# OPN4

## Overview
Opsin 4 (OPN4) is a gene that encodes the protein melanopsin, a member of the G-protein-coupled receptor (GPCR) family, characterized by its seven-transmembrane domain structure. Melanopsin is primarily expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs) and plays a pivotal role in non-image-forming visual functions, such as circadian rhythm regulation and the pupillary light reflex. Beyond the retina, OPN4 is also expressed in peripheral tissues, including the skin and brain, where it may mediate various physiological responses to light. The protein's ability to activate both Gq and Gi signaling pathways underscores its versatility in phototransduction and cellular signaling. Mutations in the OPN4 gene have been linked to clinical conditions such as Seasonal Affective Disorder and chronic insomnia, and its role in melanoma progression highlights its potential as a therapeutic target (Nissilä2016The; Kusumoto2020OPN4; de2022Melanopsin).

## Structure
Opsin 4 (OPN4), also known as melanopsin, is a photopigment found in retinal ganglion cells and is part of the G-protein-coupled receptor (GPCR) family. It has a seven-transmembrane domain structure typical of opsins, which is crucial for its function as a photoreceptor. The primary structure of OPN4 consists of a sequence of amino acids that form the protein chain, while the secondary structure includes alpha helices within the transmembrane regions (Rodgers2018Functional).

The tertiary structure involves the folding of these helices into a functional conformation, allowing OPN4 to interact with specific G proteins and initiate the phototransduction cascade. OPN4 is capable of activating both Gi and Gq pathways, with the intracellular loop 3 (IL3) playing a critical role in its interaction with these heterotrimers (Kankanamge2018Melanopsin).

Post-translational modifications, such as phosphorylation, may affect the activity of OPN4, although specific modifications are not detailed in the provided context. The gene also encodes splice variants, which can result in different isoforms with potentially distinct functions (Davies2010Vertebrate). These structural features contribute to OPN4's role in non-image forming responses to light, such as circadian photoentrainment and the pupillary light response (Rodgers2018Functional).

## Function
Opsin 4 (OPN4), also known as melanopsin, is a photopigment primarily found in intrinsically photosensitive retinal ganglion cells (ipRGCs) in the human retina. It plays a crucial role in non-image-forming visual functions, such as the regulation of circadian rhythms and the pupillary light reflex. OPN4 is essential for circadian photoentrainment, which aligns the central biological clock in the hypothalamic suprachiasmatic nucleus (SCN) with the external light-dark cycle (Moraes2021Opsins). 

In addition to its retinal functions, OPN4 is expressed in various peripheral tissues, including the skin, where it acts as a photoreceptor. In human skin cells, OPN4 mediates responses to blue light, leading to calcium influx and activation of the mitogen-activated protein kinase (MAPK) cascade, which are involved in cell growth and differentiation (Kusumoto2020OPN4). 

OPN4 is also present in the human brain, where it may influence physiological processes beyond traditional light sensing, although its exact role remains largely unexplored (Nissilä2016The). The widespread distribution of OPN4 in the brain suggests potential roles in phototransduction pathways independent of the retinohypothalamic tract (Nissilä2016The).

## Clinical Significance
Mutations and alterations in the expression of the OPN4 gene, which encodes melanopsin, have been implicated in several clinical conditions. The Pro10Leu (P10L) polymorphism in OPN4 has been associated with an increased risk of Seasonal Affective Disorder (SAD) and chronic insomnia. Individuals with the homozygous minor genotype (T/T) for this variant are significantly more likely to experience SAD, suggesting that this polymorphism may alter the non-visual light input pathway, affecting circadian photoentrainment and other light-related functions (GutiérrezAmavizca2021Association; Roecklein2009A). The P10L polymorphism is also linked to chronic insomnia, with the T allele being a significant risk factor, particularly in individuals with an eveningness chronotype, which is associated with more severe daytime sleepiness (GutiérrezAmavizca2021Association).

In the context of cancer, OPN4 has been identified as an oncogene in cutaneous melanoma. Its expression influences tumor growth and the tumor microenvironment, with OPN4 knockout tumors showing reduced proliferation and a less inflammatory tumor microenvironment. This suggests that OPN4 may play a role in melanoma progression and could be a target for therapeutic strategies (de2022Melanopsin).

## Interactions
The human gene OPN4 encodes melanopsin, a photopigment involved in various signaling pathways through interactions with G proteins. Melanopsin primarily interacts with Gq/11 and Gi/o protein families, facilitating diverse cellular responses to light. It activates the Gq/11 signaling cascade, leading to significant calcium mobilization, which is a key component of its phototransduction mechanism (Bailes2013Human). This interaction is crucial for the light-induced responses in intrinsically photosensitive retinal ganglion cells (ipRGCs), where melanopsin is predominantly expressed (Panda2005Illumination).

Melanopsin also engages with Gi/o proteins, as evidenced by a decrease in luminescence upon light exposure, which is inhibited by pertussis toxin, indicating a role in Gi/o signaling (Bailes2013Human). The ability of melanopsin to activate both Gq and Gi pathways is attributed to its intracellular loop 3 (IL3) region, which shares sequence similarities with both Gi- and Gq-coupled receptors (Kankanamge2018Melanopsin).

In human skin, OPN4 is associated with GNAQ, a G protein, suggesting that light signals are converted to intracellular signals via this interaction, influencing processes like ERK1/2 phosphorylation and calcium influx (Kusumoto2020OPN4). These interactions highlight the multifaceted role of OPN4 in light perception and signal transduction.


## References


[1. (Nissilä2016The) Juuso S. Nissilä, Satu K. Mänttäri, Terttu T. Särkioja, Hannu J. Tuominen, Timo E. Takala, Vesa J. Kiviniemi, Raija T. Sormunen, Seppo Y. O. Saarela, and Markku J. Timonen. The distribution of melanopsin (opn4) protein in the human brain. Chronobiology International, 34(1):37–44, September 2016. URL: http://dx.doi.org/10.1080/07420528.2016.1232269, doi:10.1080/07420528.2016.1232269. This article has 14 citations and is from a peer-reviewed journal.](https://doi.org/10.1080/07420528.2016.1232269)

[2. (Rodgers2018Functional) Jessica Rodgers, Stuart N. Peirson, Steven Hughes, and Mark W. Hankins. Functional characterisation of naturally occurring mutations in human melanopsin. Cellular and Molecular Life Sciences, 75(19):3609–3624, April 2018. URL: http://dx.doi.org/10.1007/s00018-018-2813-0, doi:10.1007/s00018-018-2813-0. This article has 16 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-018-2813-0)

[3. (Moraes2021Opsins) Maria Nathalia Moraes, Leonardo Vinicius Monteiro de Assis, Ignacio Provencio, and Ana Maria de Lauro Castrucci. Opsins outside the eye and the skin: a more complex scenario than originally thought for a classical light sensor. Cell and Tissue Research, 385(3):519–538, July 2021. URL: http://dx.doi.org/10.1007/s00441-021-03500-0, doi:10.1007/s00441-021-03500-0. This article has 34 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00441-021-03500-0)

[4. (Kusumoto2020OPN4) Junya Kusumoto, Makoto Takeo, Kazunobu Hashikawa, Takahide Komori, Takashi Tsuji, Hiroto Terashi, and Shunsuke Sakakibara. Opn4 belongs to the photosensitive system of the human skin. Genes to Cells, 25(3):215–225, February 2020. URL: http://dx.doi.org/10.1111/gtc.12751, doi:10.1111/gtc.12751. This article has 20 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/gtc.12751)

[5. (de2022Melanopsin) Leonardo Vinícius Monteiro de Assis, José Thalles Lacerda, Maria Nathália Moraes, Omar Alberto Domínguez-Amorocho, Gabriela Sarti Kinker, Davi Mendes, Matheus Molina Silva, Carlos Frederico Martins Menck, Niels Olsen Saraiva Câmara, and Ana Maria de Lauro Castrucci. Melanopsin (opn4) is an oncogene in cutaneous melanoma. Communications Biology, May 2022. URL: http://dx.doi.org/10.1038/s42003-022-03425-6, doi:10.1038/s42003-022-03425-6. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s42003-022-03425-6)

[6. (Davies2010Vertebrate) Wayne L. Davies, Mark W. Hankins, and Russell G. Foster. Vertebrate ancient opsin and melanopsin: divergent irradiance detectors. Photochemical & Photobiological Sciences, 9(11):1444–1457, November 2010. URL: http://dx.doi.org/10.1039/c0pp00203h, doi:10.1039/c0pp00203h. This article has 73 citations.](https://doi.org/10.1039/c0pp00203h)

[7. (GutiérrezAmavizca2021Association) Bianca Ethel Gutiérrez-Amavizca, Ernesto Prado Montes de Oca, Jaime Paul Gutiérrez-Amavizca, Oscar David Castro, Cesar Heriberto Ruíz-Marquez, Kricel Perez Conde-Andreu, Ricardo Pérez Calderón, Marisela Aguirre Ramírez, and Jorge Alberto Pérez-León. Association of p10l polymorphism in melanopsin gene with chronic insomnia in mexicans. International Journal of Environmental Research and Public Health, 18(2):571, January 2021. URL: http://dx.doi.org/10.3390/ijerph18020571, doi:10.3390/ijerph18020571. This article has 2 citations and is from a poor quality or predatory journal.](https://doi.org/10.3390/ijerph18020571)

[8. (Roecklein2009A) Kathryn A. Roecklein, Kelly J. Rohan, Wallace C. Duncan, Mark D. Rollag, Norman E. Rosenthal, Robert H. Lipsky, and Ignacio Provencio. A missense variant (p10l) of the melanopsin (opn4) gene in seasonal affective disorder. Journal of Affective Disorders, 114(1–3):279–285, April 2009. URL: http://dx.doi.org/10.1016/j.jad.2008.08.005, doi:10.1016/j.jad.2008.08.005. This article has 113 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.jad.2008.08.005)

[9. (Bailes2013Human) Helena J. Bailes and Robert J. Lucas. Human melanopsin forms a pigment maximally sensitive to blue light ( λ max ≈ 479 nm) supporting activation of g q /11 and g i/o signalling cascades. Proceedings of the Royal Society B: Biological Sciences, 280(1759):20122987, May 2013. URL: http://dx.doi.org/10.1098/rspb.2012.2987, doi:10.1098/rspb.2012.2987. This article has 379 citations.](https://doi.org/10.1098/rspb.2012.2987)

[10. (Panda2005Illumination) Satchidananda Panda, Surendra K. Nayak, Brice Campo, John R. Walker, John B. Hogenesch, and Tim Jegla. Illumination of the melanopsin signaling pathway. Science, 307(5709):600–604, January 2005. URL: http://dx.doi.org/10.1126/science.1105121, doi:10.1126/science.1105121. This article has 377 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1126/science.1105121)

[11. (Kankanamge2018Melanopsin) Dinesh Kankanamge, Kasun Ratnayake, Saroopa Samaradivakara, and Ajith Karunarathne. Melanopsin (opn4) utilizes gαi and gβγ as major signal transducers. Journal of Cell Science, June 2018. URL: http://dx.doi.org/10.1242/jcs.212910, doi:10.1242/jcs.212910. This article has 19 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.212910)