Disease relevance of Opn4

• Instead, the melanopsin-containing ganglion cells are intrinsically sensitive to light, perhaps responding via a melanopsin-based signaling pathway [1].
• Analysis of the Vibrio pathogenicity island-encoded Mop protein suggests a pleiotropic role in the virulence of epidemic Vibrio cholerae [2].

Psychiatry related information on Opn4

• We observed that mice with both outer-retinal degeneration and a deficiency in melanopsin exhibited complete loss of photoentrainment of the circadian oscillator, pupillary light responses, photic suppression of arylalkylamine-N-acetyltransferase transcript, and acute suppression of locomotor activity by light [3].

High impact information on Opn4

• Recent analyses of retinal degenerate mice lacking melanopsin or cryptochromes indicates that outer and inner photoreceptors can both contribute to non-visual photoresponses, and that both melanopsin and cryptochromes play important roles in this process [4].
• Nonvisual light responses in the Rpe65 knockout mouse: rod loss restores sensitivity to the melanopsin system [5].
• Inner retinal photoresponses are mediated by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting that the melanopsin-dependent photocycle utilizes RPE65 and Lrat [6].
• Intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin (OPN4), together with rods and cones, provide light information driving nonvisual light responses [5].
• These results demonstrate that the melanopsin-dependent ipRGC photocycle is independent of the visual retinoid cycle [6].

Biological context of Opn4

• We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms [7].
• The human melanopsin gene consists of 10 exons and is mapped to chromosome 10q22 [8].
• This spectrum matches that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells [7].
• The unique inner retinal localization of melanopsin suggests that it is not involved in image formation but rather may mediate nonvisual photoreceptive tasks, such as the regulation of circadian rhythms and the acute suppression of pineal melatonin [8].
• However, its amino-acid sequence differs from vertebrate photosensory opsins and some have suggested that melanopsin may be a photoisomerase, providing retinoid chromophore to an unidentified opsin [9].

Anatomical context of Opn4

• In this study we provide the first clear evidence that Opn4 expression is not confined to these photosensitive RGCs, but is also expressed in the retinal pigment epithelium (RPE), a tissue with no known photosensensory role [10].
• The discovery of melanopsin-dependent inner retinal photoreceptors in mammals has precipitated a fundamental reassessment of such non-image forming (NIF) light responses as circadian photoentrainment and the pupil light reflex [11].
• Our results demonstrate for the first time a melanopsin-dependent regulation of visual processing within the retina, revealing an important function for inner retinal photoreceptors in optimizing classical visual pathways according to time of day [11].
• To test this hypothesis, we have characterized melanopsin following heterologous expression in COS cells [1].
• Opn4 mRNA is also regulated on a circadian basis in the pineal gland, reaching peak values of accumulation in the late subjective night [12].

Associations of Opn4 with chemical compounds

• We found that melanopsin absorbed maximally at 424 nm after reconstitution with 11-cis-retinal [1].
• Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin [13].
• In contrast, 9-cis-retinal was unable to restore intrinsic photosensitivity to melanopsin-ablated ipRGCs, arguing against melanopsin functioning merely in photopigment regeneration [13].
• The putative counterion is not a glutamate but a tyrosine, the putative G-protein binding domain in the third cytoplasmic loop is not conserved, and they show low levels of amino acid identity (approximately 27%) to both the known photopigment opsins and to other members of the melanopsin family [14].
• Yet there is a residual phase-shifting response in melanopsin knockout mice, which suggests an alternate or redundant means for light input to the SCN of the hypothalamus [15].

Regulatory relationships of Opn4

• In summary, our experiments constitute the first direct demonstration that melanopsin forms a photopigment capable of activating a G-protein, but its spectral properties are not consistent with the action spectrum for circadian entrainment [1].
• In these mice, the proportion of melanopsin RGCs that express Fos in response to light is significantly reduced [16].
• In a reconstituted biochemical system, the reconstituted melanopsin was capable of activating transducin, the G-protein of rod photoreceptors, in a light-dependent manner [17].

Other interactions of Opn4

• Genetic knockout studies revealed that functional melanopsin and rod-cone photoreceptive systems are required for the light-inducibility of PK2 [18].
• Furthermore, melanopsin activated the photoreceptor G-protein, transducin, in a light-dependent manner [1].
• We can preclude retinal contamination of RPE extracts as levels of Opn4 expression were higher in the RPE than in the retina, and the expression of rod opsin and Thy1 (a marker of the RGC layer) were barely detectable in RPE extracts [10].
• Collectively, our data suggest that melanopsin RGCs form a heterogeneous population of neurons, and that most of the light-induced c-fos expression within these cells is associated with the endogenous photosensitivity of these neurons [16].
• (2) Could the reported age-related decline in circadian photosensitivity of rodents be linked to changes in the population of melanopsin RGCs [16]?

Analytical, diagnostic and therapeutic context of Opn4

• Despite this loss, quantitative reverse transcriptase-polymerase chain reaction showed normal levels of melanopsin expression, and immunocytochemistry demonstrated both the presence and normal cellular appearance of these cells [19].
• Here we use the aged (approximately 2 years) rodless and coneless (rd/rd cl) mouse to assess the impact of progressive inner retinal cell loss on melanopsin expression, circadian entrainment and pupillary constriction [19].
• In situ hybridization histochemistry shows that melanopsin expression is restricted to cells within the ganglion and amacrine cell layers of the primate and murine retinas [8].
• Given that the majority of RGCs die after axotomy and that grafting of a peripheral nerve to the eye provides a permissive environment for axon regrowth, the present study examined the survival and axonal regrowth of melanopsin-containing RGCs in mice [20].
• The extent of liver cell necrosis in histological sections was recorded on a 100 mm Visual Analogue Scale (VAS) and measured using the electronic Mini Mop method [21].

References