# Rhodopsin dimerization: mechanistic basis and functional consequences

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $526,839

## Abstract

The visual pigment rhodopsin is both a G protein-coupled receptor (GPCR) and a critical structural component
of the outer segment of photoreceptor cells. Mutations in rhodopsin are the most common cause of autosomal
dominant retinitis pigmentosa (RP), a blinding disease that afflicts more than 1.5 million individuals world-
wide. Rhodopsin can activate the visual signaling cascade as a monomer, but it self-associates to form dimers
and higher order multimers that have been proposed to be important for phototransduction. We discovered
that certain rhodopsin mutants that cause RP through unknown mechanisms appear to be function normally as
visual pigments but unlike wild type rhodopsin, they fail to dimerize when reconstituted into lipid vesicles. We
hypothesize that the lack of dimerization in these mutants prevents normal photoreceptor function, leading
eventually to loss of photoreceptor cells, retinal degeneration and RP pathology. The overall goal of this
application is to elucidate the biological and pathobiological aspects of photoreceptor functions that rely on
rhodopsin dimerization. The RP mutants we propose to analyze provide novel tools and an exciting new
opportunity to study the molecular basis of rhodopsin dimerization and the specific role of dimerization in
phototransduction and maintaining disc architecture. In our two specific aims, we propose to conduct a
comprehensive analysis of rhodopsin dimerization from its molecular basis (and why it fails in RP mutants) to
its biological role in living photoreceptors.
In the first aim we will use multiscale computational approaches, combined with experimental probing and
verification, to test specific hypotheses about the driving forces for rhodopsin dimerization, why dimerization is
perturbed in the RP-associated rhodopsin mutants, whether heterodimerization between mutant and wildtype
protein occurs and whether we can identify compensatory mutations that restore dimerization. In iterative
fashion, predictions from analyses in silico will be tested in direct biochemical assays and the results will serve
to refine models and computational investigations. In the second aim we will comprehensively characterize two
mouse strains that homozygously express non-dimerizing rhodopsin mutants, one each corresponding to point
mutations in TM1 (F45L) and TM5 (F220C) to reflect the different dimer interfaces that are directly implicated.
Our goal is to conduct a “360 degree” analysis of the heterozygous and homozygous knock-in mouse
phenotypes by examining photoreceptor morphology, analyzing intracellular targeting of outer segment-
resident proteins, biochemical characterization of phototransduction, and electrophysiological assessment of
light responses produced by the mutant rods.

## Key facts

- **NIH application ID:** 9930615
- **Project number:** 5R01EY027969-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Vadim Y Arshavsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $526,839
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930615

## Citation

> US National Institutes of Health, RePORTER application 9930615, Rhodopsin dimerization: mechanistic basis and functional consequences (5R01EY027969-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9930615. Licensed CC0.

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