Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Peripherins”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 487 records · Page 27Linked to original sources
PubMed2002

Functional expression of AMPA receptors on central terminals of rat dorsal root ganglion neurons and presynaptic inhibition of glutamate release.

No direct evidence has been found for expression of functional AMPA receptors by dorsal root ganglion neurons despite immunocytochemical evidence suggesting they are present. Here we report evidence for expression of functional AMPA receptors by a subpopulation of dorsal root ganglion neurons. The AMPA receptors are most prominently located near central terminals of primary afferent fibers. AMPA and kainate receptors were detected by recording receptor-mediated depolarization of the central terminals under selective pharmacological conditions. We demonstrate that activation of presynaptic AMPA receptors by exogenous agonists causes inhibition of glutamate release from the terminals, possibly via primary afferent depolarization (PAD). These results challenge the traditional view that GABA and GABA(A) receptors exclusively mediate PAD, and indicate that PAD is also mediated by glutamate acting on presynaptically localized AMPA and kainate receptors.

Action Potentials↗
PubMed1998

Neurons derived in vitro from ES cells express homeoproteins characteristic of motoneurons and interneurons.

We have characterized different neuronal subpopulations derived from in vitro differentiation of embryonic stem (ES) cells using as markers the expression of several homeodomain transcription factors. Following treatment of embryo-like aggregates with retinoic acid (RA), Pax-6, a protein expressed by ventral central nervous system (CNS) progenitors is induced. In contrast, Pax-7 expressed in vivo by dorsal CNS progenitors, and erbB3, a gene expressed by neural crest cells and its derivatives, are almost undetectable. CNS neuronal subpopulations generated expressed combinations of markers characteristic of somatic motoneurons (Islet-1/2, Lim-3, and HB-9), cranial motoneurons (Islet-1/2 and Phox2b) and interneurons (Lim-1/2 or EN1). Molecular characterization of neuron subtypes generated from ES cells should considerably facilitate the identification of new genes expressed by restricted neuronal cell lineages.

Animals↗
PubMed1995

Heterologous expression of photoreceptor peripherin/rds and Rom-1 in COS-1 cells: assembly, interactions, and localization of multisubunit complexes.

Peripherin/rds is a 39 kDa integral membrane glycoprotein essential for normal photoreceptor cell development in vertebrates. It has been implicated in several human retinal degenerative diseases including retinitis pigmentosa and macular degeneration and is thought to play a structural role at photoreceptor outer segment disk rims, where it forms a tightly-associated complex with rom-1, a nonglycosylated 37 kDa homologue. Western blot analysis of COS-1 cells transiently transfected with full-length cDNA coding for either peripherin/rds or rom-1 indicates that each protein is expressed primarily as a disulfide-linked homodimer; recombinant peripherin/rds is glycosylated while recombinant rom-1 is not--akin to their counterparts in rod photoreceptor disk membranes. Upon cotransfection of the two cDNAs, the specific assembly of a stable peripherin/rds--rom-1 complex is observed. Immunofluorescence microscopy studies demonstrate that both singly and coexpressed peripherin/rds and rom-1 complexes are localized primarily within internal membranes of transfected cells. Velocity sedimentation data indicate that the recombinant complexes (4.9 S) are assembled with a subunit stoichiometry similar to those extracted from ROS membranes (4.5 S) and are most consistent with a tetrameric arrangement of polypeptides. Sedimentation analyses of individually expressed peripherin/rds (5.1 S) and rom-1 (4.3 S) suggest that each polypeptide can also assemble into a tetrameric form in the absence of its homologue partner. Subunit assembly and interactions are discussed in terms of their potential role in hereditary retinal diseases.

Animals↗
PubMed2005

Role of the second intradiscal loop of peripherin/rds in homo and hetero associations.

Peripherin/rds (P/rds) is a disk rim protein that assembles into homo and hetero complexes with its nonglycosylated homologue, Rom-1, to maintain the integrity of the photoreceptor outer segment. Mutations in the rds gene have been identified in a variety of human retinal degenerative diseases. More than 70% of these mutations are located in the second intradiscal (D2) loop, highlighting the functional importance of this region. This study examines the involvement of different regions of the D2 loop in protein associations using a GST pull-down assay and a heterologous coexpression system. The pull-down assay suggests an association of the N-terminal portion (Phe(120)-Phe(187)) of the D2 loop with Rom-1 as well as with other P/rds molecules. Through peptide competition experiments, the region between Cys(165) and Asn(182) of the D2 loop has been identified as the domain for these associations. In a COS-1 cell heterologous expression system, coexpression of the D2 loop along with the intact P/rds and Rom-1 hindered the association of the two full-length proteins. In contrast to the homo association of P/rds molecules, it seems that the hetero association of P/rds with Rom-1 has a more stringent structural requirement. This work defines the crucial domain of the D2 loop, which mediates homo and hetero associations, specifically the regions that lay between Cys(165) and Asn(182). Elucidation of the molecular mechanisms behind the protein-protein associations of P/rds and its partners may reveal the pathogenic defects arising from the most common mutations in this gene.

Amino Acid Sequence↗
PubMed1997

Purification and light-dependent phosphorylation of a candidate fusion protein, the photoreceptor cell peripherin/rds.

The proteins peripherin/rds and rom-1 form a protein complex in the rims of photoreceptor outer segment disk membranes. Peripherin/rds plays an essential role in the morphogenesis and maintenance of disk membrane structure, with peripherin/rds gene mutations resulting in photoreceptor cell degeneration. We report two different chromatographic procedures for the purification of native peripherin/rds from bovine photoreceptor cell outer segments and show that the protein is a phosphoprotein that promotes membrane fusion in vitro. During one procedure, peripherin/rds was copurified in association with rom-1 by hyroxylapatite and Mono Q FPLC. During the other, it was purified free from rom-1 by concanavalin-A affinity chromatography and chromatofocusing. Analysis of homogeneous peripherin/rds from the second procedure showed that exposure of photoreceptor outer segments to light resulted in the incorporation of nearly 2 mol of phosphate per mole of peripherin/rds and a concomitant shift in the isoelectric point of the protein. In addition, we found that recombination of purified peripherin/rds into lipid vesicles increased membrane fusion, with more rapid fusion detected with phosphorylated peripherin/rds. In conclusion, studies with purified peripherin/rds reveal that the protein undergoes light-dependent phosphorylation and that it may function in membrane fusion.

Amino Acid Sequence↗
PubMed1998

Cysteine residues of photoreceptor peripherin/rds: role in subunit assembly and autosomal dominant retinitis pigmentosa.

Peripherin/rds is a tetraspanning membrane glycoprotein that is essential for the morphogenesis and stabilization of outer segments of vertebrate rod and cone photoreceptor cells. Mutations in the gene for peripherin/rds are responsible for retinal degeneration in the rds mouse and a variety of progressive human retinal degenerative diseases including autosomal dominant retinitis pigmentosa and macular dystrophy. Peripherin/rds associates with rom-1, a homologous subunit, to form a heterotetrameric complex. This study examines the importance of cysteine residues for the structure of peripherin/rds and its assembly with rom-1. Each of the 13 cysteine residues in bovine peripherin/rds was individually replaced with a serine residue by site-directed mutagenesis, and the resulting mutants were expressed individually or together with rom-1 in COS-1 cells. SDS-polyacrylamide gel electrophoresis, immunoprecipitation, and velocity sedimentation were carried out to evaluate the ability of these mutants to form disulfide-linked homodimers, associate with rom-1, and assemble into tetramers characteristic of wild-type peripherin/rds. Substitution of each of the six nonconserved cysteines had no apparent effect on dimer formation, folding, or subunit assembly. In contrast, replacement of any of the seven conserved cysteine residues predicted to lie within a 150 amino acid intradiscal loop significantly altered these properties. Six of these mutants, including a C214S mutant linked to autosomal dominant retinitis pigmentosa, were unable to fold normally, interact with rom-1, or self-assemble into tetramers but instead formed a mixture of large aggregates and a smaller component, most likely a dimer. The C150S mutant, on the other hand, was incapable of forming intermolecular disulfide bonds but did associate with rom-1 into a heterotetramer. These results suggest that (1) the conserved C150 residue is required for intermolecular disulfide bonding but not subunit assembly; (2) the six other conserved cysteine residues are crucial for proper folding and subunit assembly, possibly through formation of intramolecular disulfide bonds; and (3) the misfolding and defective subunit assembly of the C214S mutant is responsible for a form of monogenic autosomal dominant retinitis pigmentosa.

Animals↗
PubMed1998

Fusion between retinal rod outer segment membranes and model membranes: a role for photoreceptor peripherin/rds.

Peripherin/rds plays an essential role in the maintenance of photoreceptor rod cell disk membrane structure. The purification of this protein to homogeneity [Boesze-Battaglia, K., et al. (1997) Biochemistry 36, 6835-6846] has allowed us to characterize the functional role of peripherin/rds in the maintenance of rod outer segment (ROS) membrane fusion processes. Utilizing a cell-free fusion assay system, we report that the fusion of R18-labeled ROS plasma membrane (R18-PM) with disk membranes or peripherin/rds-enriched large unilammellar vesicles (LUVs) is inhibited upon trypsinolysis of peripherin/rds. To understand this phenomenon, we tested the ability of a series of overlapping synthetic C-terminal peripherin/rds peptides to mediate model membrane fusion. Within the 63 amino acid long region of the C-terminus, we identified a minimal 15 residue long amino acid sequence (PP-5), which is necessary to promote membrane fusion. PP-5 was able to inhibit R18-PM disk membrane fusion and promoted ANTS/DPX contents mixing in a pure vesicle system. This peptide (PP-5) promoted calcium-induced vesicle aggregation of phosphatidylethanolamine:phosphatidylserine LUVs. FTIR analysis confirmed the structural prediction of this peptide as alpha-helical. When modeled as an alpha-helix, this peptide is amphiphilic with a hydrophobicity index of 0.75 and a hydrophobic moment of 0.59. PP-5 has substantial biochemical and functional homology with other well-characterized membrane fusion proteins. These results demonstrate the necessity for peripherin/rds in ROS membrane fusion, specifically the requirement for an intact C-terminal region of this protein.

Amino Acid Sequence↗
PubMed2001

Investigating the mechanisms of retinal degenerations with antisense oligonucleotides.

Utilizing antisense oligonucleotides coupled with an intact Xenopus eye rudiment model, we have effectively demonstrated that we are able to downregulate the expression of a photoreceptor-specific protein, rds/peripherin, and generate a loss-of-function model upon which to further study the function of the rds/peripherin gene. The ultrastructure and protein expression patterns very closely resemble those previously documented in both the rds mouse and in human autosomal dominant retinitis pigmentosa due to peripherin/RDS mutations. An identical strategy can be applied to any gene correlated with a degenerative retinal phenotype. As the entire array of genes is revealed through the various genome projects, including human and mouse, it is becoming increasingly critical to evaluate and determine the function of the corresponding gene products. Discovering which gene is responsible for a particular clinical phenotype is only the first of many steps in the development of a treatment or cure for that particular disease. Using our in vitro model, in which the retina is readily accessible to the antisense oligonucleotide yet the normal three-dimensional ultrastructure of the retina is maintained, we can evaluate the function of virtually any gene as the sequence becomes available. A thorough understanding of the function of individual genes will provide insights on the role of gene product in retinal health and pathophysiology. This experimental approach will also allow for specific therapeutic interventions to be evaluated so that targeted treatments can be designed for individuals with specific genetic mutations.

Animals↗
PubMed2001

Genotype-phenotype correlations and differential diagnosis in autosomal dominant macular disease.

In the past few years, great progress has been made in the understanding of macular diseases. A number of disease-causing genes have been cloned, and numerous loci for other conditions have been mapped. The purpose of this article is to provide an overview of the current understanding of the genotype-phenotype correlations in autosomal dominant macular diseases with an emphasis on differential diagnostic issues. Whenever possible, the molecular correlates have been reviewed and the implications for age-related macular degeneration have been discussed. The many similarities of these diseases to age-related macular degeneration of the atrophic or exudative type, which can be misleading in elderly subjects, have also been addressed. While some conditions yield disease truly confined to the macula, others show widespread retinal involvement on functional testing. Clear-cut genotype-phenotype correlations are possible only for some forms of macular diseases. To further complicate the diagnostic process, there is a considerable degree of clinical overlap between many of them, making the differential diagnostic process potentially challenging. Functional testing, careful assessment of family history and extensive family work-up are essential in differentiating at the clinical level most, but not all, of these disease entities. Awareness of all of these conditions is required to direct correctly diagnostic investigations, to formulate an accurate prognosis, and for proper genetic counseling.

Amino Acid Sequence↗
PubMed2003

Macular appearance by means of OCT and electrophysiology in members of two families with different mutations in RDS (the peripherin/RDS gene).

PURPOSE: To describe the phenotype using electroretinography and optical coherence tomography (OCT) in members of two families with different mutations in RDS. METHODS: DNA was extracted from blood samples and used for mutation screening by denaturing gradient gel electrophoresis (DGGE) and nucleotide sequencing of RDS exons. Patients were examined with clinical evaluation, full-field electroretinography (ERG), multifocal electroretinography (mfERG) and OCT. RESULTS: An Arg-46 --> stop codon conversion and a Ser-125 --> Leu substitution were found, respectively, in affected members of the two families. Phenotypes included retinitis pigmentosa, central areolar choroidal dystrophy, macular dystrophy and adult vitelliform maculopathy. The vitelliform lesion was clearly delineated on OCT, but mfERG showed preserved function. Optical coherence tomography showed attenuation of retinal reflectivity in two cases. CONCLUSION: By combining traditional investigations with mfERG and OCT, we were able to obtain a more refined evaluation of contributing macular and generalized retinal dysfunction, respectively, in patients with hereditary retinal disease.

Adult↗
PubMed1991

Name dropping.

Explore the source record for details and available documents.

Intermediate Filament Proteins↗
PubMed1998

Animal models of human retinal dystrophies.

Naturally occurring retinal dystrophies in laboratory and companion animals represent a wealth of different conditions, some of which are important from a comparative point of view, and all of which offer opportunities to further the understanding of retinal function and reaction in health and disease. The study of animal models of retinal dystrophies has provided candidate genes for investigation in conditions of man such as retinitis pigmentosa and has also led to the identification of new genes and even new families of genes. Mutations in the gene for the beta subunit of cyclic GMP phosphodiesterase cause retinal dystrophies in man, mice and dog, and mutations in the gene for the structural protein peripherin/RDS result in a retinal dystrophy in the mouse and a spectrum of differing retinal dystrophies in man. Animals with homologous retinal dystrophies to man may make useful models for investigation of treatment either by drugs or by gene therapy. Furthermore the use of transgenics and gene targeting in laboratory mice offers the opportunity to create new models of human retinal dystrophies and also to investigate the effect of gene dysfunction.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1993

A null mutation in the human peripherin/RDS gene in a family with autosomal dominant retinitis punctata albescens.

The murine rds (retinal degeneration slow) allele is a semidominant null allele that causes photoreceptor degeneration. The wild-type sequence at the rds locus encodes a photoreceptor disc membrane protein named peripherin/RDS. Mutations in the homologous human peripherin/RDS gene can cause autosomal dominant retinitis pigmentosa, but these are missense mutations or deletions of single codons. No obvious null alleles have been reported in humans, so that the human phenotype corresponding to rds is as yet unknown. Here we report a 2-basepair deletion in codon 25 of the human gene in a family with autosomal dominant retinitis punctata albescens, suggesting that this disease, rather than retinitis pigmentosa, is the comparable human phenotype.

Alleles↗
PubMed2003

Intraocular gene delivery of ciliary neurotrophic factor results in significant loss of retinal function in normal mice and in the Prph2Rd2/Rd2 model of retinal degeneration.

Intraocular delivery of a variety of neurotrophic factors has been widely investigated as a potential treatment for retinal dystrophy (RD). The most commonly studied factor, ciliary neurotrophic factor (CNTF), has been shown to preserve retinal morphology and to promote cell survival in a variety of models of RD. In order to evaluate CNTF as a potential treatment for RD, we used the Prph2(Rd2/Rd2) mouse. CNTF was expressed intraocularly using AAV-mediated gene delivery either by itself or, in a second treatment group, combined with AAV-mediated gene replacement therapy of peripherin2, which we have previously shown to improve photoreceptor structure and function. We confirmed in both groups of animals that CNTF reduces the loss of photoreceptor cells. Visual function, however, as assessed over a time course by electroretinography (ERG), was significantly reduced compared with untreated controls. Furthermore, CNTF gene expression negated the effects on function of gene replacement therapy. In order to test whether this deleterious effect is only seen when degenerating retina is treated, we recorded ERGs from wild-type mice following intraocular injection of AAV expressing CNTF. Here a marked deleterious effect was noted, in which the b-wave amplitude was reduced by at least 50%. Our results demonstrate that intraocular CNTF gene delivery may have a deleterious effect on the retina and caution against its application in clinical trials.

Animals↗