Human tritanopia associated with a third amino acid substitution in the blue-sensitive visual pigment.
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Amino Acids↗
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Absence of short-wavelength sensitive cones in the retinae of seals (Carnivora) and African giant rats (Rodentia).
Most non-primate mammals have two types of cone: short-wavelength sensitive (S) and middle-to-long-wavelength sensitive (M/L) cones. In two species of African giant rats, Cricetomys gambianus and C. emini, and in two species of earless seals, Phoca hispida and P. vitulina, the retinal cone types and cone distributions were assessed with antibodies specific for the M/L-cone opsin and the S-cone opsin, respectively. All four species were found to completely lack S-cones, while M/L-cones were present in low densities. M/L-cone densities, rod densities and cone/rod ratios were determined across the retina. Cone proportions are about 0.3-0. 5% in C. gambianus, 0.5-0.8% in C. emini, and 1.5-1.8% in P. hispida. An absence of S-cones has previously been reported in a few nocturnal mammals. As earless seals are visually active during night and day, we conclude that an absence of S-cones is not exclusively associated with nocturnality. The functional and comparative aspects are discussed.
Anatomy, Comparative↗
[Rhodopsin structure: some light into the shadows of retinal degenerations].
Retinitis pigmentosa is a group of retinal degenerative diseases, within the broad family of hereditary retinopathies, for which there is no cure at present. Mutations in different genes coding for proteins related to the metabolism of photoreceptor cells, and to the visual phototransduction cascade, are the cause of this disease. Rhodopsin, the photoreceptor protein responsible for light absorption--and key in the first stages of vision--is one of the most studied molecules of the retina. Mutations in the opsin gene account for about 25% of all cases of autosomal dominant retinitis pigmentosa. Recent crystallization of this receptor in its inactive dark state has revealed new structural details yielding further insights into the intra and intermolecular mechanismsin which the protein is involved as a result of its activation.Furthermore, the in vitro study of recombinant rhodopsins carrying mutations previously found in retinitis pigmentosa patients (by means of spectroscopic and functional techniques) has shed new light on the structural requirements for its correct function, as well as the molecular defects underlying the mechanism of photoreceptor cell death. In this study, the main findings of the recent investigations carried out in this field are presented. The relevant information obtained at the molecular level is bound to facilitate our understandingof the molecular processes that will allow suitable therapiesfor different retinal degenerative diseases, particularly retinitis pigmentosa, to be proposed.
Humans↗
Targeted knockdown of an opsin gene inhibits the swimming behaviour photoresponse of ascidian larvae.
The sequencing of the ascidian Ciona intestinalis genome was completed at the end of 2002. Effective targeted gene knockdown in this model chordate would greatly enhance understanding of how the genes affect the function of the neurons that underlie behaviour. We show here that antisense morpholinos (MOs) are effective and specific translational inhibitors in C. intestinalis larvae. The larvae developed from eggs injected with a Ci-opsin1 MO lost their photoresponse, which affected their swimming behaviour. Immunohistochemical analysis showed that the expression of Ci-opsin1, the visual pigments in the photoreceptor of the ocellus, had been lost in the larvae with the Ci-opsin1 MO. The inhibition of the photic behaviour of the knockdown larvae is solely due to the suppression of the synthesis of the visual pigments in the photoreceptors. These are the first results showing the knockdown of an ascidian gene and the elucidation of that gene's role in ascidian larval behaviour.
Animals↗
Development of pigment-cup eyes in the polychaete Platynereis dumerilii and evolutionary conservation of larval eyes in Bilateria.
The role of Pax6 in eye development in insects and vertebrates supports the view that their eyes evolved from simple pigment-cup ocelli present in their last common ancestors (Urbilateria). The cerebral eyes in errant polychaetes represent prototype invertebrate pigment-cup ocelli and thus resemble the presumed ancestral eyes. We have analysed expression of conserved eye specification genes in the early development of larval and adult pigment-cup eyes in Platynereis dumerilii (Polychaeta, Annelida, Lophotrochozoa). Both larval and adult eyes form in close vicinity of the optic anlagen on both sides of the developing brain ganglia. While pax6 is expressed in the larval, but not in the developing, adult eyes, expression of six1/2 from trochophora stages onwards specifically outlines the optic anlagen and thus covers both the developing larval and adult eyes. Using Platynereis rhabdomeric opsin as differentiation marker, we show that the first pair of adult eye photoreceptor cells is detected within bilateral clusters that transitorily express ath, the Platynereis atonal orthologue, thus resembling proneural sensory clusters. Our data indicate that--similar to insects, but different from the vertebrates--polychaete six1/2 expression outlines the entire visual system from early developmental stages onwards and ath-positive clusters generate the first photoreceptor cells to appear. We propose that pax6-, six1/2- and ath-positive larval eyes, as found in today's trochophora, were present already in Urbilateria.
Amino Acid Sequence↗
Disruption of kinesin II function using a dominant negative-acting transgene in Xenopus laevis rods results in photoreceptor degeneration.
PURPOSE: Kinesin II is a motor protein that moves on microtubules and whose importance in ciliary and flagellar transport has been well documented. In the current study, the role of kinesin II in rod photoreceptors was examined by expressing a dominant negative-acting transgene that disrupts kinesin II function in Xenopus laevis rods of transgenic tadpoles. METHODS: A previously characterized dominant negative-acting kinesin II transgene tagged with enhanced green fluorescent protein (EGFP) driven by the Xenopus rod opsin promoter was used to make Xenopus transgenic tadpoles to disrupt kinesin II function specifically in rod photoreceptors. Transgenic tadpole retinas were examined to ascertain transgene expression pattern and morphologic phenotype. Rod-to-cone ratios were determined in experimental and control retinas. RESULTS: Visualized by its EGFP tag, the kinesin II transgene was expressed in rods in a mosaic pattern in the retina. Subcellular localization of transgenic kinesin II was similar to that of endogenous kinesin II subunit photoreceptor expression-that is, it was localized to the connecting cilium, inner segment, and synapse. However, in kinesin II transgene-expressing animals, fluorescence was transient. Ocular fluorescence was lost 6 days after its first detection. The disappearance of fluorescence was due to degeneration of rods expressing the transgene. Retinas of 7- to 9-day old kinesin II transgenic tadpoles had significantly fewer rods than did control retinas. CONCLUSIONS: The observation that rod degeneration is produced by expression of a dominant negative-acting kinesin II transgene in Xenopus rods is consistent with previous studies in mice, suggesting that kinesin II function is required for photoreceptor survival.
Animals↗
Photons, femtoseconds and dipolar interactions: a molecular picture of the primary events in vision.
The first 200 femtoseconds in the life of a photoexcited rhodopsin molecule are extremely important for the development of visual sensation. Immediately upon excitation, a dramatic change in the charge distribution of the cationic 11-cis-retinal protonated Schiff base chromophore occurs that is quantitated by the change in electronic dipole moment of approximately 15 Debye. The opsin protein tunes the absorption maximum of the pigment to the blue or to the red enabling colour vision by placing dipolar rather than charged residues in the chromophore binding site to differentially stabilize either the ground or the excited state charge distribution. Resonance Raman intensity analysis reveals that the 11-cis-retinal chromophore then distorts violently about the C11 = C12 double bond, reaching torsional angles of approximately 70 degrees in only 30 fs. This rapid torsional distortion is driven by the non-bonded interaction between the 13-methyl group and the 10-hydrogen that is unique to the 11-cis configuration of the chromophore. The excited state depopulates in approximately 50 fs through a rapid and vibrationally coherent transition to the ground electronic state manifold with relaxation to the formally trans photoproduct complete in only 200 fs. This unusually fast and efficient isomerization process establishes a new paradigm for condensed phase photochemical reactions.
Animals↗
Sequence divergence, polymorphism and evolution of the middle-wave and long-wave visual pigment genes of great apes and Old World monkeys.
In man, the spectral shift between the middle-wave (MW) and long-wave (LW) visual pigments is largely achieved by amino acid substitution at two codons, both located in exon 5. A third amino acid site coded by exon 3 is polymorphic between pigments. We have studied the equivalent regions of the cone opsin genes in two members of the Hominidea (the gorilla, Gorilla gorilla and the chimpanzee, Pan troglodytes) and in three members of the Cercopithecoidea family of Old World primates (the diana monkey, Cercopithecus diana, the talapoin monkey, Miopithecus talapoin, and the crab-eating macaque, Macaca fascicularis). No variation in the codons that specify the amino acids involved in spectral tuning were found. We predict therefore that the MW and LW pigments of gorilla and chimpanzee have similar spectral characteristics to those of man. Multiple copies of the same opsin gene sequence were identified in the chimpanzee, talapoin and macaque and we also show that non-human Old World primates are similar to man in showing a bunching of polymorphic sites in exon 3. We discuss the ancestry of the separate MW and LW genes of Old World primates and the equivalent polymorphic gene of the marmoset, a New World primate.
Amino Acid Sequence↗
Photoreceptive net in the mammalian retina. This mesh of cells may explain how some blind mice can still tell day from night.
We have discovered an expansive photoreceptive 'net' in the mouse inner retina, visualized by using an antiserum against melanopsin, a likely photopigment. This immunoreactivity is evident in a subset of retinal ganglion cells that morphologically resemble those that project to the suprachiasmatic nucleus (SCN), the site of the primary circadian pacemaker. Our results indicate that this bilayered photoreceptive net is anatomically distinct from the rod and cone photoreceptors of the outer retina, and suggest that it may mediate non-visual photoreceptive tasks such as the regulation of circadian rhythms.
Animals↗
Adaptations to an extreme environment: retinal organisation and spectral properties of photoreceptors in Antarctic notothenioid fish.
The Notothenioid suborder of teleosts comprises a number of species that live below the sea ice of the Antarctic. The presence of 'antifreeze' glycoproteins in these fish as an adaptation to freezing temperature has been well documented but little is known about the adaptations of the visual system of these fish to a light environment in which both the quantity and spectral composition of downwelling sunlight has been reduced by passage through ice and snow. In this study, we show that the red/long-wave sensitive (LWS) opsin gene is not present in these fish but a UV-sensitive short-wave sensitive (SWS1) pigment is expressed along with blue-sensitive (SWS2) and green/middle-wave sensitive (Rh2) pigments. The identity and spectral location of maximal absorbance of the SWS1 and Rh2 pigments was confirmed by in vitro expression of the recombinant opsins followed by regeneration with 11-cis retinal. Only the SWS2 pigment showed interspecific variations in peak absorbance. Expression of the Rh2 opsin is localised to double cone receptors in both the central and peripheral retina, whereas SWS2 opsin expression is present only in the peripheral retina. SWS1 cones could not be identified by either microspectrophotometry or in situ hybridisation, presumably reflecting their low number and/or uneven distribution across the retina. A study of photoreceptor organisation in the retina of two species, the shallower dwelling Trematomus hansoni and the deeper dwelling Dissostichus mawsoni, identified a square mosaic in the former, and a row mosaic in the latter species; the row mosaic in Dissostichus mawsoni with less tightly packed cone photoreceptors allows for a higher rod photoreceptor density.
Adaptation, Biological↗
An opsin homologue in the retina and pigment epithelium.
PURPOSE: The aim of this project was to investigate the retinal pigment epithelium (RPE) at the molecular level by identification of novel RPE-specific cDNAs that may encode proteins of signal transduction pathways or other proteins that are expressed preferentially in the RPE. METHODS: A bovine RPE cDNA library was constructed in bacteriophage lambda g10 using RPE-enriched poly(A)+ RNA. The library was screened by differential hybridization to bovine RPE and kidney cDNA probes. RESULTS: A member of the hepatahelical receptor family was identified in bovine RPE by molecular cloning. Its deduced amino acid sequence predicts a protein that has 291 amino acid residues and resembles most closely the family of visual pigments. A lysine residue, analogous to the retinaldehyde attachment site in rhodopsin, is conserved in the seventh hydrophobic segment of the novel sequence. Messenger RNA encoding the putative G protein-coupled receptor was detected by in situ hybridization in the RPE, inner nuclear layer, and specific cells of the ganglion cell layer. Immunohistochemical staining of bovine retina showed that the receptor protein is localized in Müller cells, as well as in the RPE. CONCLUSIONS: A novel heptahelical receptor defines a distant evolutionary branch of the visual pigment tree. The selective localization of this putative receptor, its abundance in RPE and retina, and its homology to the visual pigments suggest that the function of this receptor is important in a visual process involving the RPE and Müller cells.
Amino Acid Sequence↗
The retina of Spalax ehrenbergi: novel histologic features supportive of a modified photosensory role.
PURPOSE: The retina of the blind mole rat Spalax ehrenbergi was compared with other vertebrate photosensitive organs in an attempt to correlate its histologic organization with a presumptive nonvisual photoreceptor role. METHODS: The eyes of eight adult animals were analyzed by light and electron microscopy, using conventional staining and immunolabeling with antibodies against phototransduction proteins and calretinin. RESULTS: Rods accounted for most of the photoreceptor cells in the Spalax retina, although their morphology is dissimilar to that of sighted mammals, in that they contained only rudimentary outer segments. The latter showed strong rod-opsin and transducin immunoreactions. The phagosomes in the retinal pigmentary epithelium were also rod-opsin positive. Synapses were evident at the photoreceptor cells pedicles. Occasionally, several synaptic active sites were present, suggesting cone cell origin; however, cone-opsin was not immunodetected in the study samples. Synaptic ribbon fields, sometimes distant to the active sites, resembled those found in the vertebrate pineal. The other retinal layers were somewhat less organized than in sighted mammals. Some cells were displaced and the calretinin-positive inner plexiform layer had no sublayers. Calretinin immunolabeling was found in horizontal, amacrine, and ganglion cells. Folding of the retina produced rosette-like images similar to those reported before in the retina of nocturnal mammals and in the avian pineal gland. CONCLUSIONS: These data suggest that the retina of the mole rat has undergone evolutionary restructuring to a photoreceptive pineal-like organization. This supports the thesis that the photoreceptor cells of this unique organ have been reprogrammed during the subterranean adaptation of Spalax, from their original visual function to mediating photoperiodic regulation.
Animals↗
Constitutively active mutants of rhodopsin.
Two critical amino acids in the visual pigment rhodopsin are Lys-296, the site of attachment of retinal to the protein through a protonated Schiff base linkage, and Glu-113, the Schiff base counterion. Mutation of Lys-296 or Glu-113 results in constitutive activation of opsin, as assayed by its ability to activate transducin in the absence of added chromophore. We conclude that opsin is constrained to an inactive conformation by a salt bridge between Lys-296 and Glu-113. Recently, one of the mutants, K296E, was found in a family with retinitis pigmentosa, suggesting that degeneration of the photoreceptor cells in individuals with this mutation may result from persistent stimulation of the phototransduction pathway.
Amino Acid Sequence↗
Studies on retinotoxic potential of a novel antitumor antibiotic--sparsomycin--in rats.
Sparsomycin (Sm) is a potent inhibitor of protein synthesis with an anticancer potential. Two years after its discovery in 1962 a phase I clinical trial revealed serious drug-induced retinotoxicity. The mechanism of this toxicity still remains unresolved; however, its understanding is important for the reintroduction of Sm or one of its analogues in clinical practice. If Sm penetrates the retina, its toxic effect should be seen as inhibition of a protein(s) vital for the visual function. Treatment of healthy albino rats and Royal College of Surgeon (RCS) rats with subtoxic doses of Sm was unable to produce ocular toxic effects. Disruption of the blood-retina barrier with sodium iodate allowed Sm to decrease opsin content by only 27%. These results strongly indicate that Sm might become retinotoxic solely upon extreme conditions such as permeabilization of the blood-retina barrier which may happen only in some rare pathological situations.
Animals↗
Calorimetric study of thermal denaturation of vertebrate visual pigments.
The thermostability of visual pigments in bovine, rat and frog rod outer segments (ROS) has been studied by means of differential scanning calorimetry and thermal gel analysis methods. Use of the two different methods has allowed to assign calorimetric peaks to rhodopsin and opsin denaturation. The denaturation enthalpy changes for rhodopsin in bovine, rat and frog ROS are 630 kJ/mole (Td = 347 degrees C), 416 kJ/mole (Td = 340 degrees K) and 410 kJ/mole (Td = 340 degrees K), respectively. Corresponding values for opsins are 490 kJ/mole (Td = 332 degrees K), 269 kJ/mole (Td = 320 degrees K) and 158 kJ/mole (Td = 319 degrees K). The free energy of stabilization of the rhodopsin native structure is not very large and practically similar to that for native water soluble globular proteins.
Animals↗
Visual adaptations in a diurnal rodent, Octodon degus.
The degu (Octodon degus) is a diurnal rodent, native to Chile. Basic features of vision and visual organization in this species were examined in a series of anatomical, electrophysiological and behavioral experiments. The lens of the degu eye selectively absorbs short-wavelength light and shows a progressive increase in optical density as a function of age. Electroretinograms recorded using a flicker-photometric procedure reveal three spectral mechanisms: a rod with peak sensitivity of about 500 nm and two types of cone having respective spectral peaks of about 362 nm and 507 nm. Opsin antibody labeling was used to determine the retinal distributions of the three receptor types. A total of about one-third of the approximately 9 million photoreceptors of the degu retina are cones with the two types (507 nm/362 nm) represented in a ratio of about 13:1. The contributions to vision of all three receptor types were examined in a series of behavioral experiments. A consistent feature of both the electrophysiological and behavioral results is that relatively high levels of light adaptation are required to effect the full transition from rod-based to cone-based vision. In behavioral tests degus were shown to be able to make color discriminations between ultraviolet and visible lights.
Adaptation, Ocular↗
Primary structure of frog rhodopsin.
Amphibians have been employed extensively to study the anatomy, physiology, biochemistry, and cell biology of the visual system for decades, yet there have been no reports concerning the primary structure of amphibian visual transduction components. Thus, we have determined the entire nucleotide sequence of frog (Rana pipiens) rhodopsin cDNA, including a putative transcription start point and poly A tail, by sequence analysis of PCR products and mRNA. The open reading frame predicts an opsin of 354 residues, six residues longer than the mammalian rod opsins, containing 11 potential phosphorylation sites in the C-terminal domain. RNA blot analysis revealed two transcripts of ca. 1.7 and 3.1 kb. Frog rhodopsin exhibits approximately 85% identity to mammalian rhodopsin at the amino acid level. Sequence analysis of additional components will produce the framework from which a more detailed understanding of amphibian phototransduction can emerge.
Amino Acid Sequence↗
Genetic basis of photopigment variations in human dichromats.
The spectral sensitivities of the X-encoded pigments in dichromats were studied using the electroretinogram. The action spectra measured for these subjects correspond to four distinctly different X-encoded visual pigments, two different middle-wave pigments spectrally separated by 7 nm and two different long-wave pigments separated by 5 nm. Amino acid sequences were deduced from examination of the genes encoding the pigments. Pairwise comparisons of the opsin structures and pigment spectra confirm and clarify earlier conclusions. Substitutions in exon 5 of the genes produce the spectral difference that separates human X-encoded pigments into middle- and long-wave classes. Polymorphisms in exons 2-4 produce subtypes of pigments that fall within those major classes. Substitution of half of a middle-wave gene with long-wave sequence (exons 1-3) does not shift the middle-wave spectrum. Combined substitutions at positions 230, 233 and 180 produce a 7 nm shift in the in the middle-wave pigment spectrum. Two subtypes of long-wave pigments that differ in the presence of serine or alanine at position 180 and occur in dichromats, deuteranomalous trichromats, and color normals are spectrally separated by 5-7 nm.
Adolescent↗