Contreras E , Nobleman AP , Robinson PR , Schmidt TM .

RO1- EY207202 NIH HHS , DP2 EY027983 NEI NIH HHS , T32 HL007909 NHLBI NIH HHS , R21 GM134406 NIGMS NIH HHS , ZIA MH002964 Intramural NIH HHS, R01 EY027202 NEI NIH HHS

	Fig. 1. Structure of mammalian Opn4 based on squid rhodopsin. (A) 3D homology modeling of inactive mouse melanopsin based on a squid (Todarodes pacificus) rhodopsin template. Modeling was done in PyMOL (The PyMOL Moelcular Graphics System, v.1.2r3pre, Schrödinger, LLC). Mouse melanopsin boasts an exceptionally long carboxy-tail that heavily influences both activation and deactivation of melanopsin signaling. (B) An enhanced view of the transmembrane regions of mouse melanopsin, including chromophore binding. Each distinct transmembrane helix is represented in a different color. Upon isomerization of the chromophore by light, transmembrane movement of the transmembrane helices permits the binding of G-protein to intracellular loops two and three.
	Fig. 2. Overview of ipRGC subtype diversity. (A) Tracings of single M1–M6 ipRGCs. The properties of these cell types are summarized in Table 1. (B) A simplified schematic of M1–M6 stratification in the ON and OFF sublamina of the inner plexiform layer (IPL) depicting downstream targets. The projections of M3 have not been well-studied; however, they may innervate the superior colliculus (Zhao et al., 2014). The M1–M5 dye-filled cells were collected in the Schmidt laboratory, and the M6 morphology is reproduced from Quattrochi et al. (2019), with permission.
	Fig. 3. Melanopsin phototransduction cascade models in ipRGCs. Light activates melanopsin, initiating a biochemical cascade resulting in the depolarization of ipRGCs. Diverse melanopsin phototransduction cascades exist across ipRGC subtypes. Depicted are the current phototransduction models for three ipRGC subtypes. (A) In M1 ipRGCs, melanopsin signals through Gq to target TRPC channels (Warren et al., 2006; Graham et al., 2008; Xue et al., 2011; Jiang et al., 2018; Sonoda et al., 2018). (B) Similarly to M1 cells, M2 ipRGCs activate Gq to modulate TRPC channels, yet unlike M1 ipRGCs, M2 cells in parallel signal through an unknown G-protein to open HCN channels (Jiang et al., 2018; Perez-Leighton et al., 2011). (C) There are two proposed models for M4 ipRGC phototransduction (Sonoda et al., 2018; Jiang et al., 2018). (i) Sonoda et al. (2018) propose that potassium leak channels are the major phototransduction target in M4 ipRGCs with a minor role played by TRPC channels. (ii) HCN channels are the major phototransduction target in M4 cells (Jiang et al., 2018). HCN channels are primarily opened by hyperpolarization and closed by depolarization; however, in this model, HCN channels are activated by cyclic nucleotides. The structure of a cyclic nucleotide is shown above, in which the R represents the nitrogenous base (adenine or guanine) bonded to the sugar phosphate part. Further inquiry is required to explain the opposing melanopsin phototransduction models in M4 ipRGCs. cNMP, cyclic nucleotide monophosphate; HCN, hyperpolarization-activated cyclic nucleotide-gated; PLC, phospholipase C; TRPC, canonical transient receptor potential.
	Fig. 4 Phylogeny and current understanding of melanopsin phototransduction across species. (A) Phylogenetic analysis of the melanopsin protein sequence across multiple organisms using the neighbor-joining method (Saitou and Nei, 1987). Amino acid sequences of 14 melanopsin genes expressed in 9 different organisms (UniProt, Table S1) were aligned using MUSCLE alignment (Edgar, 2004) and compiled into a tree using the neighbor-joining method within Geneious Prime (Geneious Prime v.2019.1.1.; https://www.geneious.com). Amphioxus (Branchiostoma belcheri) melanopsin is used as an outgroup. Branches are labeled with percent confidence levels based on 100 bootstrap replicates. Only the melanopsin(s) of highlighted species have been studied in the context of phototransduction. (B) A summary of the current knowledge of the cognate G-proteins of melanopsin across multiple organisms. ‘Expression’ denotes either expression of protein or expression of mRNA transcripts that co-localize with melanopsin. Expression and in vitro assessment of G-protein activation has been defined across multiple organisms, whereas in vivo work has been done exclusively in the mouse.

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