# Melanopsin Photoreception and Signaling

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $409,375

## Abstract

PROJECT SUMMARY
 It is now clear that the mammalian retina has at least one other photoreceptor class besides rods and
cones, consisting of a subpopulation of retinal ganglion cells (RGCs) that express the pigment melanopsin
(OPN4) and are intrinsically photosensitive (ipRGCs). These cells project predominantly to non-image-vision
centers in the brain, serving functions such as circadian photoentrainment and pupillary light reflex. At the
same time, ipRGCs project moderately to the brain's image-vision centers, presumably serving subtle image-
forming visual functions such as possibly providing information about absolute light intensity in the visual
scene. IpRGCs are known so far to comprise 6 subtypes, M1-M6, which differ in the level of melanopsin
content, photosensitivity, somatic and dendritic-field size, exact locations of their dendritic arborizations in the
retina's inner plexiform layer, and the detailed locations of their axonal projections in the respective brain
targets.
 To fully understand the ipRGC system, it is important to know their light-response properties and the
underlying mechanisms. In recent years, we have made great progress in understanding M1-ipRGCs,
including the molecular identities of several key components in phototransduction such as Gαq-subfamily
members, the PLCβ4 enzyme and the TRPC6,7 channels. These components closely resemble those found in
fly-eye phototransduction. Most recently, we have made the exciting discovery of yet another
phototransduction pathway, found in M2- and M4-ipRGCs. This pathway involves a light-induced elevation of
cyclic nucleotide, which opens HCN channels (channels gated by membrane hyperpolarization and cyclic
nucleotide) to produce membrane depolarization and action potentials.
 This application constitutes a continuation of these successful investigations. Aim 1 is to seek some
details of the HCN-phototransduction pathway still outstanding, including establishing (i) whether cGMP or
cAMP is the second messenger, (ii) the identity of the effector enzyme that controls the second messenger,
and (iii) the identity of the G protein upstream of the HCN-pathway. Aim 2 is to characterize the
phototransduction mechanism(s) still unknown in M3-, M5- and M6-ipRGCs. Our speculation is that the same
two pathways are involved, but this requires verification. Aim 3 is to quantify the relative importance of the two
signaling pathways in different cell subtypes. We shall study sensitivity, intensity-response relation, single-
photon response, and response kinetics of each pathway, hopefully eventually to derive correlations with the
respective subtype's macroscopic functions.

## Key facts

- **NIH application ID:** 10438306
- **Project number:** 2R01EY014596-20
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** KING-WAI YAU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,375
- **Award type:** 2
- **Project period:** 2022-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438306

## Citation

> US National Institutes of Health, RePORTER application 10438306, Melanopsin Photoreception and Signaling (2R01EY014596-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10438306. Licensed CC0.

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