Recently, melanopsin has emerged as the leading candidate for the elusive photopigment of the mammalian circadian system. This novel opsin-like protein is expressed in retinal ganglion cells that form the retinohypothalamic tract, a neuronal connection between the retina and the suprachiasmatic nucleus. These hypothalamic structures contain the circadian pacemaker, which generates daily rhythms in physiology and behavior. In mammals, proper synchronization of these rhythms to the environmental light-dark cycle requires retinal input. Surprisingly, rod and cone photoreceptors are not required. Instead, the melanopsin-containing ganglion cells are intrinsically sensitive to light, perhaps responding via a melanopsin-based signaling pathway. To test this hypothesis, we have characterized melanopsin following heterologous expression in COS cells. We found that melanopsin absorbed maximally at 424 nm after reconstitution with 11-cis-retinal. Furthermore, melanopsin activated the photoreceptor G-protein, transducin, in a light-dependent manner. In agreement with the measured absorbance spectrum, melanopsin was most efficiently excited by blue light (420-440 nm). In contrast, published action spectra suggest that the photopigment underlying the intrinsic light sensitivity of SCN-projecting RGCs has an absorption maximum near 484 nm. 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.
had good-quality or fair-quality evidence relating to uterine rupture. Four studies reported uterine rupture outcomes for both TOL and ERCD and included 47,202 patients, in whom 154 uterine ruptures occurred; 148 ruptures (96%) were in the TOL group. The risk of uterine rupture for all women with a prior cesarean delivery was 0.30% (CI, 0.23%-0.41%) with risks in the TOL and ERCD groups reported as 0.47% (CI, 0.28%-0.77%) and 0.026% (CI, 0.009%-0.082%), respectively. Eight cohort studies (402,059 patients) with a moderate grade of evidence compared risks for hysterectomy between TOL and ERCD groups. The risk of hysterectomy was <0.3% in women with a prior cesarean delivery; the risks between TOL and ERCD were not significantly different (0.17% and 0.28%, respectively; RR 0.65; CI, 0.40-1.06). Nine cohort studies (401,307 patients) had moderate-grade evidence on the rate of transfusion between TOL and ERCD. The overall rates of transfusion did not differ significantly, with rates of 0.9% for TOL and 1.2% for ERCD (RR, 0.81; CI, 0.57-1.15). One study found that the route of delivery influenced the need for transfusion and may be mediated by maternal comorbid conditions. Evidence for hemorrhage was low-grade because of inconsistent and imprecise methods of defining and reporting the occurrence of this complication. From 6 studies involving 47,754 women, the risk rates for hemorrhage with ERCD ranged from 0.3% to 29% and no comparison could be done because of the poor quality of the data. Twenty-two studies with 354,060 patients reported infectious complications, with no significant differences in risk between TOL and ERCD 4.6% (CI, 1.5%-13.5%) and 3.2% (CI, 1.3%-7.3%), respectively. The 4 studies reporting surgical injury and including 53,282 patients had insufficient data to evaluate, with a low grade of evidence. As reported in 8 cohort studies, hospital length of stay was 3.9 d in patients undergoing ERCD and 2.6 d after TOL.Short-term neonatal outcomes included perinatal mortality, respiratory conditions, hypoxic-ischemic encephalopathy, sepsis, trauma, Apgar scores, and neonatal intensive care unit admission. With a moderate grade of evidence, 5 studies reported on perinatal deaths among 75,899 infants. These studies reported only on populations that delivered at term and recorded perinatal mortality through the first 7 d of life. The rate was significantly increased by TOL (0.13%; CI, 0.06%-0.30%) compared with ERCD (0.05%; CI, 0.007%-0.38%). Six studies reported neonatal death (within first 28 d) and included 108,328 infants. The rate of death for TOL was 0.11% (CI, 0.06%-0.20%) compared with 0.06% (CI, 0.02-0.15%) for ERCD, a significant difference. A subanalysis of the data showed that the rates of neonatal mortality were higher in women with high-risk conditions and those with indications for a repeat CD. Respiratory conditions were reported in 6 studies involving 5599 infants. The grade of evidence was low for the 3 studies that compared bag/mask ventilation and 3 other studies that examined transient tac...
In mammals, melanopsin is exclusively expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs), which play an important role in circadian photoentrainment and other nonimageforming functions. These ipRGCs reside in the inner retina, far removed from the pigment epithelium, which synthesizes the 11-cis retinal chromophore used by rod and cone photoreceptors to regenerate opsin for light detection. There has been considerable interest in the identification of the melanopsin chromophore and in understanding the process of photopigment regeneration in photoreceptors that are not in proximity to the classical visual cycle. We have devised an immuno-magnetic purification protocol that allows melanopsin-expressing retinal ganglion cells to be isolated and collected from multiple mouse retinas. Using this technique, we have demonstrated that native melanopsin in vivo exclusively binds 11-cis retinal in the dark and that illumination causes isomerization to the all-trans isoform. Furthermore, spectral analysis of the melanopsin photoproduct shows the formation of a protonated metarhodopsin with a maximum absorbance between 520 and 540 nm. These results indicate that even if melanopsin functions as a bistable photopigment with photo-regenerative activity native melanopsin must also use some other lightindependent retinoid regeneration mechanism to return to the dark state, where all of the retinal is observed to be in the 11-cis form.11-cis retinal ͉ photoisomerization ͉ retinal ganglion cells R od and cone photoreceptors and melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) constitute the three classes of light-detecting cells in the mouse retina (1). Rods and cones are specialized ciliary cells that provide input for image-forming vision. Melanopsin-expressing ipRGCs, which comprise Ϸ1-2% of all RGCs in the mouse retina (2), provide input to regulate circadian activity and other nonimage-forming responses of the retina (1, 3-7). Melanopsin is a G protein-coupled receptor and belongs to the opsin class of this superfamily of proteins (8, 9). Melanopsin is unique among vertebrate opsins, however, because it shares greater sequence similarity with invertebrate rhabdomeric opsins than with any other vertebrate opsins (9). The amino acid sequence of the melanopsin suggests that the photopigment may have photoactivation and pigment regeneration properties similar to those of many invertebrate rhabdomeric photopigments (IRPs).In the mammalian retina, rod and cone photoreceptors are juxtaposed to the retinal pigment epithelium (RPE), which contains the enzymatic machinery necessary to reconvert all-trans retinal released by rod and cone photopigments back to 11-cis retinal for photopigment regeneration. This chromophore regeneration cycle is essential for maintaining photosensitivity in rod and cone photoreceptors. In contrast, ipRGCs are found in the ganglion cell layer of the retina, which is the most distal retinal layer to the RPE. Therefore, it seems likely that melanopsin ...
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