Melanopsin: A Photopigment Regulating Circadian Photoentrainment May Lead to a Blue Light-Induced Treatment of Diabetes
Center for Teaching and Learning
Ross University School of Medicine
Commonwealth of Dominica, West Indies
Over the past decade there is growing acceptance that photoreception in the retina is not merely
restricted to the rods and cones, the classical photoreceptors. There is mounting evidence that a
small population (0.2%) of retinal ganglion cells (RGCs), designated as intrinsically
photosensitive retinal ganglion cells (ipRGCs), are capable of responding to light [1, 2]. The
presence of melanopsin, a blue light sensitive pigment in the ipRGCs [1, 3, 4], accounts for their
direct photosensitivity. With the largest melanopsin positive dendritic tree diameter , ipRGCs
serve as primary conduits through which photic information is relayed from the retina to non-image forming visual centers of the brain, namely the olivary pretectal nucleus (OPN), and the
suprachiasmatic nucleus of the hypothalamus (SCN). As a photo sensory pigment, melanopsin is
involved primarily in photoentrainment or alignment of the biological clock of an organism with
the environmental dusk and dawn cycle. In contrast to the classical photopigment rhodopsin
(committed to image-forming visual functions), melanopsin is associated with mediation of non-image forming visual functions, including pupillary light reflex and circadian entrainment [6, 7,
8, 9]. Melanopsin requires light stimulus of a higher irradiance and longer duration for activation
, while rhodopsin is optimized for rapid and sensitive contrast acuity. In recent years,
identification of melanopsin cell projections in the dorsal lateral geniculate nucleus (LGN) is indicative of its involvement in visual perception as well [11, 12]. The existence of a cross-talk between dopamine and
melanopsin in the context of light responsiveness of ipRGCs  is eminently interesting. The
association of the melanopsin system in allodynia (pain) to light or photophobia , sleep , mood
regulation , and the recent popularity of melanopsin as an optogenetic tool [17, 18] further
emphasizes the clinical importance of this retinal photosensory pigment. This
modest mini review aims at summarizing the importance of melanopsin as a photosensory
pigment, the genesis of which begins with its in vivo
function as a circadian photoentrainer in
mammals, to its possible future role as molecular switch for light induced regulation of
intracellular synthetic transcription/translation machineries in therapeutic cell implants.
The Blue Light Sensitive Pigment Melanopsin
Originally cloned from Xenopus
dermal melanophores , the melanopsin gene (Opn4) has
been described in a variety of vertebrates [20, 21, 22,]. Although the gene has various orthologs
, Opn4m is considered to be the mammalian ortholog [24, 25]. In humans, the melanopsin
gene, expressing mainly in the ipRGCs, produces mature melanopsin protein, which is an opsin
subgroup of G protein (guanosine nucleotide binding protein) coupled receptors  linked to a chromophore containing 11-cis retinal
(specific form of vitamin A). The membrane density of melanopsin is 104
fold lower in ipRGCs
when compared to that of rhodopsin in rod cells . Its peak spectral sensitivity is around 480
nm [27, 28], thus it is highly sensitive to blue light. Characterized by low photon catch,
melanopsin also exhibits a low phototransducing ability in bright light . The light
transduction mechanism of melanopsin is different from the classical photosensory pigments.
Irradiation of rod/cone opsins by bright light decreases cGMP levels closing cGMP-gated
membrane channels leading to membrane hyperpolarization and activation of the photoreceptors
[29, 30]. Conformational changes of melanopsin, due to photoisomerization of
by blue light, activates phospholipase C (PLC), and phosphokinase C (PKC) triggers calcium
influx into the ipRGCs. This sequence of events leads to membrane depolarization [31, 32] and
subsequent activation of ipRGCs. The distinct functional roles associated with the classical
photosensory pigments (present in rods/cones) and the blue light sensory pigment
melanopsin are illustrated in Figure 1.
Figure 1: Regulation of Image and Non-image Forming Visual Functions of the Eye. The melanopsin positive ipRGCs respond directly to ambient light and mediate a variety of non-image forming visual functions, namely circadian photoentrainment of the SCN, pupillary light response and regulation of sleep and mood. The visual functions of the eye are regulated by the classical photosensory pigments present in rods and cones through the population of classical/non-melanopsin RGCs. The role of classical RGCs in non-image forming visual functions, and the role of melanopsin in image forming, have been suggested, but the underlying mechanism still remains unknown (??). RGC (retinal ganglion cells); ipRGCs (intrinsically photosensitive retinal ganglion cells); SCN (suprachiasmatic nucleus).
Classical Functions of Melanopsin
The circadian rhythms of our physiology and behavior are
regulated by the hypothalamic SCN, the master circadian oscillator, which requires regular
synchronization with the daily and seasonal fluctuations of the environmental photoperiod. This
process is defined as circadian photoentrainment. Melanopsin serves as a primary candidate
(among other retinal photoreceptors) regulating circadian photoentrainment of the SCN .
Along with pituitary adenynyl cyclase activating peptide (PACAP), which co-expresses in the
ipRGCs [34, 35], melanopsin forms the retinohypothalamic tract [6, 36] that projects into the
SCN and synchronizes it with the solar day . The severely attenuated phase resetting
response exhibited by melanopsin null mice (Opn4-/-) in response to brief pulses of
monochromatic light , provides support for this fact. The role of classical photosensory
pigments, namely the medium wavelength opsin (MW cones) in the process of photoentrainment,
cannot be ignored [38, 39]. The influence of melanopsin is not only restricted to the master
circadian oscillator. Melanopsin mediated regulation of autonomous organ specific molecular
clocks, specifically the retinal circadian clock [40, 41, 42], has recently been established .
Melanopsin through dopamine is reported to regulate clock gene expression (period 1 and 2
genes) in the retina . Studies contradicting the role of melanopsin in circadian
photoentrainment through direct photic input to the SCN also exists , but at this particular
point they are far outweighed by the merits of those studies that have successfully established the
Pupillary Light Response:
In mammals, melanopsin expressing ipRGCs project into the LGN
and olivary pretectal nucleus (OPN), which are the centers controlling pupillary light reflex [45,
5]. Existing literature speaks of the involvement of ipRGCs in the regulation of baseline pupil
diameter , the steady state pupil diameter , and post-illumination pupillary response .
The existence of a functional melanopsin driven inner retinal pathway controlling post-stimulus
sustained pupillary response, has been identified in humans [49, 46, 50], as well as in other
mammals like mice and macaque monkeys [48, 51]. The fact that melanopsin is required for full
pupillary constriction at high irradiance, while the contribution of classical photoreceptors (rods
and cones) to pupillary control mechanisms is restricted to low irradiance, has been established
. The expression of melanopsin in the iris muscles of the eye  is a notable finding that
lends additional support to the role of melanopsin in the regulation of the pupillary light response.
Pupillary responses differ as a function of light intensity and wavelength, reflecting phototransduction primarily mediated by rods, cones, or melanopsin . Based on this fact, the use of
chromatic light stimuli to elicit transient and sustained pupillary light reflexes may well translate
into a clinical pupillary test in the near future, allowing differentiation between disorders
affecting photoreceptors and those affecting retinal ganglion cells [55, 56]. Melanopsin regulated
post-illumination pupil response (PIPR) may be important for documenting inner retinal
function in patients with diabetes without diabetic retinopathy .
Regulation of Sleep and Mood:
The daily cycle of sleep and wakefulness in humans is regulated by brain circuitry and neurotransmitters . The hypothalamus, and more specifically the SCN,
is the switch that shuts off the arousal system during sleep [58, 59, 60]. Melanopsin conveying
non-visual light information to the SCN plays a crucial role in mediating the effects of light on
sleep . Loss of sleep homeostasis in vertebrates induced by a lack of melanopsin expression
 supports the direct photic regulation of sleep by melanopsin based phototransduction [61,
Current studies are addressing the role of melanopsin in the pathogenesis of circadian and sleep
abnormalities associated with neurodegenerative disorders [63, 64]. Recurrent depressions in fall
and winter are common in patients with seasonal affective disorder (SAD), as the hormones
regulating mood and sleep become unbalanced due to seasonal changes. Individuals with low
levels of melanopsin are found to frequently suffer with mood and sleep disorder .
Melanopsin gene variants (a single missense variant, P10L of Opn4 gene) are associated with
increased risk of SAD in humans . The seasonality of these depressive episodes in SAD
patients and the favorable anti-depressive behaviors in response to light therapy (particularly
blue light in the range of 470 nm) is indicative of the fact that melanopsin sensitivity has a
unique effect of resetting the body’s internal clock and thus restoring the sleep-wake cycle and
mood issues in SAD patients [67, 68].
Optogenetics and the Importance of Melanopsin as an Optogenetic Tool
Optogenetics is an emerging research discipline that utilizes the capability of light to process
biological information in a fast and precise manner. Genetic targeting and expression of light
sensitive functional components as optogenetic tools in target cells have enabled researchers to
precisely regulate specific physiological processes in these cells in a light responsive manner.
Channelrhodopsins, rhodopsin , halorhodopsins, and melanopsin are some commonly used
opsin-based, single-component optogenetic tools in mammalian cells [70, 71]. In recent years,
optogenetics has achieved impressive progress in neuroscience, enabling electrical activity in the
neurons to be driven or silenced by pulses of light . Scientists have successfully fused light
sensitive switches to important enzymes of cellular transcription/translation machineries .
With the introduction of synthetic biology, complex genetic networks in mammalian cells can
now be optimized to respond to physical/chemical/biological signals in a predictable manner.
Synergistic partnership between optogenetics and synthetic biology has further enabled modern
researchers to engineer light sensitive synthetic signaling cascades to control those networks in
the target cells [74, 75]. These engineered synthetic regulatory cascades may have diverse
applications in medical science, ranging from diagnostics to therapeutics in the near future .
The use of melanopsin as an optogenetic tool, or molecular switch, is favored over other
photosensitive pigments (channelrhodopsin or
-AR) due to its high sensitivity to blue
light, long lasting activation of intracellular signaling cascades, and influence on intracellular
calcium dynamics . Melanopsin most commonly uses a multistep intracellular G(q/11)
-coupled signaling cascade , with significant signal amplification at each step of the cascade
. Constitutive expression of melanopsin in any mammalian cell allows blue light (450 nm)
triggered transcription control of the PNFAT
reporter through the following steps. Blue light-induced photoisomerization of the melanopsin-bound chromophore 11-cis-retinal results in a
conformational change in melanopsin. This is followed by sequential activation of the Gαq
-type G-protein, phospholipase C (PLC), phosphokinase C (PKC) and an influx of Ca+2
into the cytosol (potentially by release of Ca+2
from the endoplasmic reticulum) by activation of transient
receptor potential channels (TRPCs). The calcium influx activates the calcium sensor calmodulin
(CaM) linked to the transcription factor NFAT (nuclear factor activated T cells). CaM activates
the serine/threonine phosphatase calcineurin (CaN), which dephosphorylates the serine-rich
region in the N-terminus of the NFAT. This leads to the exposure of a nuclear import signal and
translocation of NFAT from the cytoplasm into the nucleus. Within the nucleus, NFAT binds to
its cognate promoter (PNFAT
), and induces expression of a transgene in the target cells [17, 18].
Successful Regulation of Blood Glucose Homeostasis by Melanopsin Mediated Blue Llight
Therapy in Mammals
In a novel study by Ye et al. , and described later by Auslander and Fussenegger ,
attempts were made to rewire melanopsin induced intracellular Ca+2
surge with Ca+2
dependent activation of CaN and mobilization NFAT in vitro
. Rodent and human embryonic
kidney cell lines were cotransfected with the constitutive melanopsin expressing vector pHY42
vector is composed of human melanopsin with a human
cytomegalovirus (CMV) promoter, a bovine growth hormone polyadenylation (polyA) signal,
and the gene that is resistant to the antibiotic neomycin], and PNFAT driven luciferase reporter construct (PNFAT-luc2P-pASV40; this vector contained an NFAT response element followed by luciferase, a poly A
signal, and an antibiotic resistant gene). Activation of luciferase reporter construct by a 24 hr
exposure to pulses of blue light exhibited the highest availability of intracellular melanopsin
compatible G proteins in human embryonic kidney cell lines (HEK-293 cells). The efficiency of
the intracellular NFAT signaling pathway was high, with no detrimental effects on cell survival
(as expected due to a long term exposure of cells to blue light). Transgene expression in the HEK-293
cells could be effectively blocked by administration of calcium channel blockers in a dose
dependent manner, providing further validation of the experiment .
In the next step, validation of this light triggered transcription control in a therapeutic setting was
attempted. Keeping in mind the well-established potency of glucagon-1 like peptide (GLP-1) for
treating type 2 diabetes , due to its glucose dependent insulinotropic actions [80, 81, 82],
PNFAT induced expression of GLP-1 in HEK-293 cells engineered for constitutive melanopsin
production was attempted. GLP-1 synthesized and secreted in the culture supernatant by a blue
light activated synthetic transcription device in the HEK 293 cells, was found to be sufficient to
induce insulin secretion in a beta cell line . To further test the potential of this optogenic
synthetic transcription device under in vivo
conditions, pHY42/pHY57-transgenic HEK 293
cells (capable of expressing GLP-1 peptide in response to blue light) were microencapsulated in
alginate-poly-(L)-lysine-alginate capsules, and were subcutaneously implanted into wild-type
mice as well as diabetic mice (mice induced with human type 2 diabetes). The mice were
exposed to blue light for 48 hours [17, 78]. Serum levels of GLP-1 and insulin were monitored.
A significant elevation of serum GLP-1 and insulin levels were noted in the wild-type mice
exposed to blue light, when compared to their non-illuminated control group (Figure 2). After
a meal, glucose homeostasis remarkably improved in the diabetic mice, due to higher serum GLP-1
and insulin levels. Based on the success of this study and the long proven potential of GLP-1
therapy to improve glucose homeostasis in diabetic patients [79, 83], it was claimed that the light
triggered expression of GLP-1 might evolve as a prospective treatment of glucose related
pathologies in the near future [17, 76]
Figure 2: Phototransduction Cascade Activated by Melanopsin in Response to Blue Light in
Therapeutic Cell Implants. Melanopsin-mediated release of GLP-1 and insulin in diabetic mice (mice induced with human type 2 diabetes) bearing engineered transgenic therapeutic cell implants in response to blue light. Gαq (Gαq-type G protein); PLC (phospholipase C); PKC (phosphokinase C); CaM (calmodulin); CaN (calcineurin); NFAT (nuclear factor activated T cells); PNFAT
(NFAT promoter), GLP-1 (glucagon-1 like peptide)
The Prospect of GLP-1 Therapy: A Future Alternative to Existing Insulin Therapy
The success of the above mentioned studies [17, 78] led these scientists to envision that light
induced GLP-1 therapy may transition from bench side to bedside in the days to come. If it does,
it might be a popular replacement to the existing insulin therapy as treatment for
diabetes that requires insulin. A diabetic patient could get a subcutaneous cell implant (containing blue-light
sensitive melanopsin and GLP-1 expressing transgenic cells), encapsulated in a semi-permeable
device as an outpatient in a doctor’s office .The semipermeable device would provide
protection against the host immune system . The implant would be attached to a light emitting diode (LED) lamp
(as a source of blue light) and protected from exposure to environmental light. When required
(after meals) the patient could switch on the LED lamp by pushing a button, exposing the
subcutaneous implant to blue light for a certain time period. The melanopsin mediated secretion
of GLP-1 from the implanted cells into the patient’s bloodstream would effectively regulate the
after-meal glucose homeostasis through induction of insulin secretion from the pancreatic beta
cells of the patient. After a certain period of time, when serum GLP-1 levels were sufficiently
high, the LED lamp could then be turned off.
Though evidently close to success, clinical licensing of such therapeutic cell implants would only
be possible after careful consideration of ethical, scientific and safety issues [78, 86]. The
common questions that would need to be addressed for this purpose might be: which cell lines
would be sufficiently safe for implantation into humans? How long could such an implant remain
functional? Could implanted transgenic cells cross talk with the normal host tissue? If yes, what
would be the consequences?
Success of Melanopsin as a Molecular Switch in the Regulation of Differential Cell Functions
The use of melanopsin as a molecular switch for the regulation of a wide array of functions in a
wide variety of cell types is currently under way with much success. Melanopsin mediated
regulation of Gq signaling in cardiomyocytes is being used for exploring cardiac function 
and cardiac cell differentiation (in vitro
). Expression of melanopsin in retinal ganglion cells enabled the successful restoration of vision in blind mice . Ectopic expression of
melanopsin in hypothalamic orexin neurons, led to a long term activation of these neurons
following blue light exposure .
Since its exciting discovery in 1998 in Xenopus laevis
, melanopsin has transcended its earliest functional designation as a circadian pacemaker exclusively controlling non-visual functions of the eye. Recent research indicates the involvement of melanopsin in diverse functions ranging from image-forming vision, photo-allodynia, sleep, migraine pain sensations , mood disorders, anxiety and depression . Future research will undoubtedly continue to provide further information on the diverse characteristics, functions and clinical relevance of this non-classical blue light-sensitive pigment. The successful use of melanopsin for the light-induced regulation of intracellular transcriptional/ translational functions in several in vivo
and in vitro
experiments is indicative that melanopsin might be successful as an independent optogenetic tool , or in combination with other photoactive proteins [90, 91], such as the channelrhodopsins [92, 93].
The successful marriage between optogenetics and synthetic biology may well provide programmable melanopsin-driven designer devices capable of influencing a wide variety of cellular transduction cascades through their sensitivity to blue light. These optogenetics-based gene/cell therapy approaches may ultimately involve identification of new molecular and circuit-level targets that will provide precise interventions for defined biochemical or cellular events . An example is the successful attenuation of glycemic excursions, and the blue light-induced regulation of blood-glucose homeostasis through the melanopsin-triggered expression of the GLP-1 in the human type II diabetic mouse model . Once the ethical and safety issues associated with such synthetic intracellular devices have been adequately addressed, we may then look forward to an "omics era", as described by Folcher and Fussenegger , where light-induced cell implants with integrated synthetic genetic circuits will routinely execute predictable therapeutic and metabolic functions.
I am thankful to Patrick Abramson for technical support for the preparation of the figures, and to Lawrence Brako for technical and editorial support, Morehouse School of Medicine, Atlanta GA.
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