Review articleThe manipulation of neural and cellular activities by ectopic expression of melanopsin
Highlights
► Ectopic expression of OPN4 can be used as a tool for optogenetics. ► OPN4 is more sensitive to light and shows long-lasting activation. ► OPN4 can also control intracellular Ca2+ dynamics.
Section snippets
Melanopsin as an optogenetic tool
Melanopsin (OPN4) is a 7-transmembrane G-protein-coupled receptor (GPCR) photopigment (Hatori and Panda, 2010, Sexton et al., 2012). Melanopsin-containing retinal ganglion cells, namely the intrinsic photosensitive retinal ganglion cells (ipRGC), were originally identified in the mammalian retina (Hattar et al., 2002). The ipRGCs are directly linked to brain functions such as the circadian rhythm and pupillary light reflex (Berson et al., 2002, Lucas et al., 2003). OPN4 is activated most
High sensitivity: ectopic expression of OPN4 in retinal non-ipRGC for restoring vision
Lin et al. (2008) successfully introduced ectopic OPN4 into retinal ganglion cells in vivo by adeno-virus vector injection into the eyes of mice with retinal degeneration. The OPN4-transfected ganglion cells provided an enhancement of visual function in the mice such that the pupillary light reflex (PLR) returned to near normal, the mice showed behavioral avoidance of light in an open-field test, and they could discriminate a light stimulus from a dark one in a two-choice visual discrimination
A comparison of melanopsin with channelrhodopsin variants
Recently, several researchers developed ChR2 variants with much higher sensitivity and longer activation kinetics than wild-type ChR2. Some of the improved ChR2 variants showed greater sensitivity than the original ChR2 (Berndt et al., 2009, Berndt et al., 2011, Wang et al., 2009). The bi-stable variants of ChR2, namely ChR2 C128S, showed much higher sensitivity and much longer kinetics than the wild type ChR2 (Berndt et al., 2009). Table 1 shows a comparison of melanopsin with the wild-type
Missing link: the ectopic expression of OPN4 and endogenous cation channels
As an optogenetic tool, there are known difficulties in controlling neural and cellular activities through the ectopic expression of OPN4. OPN4 itself does not form ion channels; cation channels, such as the TRPC channels, need to be functionally coupled to control neural and cellular activities in OPN4-transfected cells. For example, we preliminarily introduced human OPN4 into mouse medium spiny neurons (MSN, the predominant cell type of the striatum); however, no light responses were
Discussion
In conclusion, mammalian OPN4 is different from other types of optogenetic tools and possesses distinct features (Hatori and Panda, 2010, Sexton et al., 2012). It can control intracellular Ca2+ dynamics, which is a unique feature in an optogenetic tool that may be useful in future applications.
These optogenetic tools are expected to be useful for the treatment of human diseases such as retinal degenerative blindness (Lin et al., 2008) and common hormonal diseases such as diabetes (Ye et al.,
Acknowledgments
We thank Dr. Satoru Moritoh for technical support. This study was financially supported by a Grant-in-Aid for challenging Exploratory Research (AY and AK) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. This study was also supported by the Takeda Foundation (AY, KFT, and AK) and the Yamada Foundation (AK and KFT).
References (22)
- et al.
High-efficiency channelrhodopsins for fast neuronal stimulation at low light levels
Proc. Natl. Acad. Sci. U.S.A.
(2011) - et al.
Bi-stable neural state switches
Nat. Neurosci.
(2009) - et al.
Phototransduction by retinal ganglion cells that set the circadian clock
Science
(2002) - et al.
Melanopsin contributions to irradiance coding in the thalamo-cortical visual system
PLoS Biol.
(2010) - et al.
Immunohistochemical study on the distribution of TRPC channels in the rat hippocampus
Brain Res.
(2006) - et al.
Photon capture and signalling by melanopsin retinal ganglion cells
Nature
(2009) - et al.
Light-evoked calcium responses of isolated melanopsin-expressing retinal ganglion cells
J. Neurosci.
(2007) - et al.
The emerging roles of melanopsin in behavioral adaptation to light
Trends Mol. Med.
(2010) - et al.
Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity
Science
(2002) - et al.
Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin
Proc. Natl. Acad. Sci. U.S.A.
(2008)
Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice
Science
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2022, Cell Reports MethodsCitation Excerpt :For instance, the excitation of orexin neurons using OPN4 with blue light (19 mW, 5 s) promoted wakefulness.28 However, the authors of that paper failed to manipulate neurons in the hippocampus using the same method,52 suggesting that there is something missing to make OPN4 work efficiently. We found that the truncation of C-terminal region of OPN4 significantly increased the activity of Gq signaling (Figure S2), presumably by decreasing internalization and degradation, and, consequently, the effect on body temperature was enhanced (Figure 1B).
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2017, Current Opinion in PharmacologyCitation Excerpt :Recently, conopsin hyperpolarized DRN neurons in brain slice, and a chimera (see below) expressed in the DRN was able to modulate anxiety behavior [12]. Melanopsin, a non-visual opsin, has also successfully engaged neural circuits [13]. Melanopsins are activated by blue light, but unlike the visual opsins, are bistable and thus can be deactivated by yellow light.
Diversity of animal opsin-based pigments and their optogenetic potential
2014, Biochimica et Biophysica Acta - BioenergeticsCitation Excerpt :Therefore, jellyfish Gs-coupled opsin and bistable pigments that activate Gi-type G proteins, such as Opn3, Opn5, Go-coupled opsin, and parapinopsin, can be promising optogenetic tools for the in vivo upregulation and downregulation of cAMP levels, respectively (Fig. 2). With respect to the in vivo modulation of Gq-mediated phosphoinositol signaling by light, melanopsin has been successfully employed in several cases [57–59]. While all melanopsins investigated thus far have been revealed to be blue-sensitive pigments, invertebrate Gq-coupled visual pigments have a diverse spectral sensitivity, ranging from the UV to green region.
Ectopic expression of melanopsin in orexin/hypocretin neurons enables control of wakefulness of mice in vivo by blue light
2013, Neuroscience ResearchCitation Excerpt :We showed that optogenetical approaches to orexin neurons by ectopic expression of hOPN4 successfully controls sleep/wakefulness cycles. The advantage of using OPN4 as an optogenetical tool to control neural activity is that blue light illumination for just a short period can initiate long-lasting activation of neurons even after the blue light is switched off (Koizumi et al., 2013; Sexton et al., 2012). OPN4 just triggers the initiation of the cell's excitability by a short pulse of blue light.