Melanopsin phototransduction: beyond canonical cascades

Abstract

Melanopsin is a visual pigment that is expressed in a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs). It is involved in regulating non-image forming visual behaviors, such as circadian photoentrainment and the pupillary light reflex, while also playing a role in many aspects of image-forming vision, such as contrast sensitivity. Melanopsin was initially discovered in the melanophores of the skin of the frog Xenopus, and subsequently found in a subset of ganglion cells in rat, mouse and primate retinas. ipRGCs were initially thought to be a single retinal ganglion cell population, and melanopsin was thought to activate a single, invertebrate-like Gq/transient receptor potential canonical (TRPC)-based phototransduction cascade within these cells. However, in the 20 years since the discovery of melanopsin, our knowledge of this visual pigment and ipRGCs has expanded dramatically. Six ipRGC subtypes have now been identified in the mouse, each with unique morphological, physiological and functional properties. Multiple subtypes have also been identified in other species, suggesting that this cell type diversity is a general feature of the ipRGC system. This diversity has led to a renewed interest in melanopsin phototransduction that may not follow the canonical Gq/TRPC cascade in the mouse or in the plethora of other organisms that express the melanopsin photopigment. In this Review, we discuss recent findings and discoveries that have challenged the prevailing view of melanopsin phototransduction as a single pathway that influences solely non-image forming functions.

Melanopsin activates divergent phototransduction pathways in ipRGC subtypes

“…In M4 cells, researchers have reached conflicting conclusions about the identity of the melanopsin transduction channel(s). Our previous findings in M4 cells point to closure of potassium leak channels by melanopsin phototransduction and a minor contribution from TRPC3/6/7 channel opening, while a concurrent study concluded that melanopsin phototransduction leads to opening of HCN channels in M4 cells with no contribution from TRPC3/6/7 channels (Sonoda et al, 2018;Jiang et al, 2018;Contreras et al, 2021). Potassium channel closure versus HCN channel opening would lead to distinct, laregely opposing impacts on M4 cell physiology and signaling, and thus a major goal of this study was to resolve the role of HCN and TRPC channels in ipRGC phototransduction in M4 cells, as well as to re-assess their role in M2 ipRGCs.…”

“…Performed statistical analysis with Mann Whitney U test (see methods). Contreras et al, 2021. (Warren et al, 2006, Graham et al, 2008, Xue et al, 2011, Jiang et al, 2018, Sonoda et al, 2018Perez-Leighton et al, 2011).…”

“…Diverse melanopsin phototransduction pathways in ipRGC subtypes Diagram depicting melanopsin phototransduction in M1, M2, and M4 ipRGCs updated from previous work based on current findings. Figure adapted from Contreras et al, 2021. (Warren et al, 2006, Graham et al, 2008, Xue et al, 2011, Jiang et al, 2018, Sonoda et al, 2018Perez-Leighton et al, 2011).…”

“…Melanopsin shares greater sequence homology with invertebrate rhodopsins than vertebrate opsins, which led to an early expectation that melanopsin phototransduction in all ipRGC subtypes would work through an identical, invertebrate-like signaling pathway involving activation of a Gq/PLC-based cascade that opens canonical transient receptor potential (TRPC) channels such as TRPC 3, 6, or 7 (Provencio et al, 1998, 2000, 2002; Koyanagi et al, 2005; Koyanagi and Terakita, 2008; Graham et al, 2008; Hartwick et al, 2007; Perez-Leighton et al, 2011; Warren et al, 2006; Xue et al, 2011). However, though M1 ipRGCs use the predicted Gq/PLC based cascade to open only TRPC6/7 channels, phototransduction in non-M1 ipRGCs has been reported to rely less exclusively on TRPC channels and to also target additional channel types (Warren et al, 2006; Hartwick et al, 2007; Graham et al, 2008; Xue et al, 2011; Perez-Leighton et al, 2011; Sonoda et al, 2018; Jiang et al, 2018; Contreras et al, 2021). In M2 cells, for example, melanopsin phototransduction is reported to open both TRPC channels and Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels (Perez-Leighton et al, 2011; Jiang et al, 2018; Contreras et al, 2021).…”

Rhodopsins: An Excitingly Versatile Protein Species for Research, Development and Creative Engineering

“…For instance, the VA-opsin and melanopsin family also show this feature, except that the pentapeptide insertion does not occur. Here the extra sequence probably has a function in complex regulation of signal processing and desensitization ( Valdez-Lopez et al, 2020 ; Contreras et al, 2021 ). Some VA-opsins and melanopsins are even produced in two or more splicing isoforms, with longer and shorter C-terminals ( Davies et al, 2010 ).…”