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PubMed1992

Cloning and sequencing of the 23 kDa mouse photoreceptor cell-specific protein.

The 23 kDa protein was localized by immunocytochemistry to photoreceptor cells of the mouse retina, and bovine and mouse cDNA clones were isolated and sequenced. The deduced amino acid sequences showed that the mouse 23 kDa protein is 91% identical to the bovine protein, and is the same as S-modulin, the CAR (cancer-associated retinopathy) protein and recoverin, the Ca(2+)-dependent activator of photoreceptor guanylate cyclase. The amino acid sequence reveals two Ca2+ binding sites, no internal repeats, 59% homology to the chicken visinin protein and 40% homology to calmodulin while Northern analysis demonstrated a single 1.0 kb mRNA species in bovine and mouse retina.

Amino Acid Sequence↗
PubMed1994

Recoverin mediates the calcium effect upon rhodopsin phosphorylation and cGMP hydrolysis in bovine retina rod cells.

Rhodopsin phosphorylation and in consequence cGMP hydrolysis in bovine rod outer segments are Ca2+ dependent in the presence of ATP. The level of rhodopsin phosphorylation decreases and the lifetime of active phosphodiesterase increases when the free [Ca2+] is raised from < 1 nM to about 1 microM; in both cases the half-maximal effect was observed at 140-170 nM of free Ca2+. Antibodies to recoverin reverse both effects at high [Ca2+] but have no influence at low [Ca2+]. We conclude that the Ca2+ effects observed are mediated by recoverin which inhibits rhodopsin kinase at a high Ca2+ level.

Adenosine Triphosphate↗
PubMed1994

Calcium-sensitive control of rhodopsin phosphorylation in the reconstituted system consisting of photoreceptor membranes, rhodopsin kinase and recoverin.

Rhodopsin phosphorylation in the reconstituted system consisting of urea-washed photoreceptor membranes, rhodopsin kinase and recoverin is regulated by Ca2+: the process takes place at low [Ca2+] but is suppressed at high [Ca2+]. In the absence of recoverin, rhodopsin kinase is active irrespective of the cation concentration used. Hence, recoverin is an inhibitor (at high [Ca2+]) but not an activator of rhodopsin kinase. Based jointly on these data obtained on the reconstituted system and on our preceding experiments on rod outer segments suspension, one may conclude that (i) the function of recoverin in retina rod cells is the Ca(2+)-sensitive control of rhodopsin phosphorylation and (ii) the presence of recoverin is essential and sufficient to provide rhodopsin kinase with the Ca2+ sensitivity.

Animals↗
PubMed1995

N-myristoylation of recoverin enhances its efficiency as an inhibitor of rhodopsin kinase.

Recoverin, a recently identified member of the EF-hand superfamily of Ca(2+)-binding proteins, is capable to inhibit rhodopsin phosphorylation by rhodopsin kinase at high but not at low free [Ca2+]. The N-terminal glycine residue of retinal recoverin is heterogeneously acylated with myristoyl or related N-acyl group. To clarify the role of the N-terminal acylation of recoverin in its inhibitory action upon rhodopsin phosphorylation, we compared the efficiency of myristoylated and non-myristoylated forms of recombinant recoverin as inhibitors of rhodopsin kinase activity. We have found that rhodopsin phosphorylation by purified rhodopsin kinase, which does not depend on free [Ca2+] in the absence of recoverin, is regulated by Ca2+ in the presence of both forms of the recombinant protein. EC50 values for Ca2+ are the same (2 microM) for the myristoylated and non-myristoylated forms; the Hill coefficients of 1.7 and 0.9, respectively, indicate that the effect is cooperative with respect to Ca2+ only for myristoylated recoverin. In the presence of Ca2+, both forms of recoverin taken at saturated concentrations cause an almost equal inhibition of rhodopsin phosphorylation. However, the inhibitory action of the myristoylated form occurs at much lower its concentrations than that of the non-myristoylated form (EC50 are 0.9 and 6.5 microM, respectively).

Animals↗
PubMed1996

Calcium-bound recoverin targets rhodopsin kinase to membranes to inhibit rhodopsin phosphorylation.

In rod photoreceptor cells, Ca2+-bound recoverin associates with disk membranes and inhibits light-dependent phosphorylation of rhodopsin. However, the functional significance of Ca2+-induced membrane association of recoverin has not been fully evaluated. We found that Ca2+-bound recoverin forms a complex with rhodopsin kinase preferentially at the membrane surface. Addition of increasing amounts of membranes promoted the membrane association of recoverin, and remarkably suppressed rhodopsin kinase activity. It was concluded that the Ca2+-recoverin-rhodopsin kinase complex is stabilized by membrane association, leading to effective suppression of the kinase activity.

Animals↗
PubMed1993

Three-dimensional structure of recoverin, a calcium sensor in vision.

Recoverin, a recently discovered member of the EF hand superfamily, serves as a calcium sensor in vision. We report here the crystal structure of recombinant unmyristoylated recoverin at 1.9 A resolution. The four EF hands of the protein are arranged in a compact array that contrasts with the dumbbell shape of calmodulin and troponin C. A calcium ion is bound to EF hand 3, while EF hand 2 can bind samarium but not calcium in this crystal form. The other two EF hands have novel structural features that prevent or impair calcium binding. A concave hydrophobic surface formed by EF hands 1 and 2 may participate in the read out of calcium signals by recoverin and its homologs.

Amino Acid Sequence↗
PubMed1992

Recoverin, a novel calcium-binding protein from vertebrate photoreceptors.

Photoreceptor guanylyl cyclase activity is modulated by an endogenous calcium-binding protein called recoverin. A modified isolation procedure for recoverin using gel-filtration chromatography instead of a heat denaturation step is presented. The elution volume of recoverin corresponds to a monomer. Recoverin exhibits a calcium-dependent mobility shift in a native gel electrophoresis. Isoelectric focusing revealed a pI of 5.25. No subspecies of recoverin were detected.

Animals↗
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↗
PubMed1992

VILIP, a cognate protein of the retinal calcium binding proteins visinin and recoverin, is expressed in the developing chicken brain.

Using a selective cloning approach we previously isolated a number of cDNAs of transcripts that are newly expressed during terminal differentiation of the chicken optic tectum. Here, we have characterized one of these cDNAs (OZ1) by Northern analysis and in situ hybridization. The OZ1 cDNA hybridizes to two transcripts of 1.6 kb and 2.9 kb which are widely expressed in the brain but not detectable in liver, heart or skeletal muscle. Cloning of overlapping cDNAs revealed that both transcripts encode the same open reading frame for a polypeptide of 191 amino acids. The deduced protein contains 4 EF-hand consensus motifs characteristic of calmodulin-like Ca(2+)-binding proteins. It displays 40% and 46% sequence identity with the retinal photoreceptor-specific Ca(2+)-binding proteins visinin and recoverin, respectively, and was termed VILIP (visinin-like protein). VILIP transcripts are also expressed in the retina. However, the expression pattern does not overlap with that of visinin or recoverin. The possible functional implications of the similarity to recoverin, which regulates guanylate cyclase activity of retinal rod cells in a Ca(2+)-dependent manner, are discussed.

Animals↗
PubMed1996

Cancer-associated retinopathy syndrome: a case of small cell lung cancer expressing recoverin immunoreactivity.

Cancer-associated retinopathy (CAR) syndrome is a rare paraneoplastic neuropathy syndrome often found in patients with small cell lung cancer (SCLC). Serological studies have indicated that the process could include autoimmune reactions directing retinal antigens. Recently, the CAR antigen was identified as a photoreceptor protein, recoverin, by screening retinal proteins using the CAR patient's serum. The present case of SCLC showed rapidly deteriorated bilateral visual acuity lacking the inflammatory findings at the retina which were compatible with CAR. The immunohistochemical study revealed that the cancer cells expressed recoverin or recoverin-like immunoreactivity. This is the first observation in CAR syndrome. The presence of recoverin or recoverin-like immunoreactivity in SCLC with CAR syndrome supports the hypothesis that the cancer-retina immunologic cross-reaction contributes to visual loss in this syndrome.

Aged↗
PubMed1993

The effect of recoverin-like calcium-binding proteins on the photoresponse of retinal rods.

The rod photoresponse is triggered by an enzyme cascade that stimulates cGMP hydrolysis. The resulting fall in cGMP leads to a decrease in Ca2+, which promotes photoresponse recovery by activating guanylate cyclase, causing cGMP resynthesis. In vitro biochemical studies suggest that Ca2+ activation of guanylate cyclase is medicated by recoverin, a 26 kd Ca(2+)-binding protein. To evaluate this, exogenous bovine recoverin and two other homologous Ca(2+)-binding proteins from chicken and Gecko retina were dialyzed into functionally intact Gecko rods using whole-cell recording. All three proteins prolonged the rising phase of the photoresponse without affecting the kinetics of response recovery. These results suggest that recoverin-like proteins affect termination of the transduction cascade, rather than mediate Ca(2+)-sensitive activation of guanylate cyclase.

Animals↗
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↗
PubMed1992

Biochemical mechanism of light adaptation in vertebrate photoreceptors.

Vertebrate photoreceptors can adjust their sensitivity to a wide range of light intensities spanning several orders of magnitude, the phenomenon of which is called light adaptation. Electrophysiological and biochemical studies have revealed that calcium can serve as an intracellular transmitter of light adaptation under the control of cGMP metabolism. After illumination, the cytoplasmic calcium concentration of a photoreceptor decreases, which in turn strongly activates photoreceptor guanylate cyclase. This calcium-dependent effect is mediated by a novel calcium-binding protein (recoverin) and leads to the restoration of the depleted cGMP pool after illumination.

Adaptation, Ocular↗
PubMed2004

Clinical and immunologic aspects of cancer-associated retinopathy.

PURPOSE: To report clinical and immunologic aspects of cancer-associated retinopathy (CAR). DESIGN: Observational consecutive case series. METHODS: A retrospective review was made of 18 consecutive patients with cancer-associated retinopathy who had antiretinal antibody determination by Western blot testing. RESULTS: Clinically, a variety of ophthalmic observations including electroretinography impairment, retinal vessel narrowing, deterioration of visual acuity, visual field changes, and uveitis were frequently observed. As retinal autoantigens in the 18 cases, recoverin was found in all 18 cases (100%), heat shock cognate protein 70 (HSC70) was found in six cases (33%), and other proteins were found in four cases (20%). These antibodies were detected in only 60% of the patients at the initial examination, however, and then became increasingly apparent on the subsequent testing that was performed three times on serum samples obtained sequentially during the following months. CONCLUSION: For diagnosis of cancer-associated retinopathy, the presence of serum autoantibody toward recoverin is essentially required in addition to the characteristic clinical aspects noted above.

Adult↗
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↗
PubMed2004

Recoverin as a paraneoplastic antigen in lung cancer: the occurrence of anti-recoverin autoantibodies in sera and recoverin in tumors.

Using immunoblotting with recombinant recoverin as an antigen, we have examined 279 serum samples from individuals with small cell lung carcinoma (SCLC, 99 patients), non-small cell lung carcinoma (NSCLC, 44 patients), and non-malignant pulmonary disorders (86 patients) as well as sera from 50 healthy donors. Autoantibodies against recoverin (anti-Rc) were detected in sera from 15 patients with SCLC (15% of cases) and from 9 patients with NSCLC (about 20% of cases). Only two anti-Rc positive cases were detected in patients with non-malignant pulmonary disorders, while no such cases were found in healthy individuals. Immunohistochemical investigation of paraffin sections of 44 SCLC and 40 NSCLC tumors revealed recoverin-positive reaction in 30 SCLC (68%) and 34 NSCLC (85%) sections. Despite the high specificity (98%), the low sensitivity (less than 20%) does not allow serum anti-Rc to be considered as a valuable marker of lung cancer. However, taking into account the high occurrence of aberrant expression of recoverin in lung tumors, this PNA could be considered as a potential target for immunotherapy of lung cancer.

Aged↗
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↗