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At least 379 records · Page 21Linked to original sources
PubMed1994

Photoreceptor light-adaptation mediated by S-modulin, a member of a possible regulatory protein family of protein phosphorylation in signal transduction.

In vertebrate retinal photoreceptors, cytoplasmic [Ca2+] decreases upon exposure to light. A Ca(2+)-binding protein, S-modulin, detects this [Ca2+] decrease and reduces the light-sensitivity of the cell to induce light-adaptation. The reduction of the sensitivity is attained by disinhibition or facilitation of rhodopsin phosphorylation, a quenching mechanism of light-activated rhodopsin. S-modulin-like proteins are found in the brain as well. Several of these proteins show similar S-modulin effects, suggesting that these proteins also participate in the regulation of protein phosphorylation in the signal transduction in their host cells.

Adaptation, Physiological↗
PubMed1994

Molecular cloning and characterization of retinal photoreceptor guanylyl cyclase-activating protein.

Guanylyl cyclase-activating protein (GCAP) is thought to mediate Ca(2+)-sensitive regulation of guanylyl cyclase (GC), a key event in recovery of the dark state of rod photoreceptors following light exposure. Here, we characterize GCAP from several vertebrate species by molecular cloning and provide evidence that GCAP contains a heterogeneously acylated N-terminal region that interacts with GC. Vertebrate GCAPs consist of 201-205 amino acids, and sequence analysis indicates the presence fo three EF hand Ca(2+)-binding motifs. These results establish that GCAP is a novel photoreceptor-specific member of a large family of Ca(2+)-binding proteins and suggest that it participates in the Ca(2+)-binding proteins and suggest that it participates in the Ca(2+)-sensitive activation of GC.

Amino Acid Oxidoreductases↗
PubMed2005

Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies.

PURPOSE: Paraneoplastic and autoimmune retinopathies are immunologically mediated retinal degenerations that are associated with antibodies directed against any of several retinal proteins, including alpha-enolase. We report the clinical and electrophysiological features of antienolase retinopathy in contrast to the features of antirecoverin retinopathy. DESIGN: Retrospective, observational case series. METHODS: Patients were referred for evaluation of unexplained acquired visual symptoms, including photopsias, and loss of visual acuity or field considered of possible retinal origin. Full-field and multifocal electroretinograms (ERGs) were performed. Sera from patients were examined for antiretinal antibodies by Western blot analysis using proteins extracted from human retinas and by immunohistochemistry; antienolase was confirmed by incubating patient sera with purified alpha-enolase. RESULTS: Of 87 patients with unexplained retinal visual symptoms associated with abnormal ERGs, 37 (43%) demonstrated autoantibodies to retinal antigens, including 12 against alpha-enolase, of whom 4 had cancer. Initial visual loss was typically central and often asymmetric. The ERGs demonstrated mostly normal rod responses but central cone abnormalities (evident on multifocal ERG) and, for many, global cone abnormalities. Seven patients developed optic disk pallor. Corticosteroid and immunosuppressive therapy, when attempted, was clinically ineffective. CONCLUSIONS: Antienolase retinopathy is a protean autoimmune retinopathy that characteristically presents with cone dysfunction. The visual impairment and course vary from relative stability for years to slow progression with loss of central vision. With time, optic disk pallor can evolve, presumably from attrition of ganglion cells.

Adult↗
PubMed2006

Ca2+/recoverin dependent regulation of phosphorylation of the rhodopsin mutant R135L associated with retinitis pigmentosa.

No single molecular mechanism accounts for the effect of mutations in rhodopsin associated with retinitis pigmentosa. Here we report on the specific effect of a Ca2+/recoverin upon phosphorylation of the autosomal dominant retinitis pigmentosa R135L rhodopsin mutant. This mutant shows specific features like impaired G-protein signaling but enhanced phosphorylation in the shut-off process. We now report that R135L hyperphosphorylation by rhodopsin kinase is less efficiently inhibited by Ca2+/recoverin than wild-type rhodopsin. This suggests an involvement of Ca2+/recoverin into the molecular pathogenic effect of the mutation in retinitis pigmentosa which is the cause of rod photoreceptor cell degeneration. This new proposed role of Ca2+/recoverin may be one of the specific features of the proposed new Type III class or rhodopsin mutations associated with retinitis pigmentosa.

Animals↗
PubMed2004

The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics.

We identified the UDP-glucuronosyltransferase (UGT) 1A1 5'-upstream region that confers UGT1A1 induction by various agents, including flavonoids, on a luciferase reporter gene and has the properties of a transcriptional enhancer. Chrysin- and rifampicin-response activities were traced to the same element as a 290-bp distal enhancer module (-3483/-3194), in which the reporter activities were enhanced by activators of nuclear receptors [constitutive androstane receptor (CAR) and pregnane X receptor (PXR)] and transcription factor [aryl hydrocarbon receptor (AhR)]. Utilizing transactivation experiments with the UGT1A1 290-bp reporter gene, we assessed UGT1A1 induction by various flavonoids. 5,7-Dihydroxyflavones with varying substituents in the B-ring and gallocatechin dimers increased the reporter activity in a time- and dose-dependent manner. The treatment of HepG2 cells with the flavonoids for 24 hr elevated the expression of mRNAs and proteins of UGT1A1 and CYP1A1, while the mRNA levels of CYP2B6, CYP3A4, CAR, PXR and AhR was not altered. Chrysin and rifampicin induced the activation of the wild-type reporter gene and T-3263G-mutated gene to a similar extent in HepG2 cells cotransfected with expression vectors of CAR and PXR. Mutation of the AhR core binding region most prominently suppressed the activation of the 290-bp reporter gene by chrysin and baicalein, while mutations of four putative nuclear receptor motifs (DR4 element, PXRE, CARE and DR3 element) partly decreased its activation. Taken together, the results indicate that UGT1A1 was induced in response to flavonoids and xenobiotics through the transactivation of the 290-bp reporter gene, that was a multi-component enhancer containing CAR, PXR and AhR motifs.

Analysis of Variance↗
PubMed2005

CAR and PXR expression and inducibility of CYP2B and CYP3A activities in rat and rabbit lungs.

Several CYP enzymes are expressed in the lung of mammals but studies on their regulation have been rather neglected. In this study, the CAR and PXR expression and the inducibility of CYP 2B and CYP 3A isoforms in the lung rats and rabbits were investigated. Rats were treated with phenobarbital, clotrimazole or a mixture of dexametasone plus pregnenolone 16alpha-carbonitrile, whereas rabbits were treated with phenobarbital or rifampicin. A low constitutive expression of CAR mRNA was demonstrated by RT-PCR analysis in the lung of rat but not in rabbit. Phenobarbital treatment did not change the CAR expression profiles and did not induce in either rats and rabbits the pulmonary CYP 2B isoforms, as judged by western blot analysis and the marker pentoxyresorufin O-dealkylase and 7-ethoxy-4-trifluoroethylcoumarin O-deethylase activities. On the contrary, these marker activities were strongly induced by phenobarbital in the liver of both species. A low constitutive level of PXR mRNA was also detected by RT-PCR in the lung of rabbit but not in rat. However, also in this case, their expressions were not altered by the administration of strong CYP 3A inducers such as clotrimazole or a mixture of dexametasone plus pregnenolone 16alpha-carbonitrile for the rat and rifampicin or phenobarbital for the rabbit. For the first time, it was demonstrated by RT-PCR that rat lung expresses CYP 3A2, 3A9, 3A18 and 3A23 whereas the rabbit lung expresses the CYP 3A6, the only CYP 3A isoform identified in the rabbit so far. However, notwithstanding the differences observed in the constitutive presence of PXR and CYP 3A transcripts in both species, the above mentioned treatments did not affect in their lungs, unlike their livers, neither the anti-rat 3A immunoreactive proteins nor the CYP 3A marker 7-benzyloxyquinoline O-debenzylase and the 6beta-testosterone hydroxylase activities. The results obtained indicate that the role of CAR and PXR in the lung of rat and rabbit is different from that observed in the liver or other extrahepatic tissues where the induction of the CYP 2B and CYP 3A isoforms is regulated by these receptors.

Air Pollutants↗
PubMed2005

Cytolytic replication of coxsackievirus B2 in CAR-deficient rhabdomyosarcoma cells.

The six coxsackievirus B serotypes (CVB1-6) use the coxsackie- and adenovirus receptor (CAR) for host cell entry. Four of these serotypes, CVB1, 3, 5 and 6, have also shown the capacity to replicate and cause cytolysis in rhabdomyosarcoma (RD) cells, a CAR-deficient cell line. This extended tropism has been associated with an acquired ability to bind decay accelerating factor (DAF). In this study, we have adapted the CVB2 prototype strain Ohio-1 (CVB2/O) to replicate in RD cells. Two types of infection were identified: (I) an enterovirus-typical, lytic infection, and (II) a non-lytic infection. Both CVB2/O-RD variants retained the prototype-ability to cause cytopathic effect in HeLa cells using CAR as receptor. Phenotypic and genotypic changes in the CVB2/O-RD-variants were determined and compared to the prototype cultured in HeLa cells. Inhibition studies using antibodies against CAR and DAF revealed a maintained ability of the CVB2/O-RD-variants to bind CAR, but no binding to DAF was observed. In addition, neither the prototype nor the CVB2/O-RD-variants were able to cause hemagglutination in human red blood cells, an enterovirus feature associated with affinity for DAF. Sequence analysis of the CVB2/O-RD-variants showed acquired mutations in the capsid region, suggesting extended receptor usage towards an alternative, yet unidentified, receptor for CVB2.

Adaptation, Physiological↗
PubMed2002

Cancer-associated retinopathy associated with invasive thymoma.

PURPOSE: To report a case of cancer-associated retinopathy associated with invasive thymoma. DESIGN: Interventional case report. METHOD: A 41-year-old Japanese woman was observed between February 1998 and May 2001. Ophthalmologic examinations and systemic examinations were performed. The patient received treatment including corticosteroid pulse therapy, plasmapheresis, and thymectomy. RESULTS: The patient developed progressive visual dysfunction including bilateral visual acuity loss, concentric contraction of visual fields, and color vision loss. In both eyes, retinal vessel attenuation and retinal pigment epithelium degeneration were observed with fundus ophthalmoscopy and fluorescein angiography. Response in electroretinogram was reduced, suggesting both rod and cone dysfunction. Autoantibody against 23-kD cancer-associated retinopathy (CAR) antigen (antirecoverin antibody) was detected in the patient's serum. A mediastinal tumor that was histopathologically diagnosed as invasive thymoma was detected and was surgically resected. During more than 3 years of follow-up, no other malignancy was detected despite extensive systemic evaluation. The patient also suffered from subclinical myasthenia gravis. Although temporary improvement of visual function was observed after treatment with steroid pulse therapy and plasmapheresis' light perception of each eye was lost in the end. CONCLUSIONS: The patient was diagnosed as having CAR. Invasive thymoma was considered to be the causative tumor because there had been no evidence that suggested other systemic malignancy during more than 3 years of follow-up.

Adult↗
PubMed2002

Antirecoverin antibody in the aqueous humor of a patient with cancer-associated retinopathy.

PURPOSE: To describe a patient with cancer-associated retinopathy (CAR) in whom antirecoverin antibody was found in the aqueous humor. DESIGN: Interventional case report. METHODS: A 65-year-old man underwent resection of adenocarcinoma of the lung in June 1991 and noted deterioration of vision 10 months later. Goldmann perimetry revealed a ring-like scotoma in each eye, and the electroretinogram was nonrecordable. Aqueous humor and peripheral venous blood were collected for Western blot analysis from this patient and three other patients during surgery for age-related cataract. RESULTS: We found antirecoverin antibody within the aqueous humor and serum in the patient with CAR. In contrast, such imunoreactivities were not observed in specimens from the control patients. CONCLUSION: These observations strongly suggest that antirecoverin antibody penetrates into the aqueous humor and vitreous cavity beyond the blood-retina barrier in CAR.

Adenocarcinoma↗
PubMed1996

Cancer-associated retinopathy in a patient with endometrial cancer.

PURPOSE: We studied a case of unusual retinopathy in a 60-year-old woman. METHOD: The patient developed bilateral retinopathy with iridocyclitis and vitreitis. Corticosteroid therapy could not prevent deterioration of visual acuity and field. The electroretinogram became nonrecordable, and fluorescein angiogram exhibited retinal pigment epithelium window defects, fluorescein stainings to the vascular walls, and narrowed arterioles. RESULTS: The patient underwent hysterectomy and lymphadenectomy for endometrial cancer in the corporis uteri. She was found to possess antibodies against retinal 34-kd protein, leading to a diagnosis of cancer-associated retinopathy. CONCLUSION: Cancer-associated retinopathy may occur in patients with endometrial cancer of the corporis uteri.

Antibodies, Neoplasm↗
PubMed1997

Autoimmune retinopathy in the absence of cancer.

PURPOSE: To report the clinical and immunologic features of two patients with progressive retinal degeneration and circulating antiretinal antibodies without systemic malignancy. METHODS: Two patients were followed up for 5 to 7 years. Comprehensive medical and ophthalmic examinations and visual function testing included manual perimetry and standardized electroretinography. Patient sera were tested for antiretinal antibodies by Western blot and immunoperoxidase indirect cytochemistry techniques. RESULTS: Two patients had family history of autoimmune disease. Each had severe monocular visual loss with photopsia, a ring scotoma, and abnormal electroretinogram despite a normal-appearing ocular fundus. One had a flat electroretinogram; the other had inner retina dysfunction, with selective b wave loss and abnormal oscillatory potentials. Both patients' sera had antiretinal antibodies that specifically labeled the inner plexiform layer of donor retina by indirect immunoperoxidase testing. Neither had any sign of cancer. CONCLUSIONS: In two patients without systemic malignancy, the symptoms, perimetric findings, and normal fundus appearance resembled cancer associated retinopathy. Electroretinography and antibody findings indicating dysfunction of the inner retina are distinct from those of cancer-associated retinopathy. These two cases raise the possibility of an autoimmune mechanism for retinal degeneration that is not cancer associated. Further study is necessary to determine the role of antiretinal antibodies in these patients.

Adult↗
PubMed1996

Cancer-associated retinopathy with presumed vasculitis.

PURPOSE: To treat a 63-year-old woman who experienced fairly rapid vision loss in association with small-cell carcinoma of the lung. METHODS: She underwent a full ophthalmologic examination, including fluorescein angiography and an immunologic study by Western blot analysis. RESULTS: Fluorescein angiography demonstrated diffuse staining of the retinal vessels. She had 62-kd antiretinal antibody in her serum. Cancer-associated retinopathy was diagnosed. CONCLUSION: The staining seen on the angiogram appears to indicate vasculitis, which would cause the characteristic attenuation of retinal vessels in this disease.

Anti-Inflammatory Agents↗
PubMed1992

Purification and characterization of S-modulin, a calcium-dependent regulator on cGMP phosphodiesterase in frog rod photoreceptors.

S-modulin is a 26 kDa protein that regulates light sensitivity of cGMP phosphodiesterase in a Ca(2+)-dependent manner in frog rod outer segments (ROSs). In the present study, we purified S-modulin by taking advantage of a hydrophobic interaction between Phenyl Sepharose and S-modulin at high Ca2+ concentrations. The yield was greater than 90%. 45Ca(2+)-binding experiment showed that S-modulin is a Ca(2+)-binding protein. At high Ca2+ concentrations, S-modulin binds to ROS membranes. The binding target of the Ca2+/S-modulin complex is possibly a ROS membrane lipid(s), but it was difficult to identify. The binding was observed mainly at greater than 1 microM Ca2+. The amino acid sequence deduced from proteolytic fragments of S-modulin was approximately 80% and 60% identical to those of recovering and visinin, respectively.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1999

Clinical and immunocytochemical findings in a case of melanoma-associated retinopathy.

OBJECTIVE: To describe an unusual case of melanoma-associated retinopathy (MAR). DESIGN: Retrospective, observational case report and experimental study. PARTICIPANTS: A 61-year-old man with a history of cutaneous melanoma, acquired bilateral central scotomas, and night blindness. INTERVENTION: Serial full-field electroretinography (ERG) and Goldmann perimetry were performed. Serum was screened for cancer-associated retinopathy (CAR) antibodies by Western blotting. Sections of human and rat retina were examined by immunofluorescence microscopy to determine whether retinal cells were reactive with this patient's serum. A metastatic workup was performed. MAIN OUTCOME MEASURES: Electroretinography, Goldmann visual field testing, and immunocytochemistry were performed. RESULTS: The results were as follows: (1) The ERG showed a profound loss of the b-wave amplitude and a "negative" b-wave characteristic of congenital stationary night blindness; (2) a central scotoma and peripheral constriction were identified on Goldmann visual field tests; (3) as in other patients with MAR, bipolar cells in human and rat retinas were immunolabeled with this patient's serum; and (4) a previously unsuspected focus of metastatic melanoma was discovered. CONCLUSIONS: Recognition of this condition may help to identify an occult focus of metastatic melanoma.

Blotting, Western↗