# Opsin signaling in mammalian rod photoreceptors

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $406,573

## Abstract

ABSTRACT
Light detection in rod photoreceptors is mediated by a G protein-signaling cascade triggered when the
visual pigment rhodopsin, a prototypical G protein-coupled receptor, is activated by light and initiates
the rod light response. Eventually, the photoactivated rhodopsin decays to all-trans-retinal and free
opsin. The chromophore-free opsin produces persistent transduction activity even in darkness. This, in
turn desensitizes the photoreceptors and limits our ability to see following exposure to bright light.
Abnormally high opsin activity due to opsin mutations or slow pigment regeneration can be detrimental
to rod function and survival. Despite the role of opsin activity in modulating rod physiology in normal
and disease conditions, the molecular mechanism by which opsin stimulates rod transduction has
remained unclear. The prevailing view is that each opsin has low uniform constitutive activity. We will
evaluate an alternative hypothesis that, similar to rhodopsin, opsin exists in equilibrium between a
distinct inactive state and a rare but highly efficient active state. This hypothesis is based on our
preliminary data showing that introduction of a small amount of free opsin by rhodopsin bleaching
results in the generation of discrete, photoresponse-like events in mouse rods. We will perform
experiments to determine the amplitude and kinetics of the quantal response produced by a single
opsin molecule in mouse, primate, and human rod photoreceptors. We will also determine the
mechanism of modulation of opsin activity by non-covalent binding of chromophore analogs and
chaperones, and whether blocking opsin signaling either by quenching with chaperones, or by using 5-
or 6-locked rhodopsin that does not dissociate upon photoactivation restores the sensitivity of
chromophore-deficient rods. Finally, we will perform experiments to determine the role of
phosphorylation and arrestin binding in the inactivation of opsin signaling. These experiments will
establish the molecular mechanisms by which opsin activates the rod transduction cascade to produce
bleaching adaptation. They will also help us understand how this activity can be modulated
pharmacologically, potentially leading to the development of treatments for a range of opsin-related
visual disorders such as congenital stationary night blindness and retinitis pigmentosa.

## Key facts

- **NIH application ID:** 9866895
- **Project number:** 1R01EY030912-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Vladimir Jivkov Kefalov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $406,573
- **Award type:** 1
- **Project period:** 2020-06-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9866895

## Citation

> US National Institutes of Health, RePORTER application 9866895, Opsin signaling in mammalian rod photoreceptors (1R01EY030912-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9866895. Licensed CC0.

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