its fundamental importance for the photoreceptor signaling and
survival have been established, and the first clinical trials for RetGC-linked blindness now have begun, evolved
from the earlier molecular studies. Yet, some key molecular and cellular aspects of RetGC regulation still remain
insufficiently understood, including the molecular structure and the interactions of RetGC with the regulatory
proteins that define its biological function in photoreceptors. This proposal, conforming to the NEI mission to
support research with respect to blinding eye diseases, visual disorders and mechanisms of visual function, is
built on recent advancements in understanding of how RetGC enables the photoreceptor function: (i)
identification of mutations that affect RetGC interactions with GCAPs and RD3; (ii) establishing the structure on
RD3 and identification of its RetGC-binding interface; (iii) development of new mouse genetic models for
studying mechanisms of signal transduction and their abnormalities caused by mutations in RetGC1, GCAP1,
and RD3; (iv) establishing the complex physiological role of RD3 in photoreceptor function and survival. We
here propose a diversified study designed to achieve, by integrating protein biochemistry, molecular biology,
and molecular genetics, better mechanistic understanding of the regulatory processes that control cGMP
synthesis in photoreceptors and underlie their function and diseases. Aim 1 seeks establishing the presently
unknown structure of RetGC1, the main source of cGMP in photoreceptors, whose mutants cause severe forms
of blindness. Aim 2 addresses the molecular determinant of RD3 that controls RetGC trafficking in
photoreceptors using transgenic mouse models. Aim 3 will delineate the dynamics of RetGC complexes with
GCAPs and RD3 that enable RetGC to function in vivo. By completing these specific aims, we expect to achieve
deeper and more reliable understanding of the mechanistic interactions that define the fundamental role of
RetGC in photoreceptor biology and cause physiological abnormalities in congenital retinal diseases.

## Key facts

- **NIH application ID:** 11160203
- **Project number:** 7R01EY011522-29
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** ALEXANDER M DIZHOOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $514,093
- **Award type:** 7
- **Project period:** 1996-08-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11160203

## Citation

> US National Institutes of Health, RePORTER application 11160203, Regulation of Cyclic GMP Synthesis in Photoreceptors (7R01EY011522-29). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11160203. Licensed CC0.

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