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Homologs of Vertebrate Opn3 Potentially Serve As a Light Sensor in Nonphotoreceptive Tissue

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Homologs of Vertebrate Opn3 Potentially Serve As a Light Sensor in Nonphotoreceptive Tissue Homologs of vertebrate Opn3 potentially serve as a light sensor in nonphotoreceptive tissue Mitsumasa Koyanagi1, Eiichiro Takada1, Takashi Nagata, Hisao Tsukamoto, and Akihisa Terakita2 Department of Biology and Geosciences, Graduate School of Science, Osaka City University, Osaka 558-8585, Japan Edited by King-Wai Yau, The Johns Hopkins School of Medicine, Baltimore, MD, and approved February 15, 2013 (received for review November 7, 2012) Most opsins selectively bind 11-cis retinal as a chromophore to opsins, the members of the retinochrome and peropsin groups form a photosensitive pigment, which underlies various physiolog- preferentially bind all-trans retinal, and light absorption causes ical functions, such as vision and circadian photoentrainment. Re- all-trans to 11-cis isomerization (8, 11–13). Therefore, the mem- cently, opsin 3 (Opn3), originally called encephalopsin or panopsin, bers of these two groups are considered to be retinal photo- and its homologs were identified in various tissues including brain, isomerases that produce 11-cis retinal. Collectively, opsins from eye, and liver in both vertebrates and invertebrates, including hu- seven of the eight phylogenetic groups have been characterized man. Because Opn3s are mainly expressed in tissues that are not to date. considered to contain sufficient amounts of 11-cis retinal to form The Opn3 group is the final distinct group, containing mam- pigments, the photopigment formation ability of Opn3 has been malian ospin 3 (Opn3), originally called encephalopsin or pan- of interest. Here, we report the successful expression of Opn3 opsin, teleost multiple tissue (TMT) opsin, insect pteropsin, and homologs, pufferfish teleost multiple tissue opsin (PufTMT) and annelid c-opsin (14–17). Despite the wide distribution of Opn3 mosquito Opn3 (MosOpn3) and show that these proteins formed homologs from vertebrates to invertebrates, which is similar to functional photopigments with 11-cis and 9-cis retinals. The that of Gq-coupled opsins, the molecular properties of these PufTMT- and MosOpn3-based pigments have absorption maxima proteins have not yet been revealed. Therefore, the character- in the blue-to-green region and exhibit a bistable nature. These ization of the Opn3 group is the last remaining requirement for Opn3 homolog-based pigments activate Gi-type and Go-type G an overall understanding of the diversity of opsin-based pig- proteins light dependently, indicating that they potentially serve ments. In addition, the molecular properties of members of the BIOCHEMISTRY as light-sensitive Gi/Go-coupled receptors. We also demonstrated Opn3 group are important for an understanding of the evolution that mammalian cultured cells transfected with the MosOpn3 or of the Gt-coupled opsins, including vertebrate visual pigments, PufTMT became light sensitive without the addition of 11-cis ret- because the Opn3 group forms the sister group to the Gt-coupled inal and the photosensitivity retained after the continuous light opsin group. More interestingly, Opn3 and its homologs are exposure, showing a reusable pigment formation with retinal en- expressed in various tissues, such as the brain (human, mouse, dogenously contained in culture medium. Interestingly, we found pufferfish, zebrafish, honey bee, and annelid), liver (human and that the MosOpn3 also acts as a light sensor when constituted pufferfish), kidney (human and zebrafish), and heart (zebrafish), with 13-cis retinal, a ubiquitously present retinal isomer. Our find- in addition to the eye (human, pufferfish, and zebrafish) (14–17). ings suggest that homologs of vertebrate Opn3 might function as Because Opn3 homologs are expressed in tissues that are not photoreceptors in various tissues; furthermore, these Opn3s, par- considered photosensitive, it will be important to determine ticularly the mosquito homolog, could provide a promising opto- whether they form photopigments. Recently, it was reported that genetic tool for regulating cAMP-related G protein-coupled the introduction of the zebrafish TMT gene to cavefish fin cells, receptor signalings. which were suggested to have originally been photosensitive for circadian photoentrainment but to have lost their photosensi- rhodopsin | phototransduction | nonvisual photoreception | opsin diversity tivity during evolution, restored the circadian photoentrainment capacity of the cells, suggesting that Opn3 homologs can serve as ost opsins bind 11-cis retinal as a chromophore to form a light-sensor proteins (18). Therefore, the molecular properties Mphotosensitive pigment (opsin-based pigment) that serves of Opn3 homologs should be investigated to know their potential as a light-sensitive G protein-coupled receptor (GPCR). The 11- functionality for light sensors in nonphotoreceptor cells. Here, cis to all-trans isomerization of the chromophore in an opsin- we report that Opn3 homologs of vertebrate and invertebrate based pigment upon light absorption triggers G protein activa- form functional blue- and green-sensitive photosensitive pig- tion (1–4), and the photoreception of the opsin-based pigment ments with 11-cis retinal, respectively, and activate Gi- and Go- initiates vision and nonvisual functions, including circadian en- type G proteins in a light-dependent manner. Furthermore, we trainment and pupil responses. Several thousand opsins have fi fi found that mammalian cultured cells transfected with the Opn3 been identi ed, and they are phylogenetically classi ed into eight homologs became light sensitive without the addition of 11-cis groups based on the members that have existed early in animal fi retinal, indicating that the Opn3 homologs formed pigments by evolution (5). The phylogenetic classi cation of each opsin also binding retinal endogenously present in the culture medium. In roughly corresponds to its molecular function. The Gt-coupled opsin group contains vertebrate visual pigments, which activate transducin (G )-type G proteins, and some nonvisual pigments, t Author contributions: M.K. and A.T. designed research; M.K., E.T., T.N., H.T., and A.T. such as pinopsin, VA-opsin, parapinopsin, and parietopsin (1–4). performed research; M.K., E.T., and A.T. analyzed data; and M.K. and A.T. wrote The Gq-coupled opsin group is composed of the visual pigments the paper. from many invertebrates, such as insects and cephalopods, and The authors declare no conflict of interest. the vertebrate opsin 4 (Opn4) homologs (melanopsins), which This article is a PNAS Direct Submission. function as circadian photoreceptors in mammals (6). The scallop Data deposition: The sequences reported in this paper have been deposited in the DNA Go-coupled rhodopsin and amphioxus rhodopsin comprise the Data Bank of Japan (DDBJ) (accession nos. AB753162 and AB753163). 1 Go-coupled opsin group (7, 8), and vertebrate opsin 5 (Opn5) was M.K. and E.T. contributed equally to this work. revealed to activate Gi-type G proteins (9, 10). In addition to 2To whom correspondence should be addressed. E-mail: [email protected]. these bilaterian opsins, we discovered a Gs-coupled opsin in the This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. visual cells of prebilaterian jellyfish (5). In contrast to these 1073/pnas.1219416110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1219416110 PNAS Early Edition | 1of6 Downloaded by guest on October 2, 2021 addition, the invertebrate Opn3 homolog acts as a photopigment a more than 50-fold higher yield of the purified MosOpn3-based when bound to 13-cis retinal, which is thermally equilibrated with pigment, which allowed us to determine the absorption maximum all-trans retinal and, therefore, ubiquitously present in animals of the MosOpn3-based pigment at ∼500 nm (Fig. 1B). Irradiation (19, 20). These results suggest that Opn3 homolog-expressing with green light resulted in a blue-shifted spectrum with a larger tissues may be photosensitive. Based on these unique properties, extinction coefficient and an absorption maximum at 485 nm. The we also propose that Opn3 homologs, especially the invertebrate difference spectrum of the dark minus irradiated MosOpn3-based homolog, may have an optogenetic potential for regulating pigment matched well with that of the full-length MosOpn3-based cAMP-related GPCR signaling. pigment (Fig. S1, Inset), indicating that the C-terminal truncation did not alter the spectroscopic features of the Opn3 homolog. Results Accordingly, we concluded that the MosOpn3-based pigment is Bistable Photopigment Opn3. To examine whether the members of a green-sensitive pigment with a peak absorbance at ∼500 nm and the Opn3 group form photosensitive pigments, we expressed the used the C-terminal truncated MosOpn3 for most of further pufferfish (Takifugu rubripes) Opn3 homolog TMT (PufTMT) and studies because of its higher expression in the cultured cells. the mosquito (Anopheles stephensi) Opn3 homolog (MosOpn3) as We also analyzed the chromophore configurations of the dark representatives of vertebrate and invertebrate members of the and irradiated PufTMT- and MosOpn3-based pigments. HPLC Opn3 group, respectively, in mammalian cultured cells. We suc- analyses showed that both the PufTMT- and MosOpn3-based ceeded in obtaining purified pigments for both Opn3 homologs pigments bound to 11-cis retinal in the dark and that light irra- after incubation with 11-cis retinal. The PufTMT-based pigment is diation caused 11-cis to all-trans isomerization (Fig. 1). This a blue-sensitive pigment, with an absorption maximum at ∼460 nm photoisomerization
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