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Jason R Schnell - One of the best experts on this subject based on the ideXlab platform.
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characterization of the human sigma 1 receptor chaperone domain structure and Binding Immunoglobulin Protein bip interactions
Journal of Biological Chemistry, 2013Co-Authors: Jose Luis Ortegaroldan, Felipe Ossa, Jason R SchnellAbstract:Abstract The sigma-1 receptor (S1R) is a ligand-regulated membrane Protein chaperone involved in the ER stress response. S1R activity is implicated in diseases of the central nervous system including amnesia, schizophrenia, depression, Alzheimer disease, and addiction. S1R has been shown previously to regulate the Hsp70 Binding Immunoglobulin Protein (BiP) and the inositol triphosphate receptor calcium channel through a C-terminal domain. We have developed methods for bacterial expression and reconstitution of the chaperone domain of human S1R into detergent micelles that enable its study by solution NMR spectroscopy. The chaperone domain is found to contain a helix at the N terminus followed by a largely dynamic region and a structured, helical C-terminal region that encompasses a membrane associated domain containing four helices. The helical region at residues ∼198–206 is strongly amphipathic and proposed to anchor the chaperone domain to micelles and membranes. Three of the helices in the C-terminal region closely correspond to previously identified cholesterol and drug recognition sites. In addition, it is shown that the chaperone domain interacts with full-length BiP or the isolated nucleotide Binding domain of BiP, but not the substrate Binding domain, suggesting that the nucleotide Binding domain is sufficient for S1R interactions.
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characterization of the human sigma 1 receptor chaperone domain structure and Binding Immunoglobulin Protein bip interactions
Journal of Biological Chemistry, 2013Co-Authors: Jose Luis Ortegaroldan, Felipe Ossa, Jason R SchnellAbstract:The sigma-1 receptor (S1R) is a ligand-regulated membrane Protein chaperone involved in the ER stress response. S1R activity is implicated in diseases of the central nervous system including amnesia, schizophrenia, depression, Alzheimer disease, and addiction. S1R has been shown previously to regulate the Hsp70 Binding Immunoglobulin Protein (BiP) and the inositol triphosphate receptor calcium channel through a C-terminal domain. We have developed methods for bacterial expression and reconstitution of the chaperone domain of human S1R into detergent micelles that enable its study by solution NMR spectroscopy. The chaperone domain is found to contain a helix at the N terminus followed by a largely dynamic region and a structured, helical C-terminal region that encompasses a membrane associated domain containing four helices. The helical region at residues ∼198–206 is strongly amphipathic and proposed to anchor the chaperone domain to micelles and membranes. Three of the helices in the C-terminal region closely correspond to previously identified cholesterol and drug recognition sites. In addition, it is shown that the chaperone domain interacts with full-length BiP or the isolated nucleotide Binding domain of BiP, but not the substrate Binding domain, suggesting that the nucleotide Binding domain is sufficient for S1R interactions. Background: Sigma-1 receptor is a ligand-regulated membrane Protein chaperone involved in BiP regulation and the ER stress response. Results: The chaperone domain of human sigma-1 receptor is mostly helical with short extended regions. Conclusion: Regions of the sigma-1 receptor chaperone domain implicated in ligand and cholesterol Binding can be mapped to separate helices. Significance: A structural framework for delineating sigma-1 receptor BiP and ligand interactions is presented.
Valerie Corrigall - One of the best experts on this subject based on the ideXlab platform.
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Systemic gene transfer of Binding Immunoglobulin Protein (BiP) prevents disease progression in murine collagen-induced arthritis
Clinical and experimental immunology, 2015Co-Authors: Adrian M. Shields, Stephen J. Thompson, Gabriel S. Panayi, Linda S. Klavinskis, Michael Antoniou, Paul H. Wooley, Helen L. Collins, Valerie CorrigallAbstract:Summary Recombinant human Binding Immunoglobulin Protein (BiP) has previously demonstrated anti-inflammatory properties in multiple models of inflammatory arthritis. We investigated whether these immunoregulatory properties could be exploited using gene therapy techniques. A single intraperitoneal injection of lentiviral vector containing the murine BiP (Lenti-mBiP) or green fluorescent Protein (Lenti-GFP) transgene was administered in low- or high-dose studies during early arthritis. Disease activity was assessed by visual scoring, histology, serum cytokine and antibody production measured by cell enzyme-linked immunosorbent assay (ELISA) and ELISA, respectively. Lentiviral vector treatment caused significant induction of interferon (IFN)-γ responses regardless of the transgene; however, further specific effects were directly attributable to the BiP transgene. In both studies Lenti-mBiP suppressed clinical arthritis significantly. Histological examination showed that low-dose Lenti-mBiP suppressed inflammatory cell infiltration, cartilage destruction and significantly reduced pathogenic anti-type II collagen (CII) antibodies. Lenti-mBiP treatment caused significant up-regulation of soluble cytotoxic T lymphocyte antigen-4 (sCTLA-4) serum levels and down-regulation of interleukin (IL)-17A production in response to CII cell restimulation. In-vitro studies confirmed that Lenti-mBiP spleen cells could significantly suppress the release of IL-17A from CII primed responder cells following CII restimulation in vitro, and this suppression was associated with increased IL-10 production. Neutralization of CTLA-4 in further co-culture experiments demonstrated inverse regulation of IL-17A production. In conclusion, these data demonstrate proof of principle for the therapeutic potential of systemic lentiviral vector delivery of the BiP transgene leading to immunoregulation of arthritis by induction of soluble CTLA-4 and suppression of IL-17A production.
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A New-Age for Biologic Therapies: Long-Term Drug-Free Therapy with BiP?
Frontiers in immunology, 2012Co-Authors: Adrian M. Shields, Gabriel S. Panayi, Valerie CorrigallAbstract:Heat shock Proteins (HSPs) and other members of the much broader stress Protein family have been shown to play important roles in coordinating multiple phases of immunological reactions; from facilitating immunological recognition, to promoting and regulating immunological responses and finally augmenting the resolution of inflammation and return to immunological homeostasis. In this review, we consider the challenges facing the stress Protein field as we enter 2012; in particular we consider the role that HSPs and stress Proteins may play in the initiation and termination of immunological responses. Special attention is afforded to the resolution-associated molecular pattern, Binding Immunoglobulin Protein (BiP, also known as glucose regulated Protein-78). We review the evidence that resolution-promoting Proteins such as BiP may herald a new generation of biologics for inflammatory disease and reflect on the challenges of achieving clinical remission in rheumatoid arthritis with novel therapeutics and correlating clinical remission with immunological parameters of resolution of inflammation.
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Pro-resolution immunological networks: Binding Immunoglobulin Protein and other resolution-associated molecular patterns
Rheumatology (Oxford England), 2011Co-Authors: Adrian M. Shields, Stephen J. Thompson, Gabriel S. Panayi, Valerie CorrigallAbstract:Appropriate regulation and subsequent resolution of acute inflammatory events is critical to the prevention of autoinflammatory diseases. Indeed, the chronic inflammation observed in diseases such as RA is at least partially consequent on the failure of endogenous immunoregulation. Current RA therapies (e.g. anti-TNF-a inhibitors and MTX) inhibit components of the inflammatory disease process without directly promoting the resolution of inflammation. We propose that the next generation of RA therapeutics will complement and augment endogenous immunoregulatory and pro-resolution immunological networks, thus promoting the definitive resolution of inflammation rather than temporary immunological control. Of particular interest with respect to this therapeutic approach is Binding Immunoglobulin Protein [BiP; also known as glucose-regulated Protein-78 (GRP78)], a member of the recently defined resolution-associated molecular pattern (RAMP) family of molecules. In this review, we consider the preclinical evidence from experiments in mouse and man that suggests BiP and other members of the RAMP family have the potential to herald a new generation of immunotherapeutics.
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Binding Immunoglobulin Protein resolves rheumatoid synovitis: a xenogeneic study using rheumatoid arthritis synovial membrane transplants in SCID mice
Arthritis research & therapy, 2011Co-Authors: Kaoru Yoshida, Gabriel S. Panayi, Akira Ochiai, Hiroaki Matsuno, Valerie CorrigallAbstract:Introduction: Binding Immunoglobulin Protein (BiP) has previously shown powerful anti-inflammatory properties in the collagen-induced arthritis (CIA) model, where a single dose of BiP has proved to be both a long-term prophylactic and therapeutic. In both CIA and human in vitro studies, BiP induced regulatory T cells. The present investigation looked at the anti-inflammatory effect of BiP on inflamed human synovial tissue transplanted into severe combined immunodeficient mice (SCID), a chimaeric in vivo model previously used to test the efficacy of biologic therapies. Methods: Rheumatoid arthritis synovial membrane (RASM) was engrafted into SCID mice. Following successful engraftment, mice were intravenously injected with BiP or human serum albumin in the presence or absence of anti-IL-10 mAb. Twelve days later the grafts were removed for analysis and human cytokines in the sera were quantified by ELISA. The extent of residual inflammatory cellular infiltrate in the synovial explants was determined by weight of the explants. Results: The RASM transplants from mice treated with BiP showed visual reduction in cellular infiltrate and downregulation of all quantifiable features of inflammation as assessed by the Koizumi or Rooney histological criteria. Also downregulated were HLA-DR, CD86, IL-6 and TNFa expression as assessed by immunohistology. ELISA detected significantly less human IL-6 circulating in the BiP-treated mouse serum. After removal of transplanted tissue 12 days post administration of BiP, the RASM explants from the BiP-treated SCID mice weighed significantly less, indicating a suppression of tissue inflammation. Mice given concomitant neutralising anti-IL-10 antibody and BiP showed no such suppression. Conclusions: BiP has anti-inflammatory properties partially dependent on the downregulation of HLA-DR and costimulatory molecules and the predominant production of IL-10.
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Resolution‐associated molecular patterns (RAMP): RAMParts defending immunological homeostasis?
Clinical & Experimental Immunology, 2011Co-Authors: Adrian M. Shields, Gabriel S. Panayi, Valerie CorrigallAbstract:The resolution of inflammation is central to the maintenance of good health and immune homeostasis. Recently, several intracellular stress Proteins have been described as having extracellular properties that are anti-inflammatory or favour the resolution of inflammation. We propose that these molecules should be defined as resolution-associated molecular patterns (RAMPs). RAMPs are released at times of cellular stress and help to counterbalance the inflammatory effects of pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns. We propose that heat shock Protein 10 (HSP10), αB-crystallin (αBC), HSP27 and Binding Immunoglobulin Protein (BiP) should be considered founding members of the RAMP family. A greater understanding of RAMP biology may herald the development of novel immunotherapies.
Gabriel S. Panayi - One of the best experts on this subject based on the ideXlab platform.
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Safety and patient response as indicated by biomarker changes to Binding Immunoglobulin Protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis
Rheumatology (Oxford England), 2016Co-Authors: Bruce Kirkham, Christopher Hall, Khaldoun Chaabo, Toby Garrood, Timothy Mant, Elizabeth Allen, Alexandra Vincent, Joana C. Vasconcelos, A T Prevost, Gabriel S. PanayiAbstract:Objectives Binding Immunoglobulin Protein (BiP) is a human endoplasmic reticulum-resident stress Protein. In pre-clinical studies it has anti-inflammatory properties due to the induction of regulatory cells. This randomized placebo-controlled, dose ascending double blind phase I/IIA trial of BiP in patients with active RA, who had failed accepted therapies, had the primary objective of safety. Potential efficacy was measured by DAS28-ESR and changes in biomarkers. Methods Twenty-four patients with active RA who had failed one or more DMARDs were sequentially assigned to three groups each of eight patients randomly allocated to receive placebo (two patients) or BiP (six patients), 1, 5 or 15 mg. Patients received a single i.v. infusion over 1 h and were observed as inpatients overnight. A 12-week follow-up for clinical, rheumatological and laboratory assessments for safety, efficacy (DAS28-ESR) and biomarker analysis was performed. Results No infusion reactions or serious adverse drug reactions were noted. Adverse events were evenly distributed between placebo and BiP groups with no BiP-related toxicities. Haematological, renal and metabolic parameters showed no drug-related toxicities. Remission was only achieved by patients in the 5 and 15 mg groups, and not patients who received placebo or 1 mg BiP. Good DAS28-ESR responses were achieved in all treatment groups. The BiP responding patients showed significantly lower serum concentrations of CRP, 2 weeks post-infusion compared with pre-infusion levels, and of VEGF and IL-8 from the placebo group. Conclusion BiP (⩽15 mg) is safe in patients with active RA. Some patients had clinical and biological improvements in RA activity. BiP merits further study. Trial registration ISRCTN registry, http://isrctn.com, ISRCTN22288225 and EudraCT, https://eudract.ema.europa.eu, 2011-005831-19.
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Systemic gene transfer of Binding Immunoglobulin Protein (BiP) prevents disease progression in murine collagen-induced arthritis
Clinical and experimental immunology, 2015Co-Authors: Adrian M. Shields, Stephen J. Thompson, Gabriel S. Panayi, Linda S. Klavinskis, Michael Antoniou, Paul H. Wooley, Helen L. Collins, Valerie CorrigallAbstract:Summary Recombinant human Binding Immunoglobulin Protein (BiP) has previously demonstrated anti-inflammatory properties in multiple models of inflammatory arthritis. We investigated whether these immunoregulatory properties could be exploited using gene therapy techniques. A single intraperitoneal injection of lentiviral vector containing the murine BiP (Lenti-mBiP) or green fluorescent Protein (Lenti-GFP) transgene was administered in low- or high-dose studies during early arthritis. Disease activity was assessed by visual scoring, histology, serum cytokine and antibody production measured by cell enzyme-linked immunosorbent assay (ELISA) and ELISA, respectively. Lentiviral vector treatment caused significant induction of interferon (IFN)-γ responses regardless of the transgene; however, further specific effects were directly attributable to the BiP transgene. In both studies Lenti-mBiP suppressed clinical arthritis significantly. Histological examination showed that low-dose Lenti-mBiP suppressed inflammatory cell infiltration, cartilage destruction and significantly reduced pathogenic anti-type II collagen (CII) antibodies. Lenti-mBiP treatment caused significant up-regulation of soluble cytotoxic T lymphocyte antigen-4 (sCTLA-4) serum levels and down-regulation of interleukin (IL)-17A production in response to CII cell restimulation. In-vitro studies confirmed that Lenti-mBiP spleen cells could significantly suppress the release of IL-17A from CII primed responder cells following CII restimulation in vitro, and this suppression was associated with increased IL-10 production. Neutralization of CTLA-4 in further co-culture experiments demonstrated inverse regulation of IL-17A production. In conclusion, these data demonstrate proof of principle for the therapeutic potential of systemic lentiviral vector delivery of the BiP transgene leading to immunoregulation of arthritis by induction of soluble CTLA-4 and suppression of IL-17A production.
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A New-Age for Biologic Therapies: Long-Term Drug-Free Therapy with BiP?
Frontiers in immunology, 2012Co-Authors: Adrian M. Shields, Gabriel S. Panayi, Valerie CorrigallAbstract:Heat shock Proteins (HSPs) and other members of the much broader stress Protein family have been shown to play important roles in coordinating multiple phases of immunological reactions; from facilitating immunological recognition, to promoting and regulating immunological responses and finally augmenting the resolution of inflammation and return to immunological homeostasis. In this review, we consider the challenges facing the stress Protein field as we enter 2012; in particular we consider the role that HSPs and stress Proteins may play in the initiation and termination of immunological responses. Special attention is afforded to the resolution-associated molecular pattern, Binding Immunoglobulin Protein (BiP, also known as glucose regulated Protein-78). We review the evidence that resolution-promoting Proteins such as BiP may herald a new generation of biologics for inflammatory disease and reflect on the challenges of achieving clinical remission in rheumatoid arthritis with novel therapeutics and correlating clinical remission with immunological parameters of resolution of inflammation.
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Pro-resolution immunological networks: Binding Immunoglobulin Protein and other resolution-associated molecular patterns
Rheumatology (Oxford England), 2011Co-Authors: Adrian M. Shields, Stephen J. Thompson, Gabriel S. Panayi, Valerie CorrigallAbstract:Appropriate regulation and subsequent resolution of acute inflammatory events is critical to the prevention of autoinflammatory diseases. Indeed, the chronic inflammation observed in diseases such as RA is at least partially consequent on the failure of endogenous immunoregulation. Current RA therapies (e.g. anti-TNF-a inhibitors and MTX) inhibit components of the inflammatory disease process without directly promoting the resolution of inflammation. We propose that the next generation of RA therapeutics will complement and augment endogenous immunoregulatory and pro-resolution immunological networks, thus promoting the definitive resolution of inflammation rather than temporary immunological control. Of particular interest with respect to this therapeutic approach is Binding Immunoglobulin Protein [BiP; also known as glucose-regulated Protein-78 (GRP78)], a member of the recently defined resolution-associated molecular pattern (RAMP) family of molecules. In this review, we consider the preclinical evidence from experiments in mouse and man that suggests BiP and other members of the RAMP family have the potential to herald a new generation of immunotherapeutics.
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Binding Immunoglobulin Protein resolves rheumatoid synovitis: a xenogeneic study using rheumatoid arthritis synovial membrane transplants in SCID mice
Arthritis research & therapy, 2011Co-Authors: Kaoru Yoshida, Gabriel S. Panayi, Akira Ochiai, Hiroaki Matsuno, Valerie CorrigallAbstract:Introduction: Binding Immunoglobulin Protein (BiP) has previously shown powerful anti-inflammatory properties in the collagen-induced arthritis (CIA) model, where a single dose of BiP has proved to be both a long-term prophylactic and therapeutic. In both CIA and human in vitro studies, BiP induced regulatory T cells. The present investigation looked at the anti-inflammatory effect of BiP on inflamed human synovial tissue transplanted into severe combined immunodeficient mice (SCID), a chimaeric in vivo model previously used to test the efficacy of biologic therapies. Methods: Rheumatoid arthritis synovial membrane (RASM) was engrafted into SCID mice. Following successful engraftment, mice were intravenously injected with BiP or human serum albumin in the presence or absence of anti-IL-10 mAb. Twelve days later the grafts were removed for analysis and human cytokines in the sera were quantified by ELISA. The extent of residual inflammatory cellular infiltrate in the synovial explants was determined by weight of the explants. Results: The RASM transplants from mice treated with BiP showed visual reduction in cellular infiltrate and downregulation of all quantifiable features of inflammation as assessed by the Koizumi or Rooney histological criteria. Also downregulated were HLA-DR, CD86, IL-6 and TNFa expression as assessed by immunohistology. ELISA detected significantly less human IL-6 circulating in the BiP-treated mouse serum. After removal of transplanted tissue 12 days post administration of BiP, the RASM explants from the BiP-treated SCID mice weighed significantly less, indicating a suppression of tissue inflammation. Mice given concomitant neutralising anti-IL-10 antibody and BiP showed no such suppression. Conclusions: BiP has anti-inflammatory properties partially dependent on the downregulation of HLA-DR and costimulatory molecules and the predominant production of IL-10.
Tomohiko Aoe - One of the best experts on this subject based on the ideXlab platform.
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Conflicting Actions of Inhalational Anesthetics, Neurotoxicity and Neuroprotection, Mediated by the Unfolded Protein Response.
International journal of molecular sciences, 2020Co-Authors: Hiroshi Kokubun, Hisayo Jin, Mari Komita, Tomohiko AoeAbstract:Preclinical studies have shown that exposure of the developing brain to inhalational anesthetics can cause neurotoxicity. However, other studies have claimed that anesthetics can exert neuroprotective effects. We investigated the mechanisms associated with the neurotoxic and neuroprotective effects exerted by inhalational anesthetics. Neuroblastoma cells were exposed to sevoflurane and then cultured in 1% oxygen. We evaluated the expression of Proteins related to the unfolded Protein response (UPR). Next, we exposed adult mice in which Binding Immunoglobulin Protein (BiP) had been mutated, and wild-type mice, to sevoflurane, and evaluated their cognitive function. We compared our results to those from our previous study in which mice were exposed to sevoflurane at the fetal stage. Pre-exposure to sevoflurane reduced the expression of CHOP in neuroblastoma cells exposed to hypoxia. Anesthetic pre-exposure also significantly improved the cognitive function of adult wild-type mice, but not the mutant mice. In contrast, mice exposed to anesthetics during the fetal stage showed cognitive impairment. Our data indicate that exposure to inhalational anesthetics causes endoplasmic reticulum (ER) stress, and subsequently leads to an adaptive response, the UPR. This response may enhance the capacity of cells to adapt to injuries and improve neuronal function in adult mice, but not in developing mice.
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Late-onset of spinal neurodegeneration in knock-in mice expressing a mutant BiP.
PloS one, 2014Co-Authors: Hisayo Jin, Naoya Mimura, Makiko Kashio, Haruhiko Koseki, Tomohiko AoeAbstract:Most human neurodegenerative diseases are sporadic, and appear later in life. While the underlying mechanisms of the progression of those diseases are still unclear, investigations into the familial forms of comparable diseases suggest that endoplasmic reticulum (ER) stress is involved in the pathogenesis. Binding Immunoglobulin Protein (BiP) is an ER chaperone that is central to ER function. We produced knock-in mice expressing a mutant BiP that lacked the retrieval sequence in order to evaluate the effect of a functional defect in an ER chaperone in multi-cellular organisms. Here we report that heterozygous mutant BiP mice revealed motor disabilities in aging. We found a degeneration of some motoneurons in the spinal cord accompanied by accumulations of ubiquitinated Proteins. The defect in retrieval of BiP by the KDEL receptor leads to impaired activities in quality control and autophagy, suggesting that functional defects in the ER chaperones may contribute to the late onset of neurodegenerative diseases.
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Endoplasmic reticulum stress and opioid tolerance withdrawal
Masui. The Japanese journal of anesthesiology, 2013Co-Authors: Tomohiko AoeAbstract:Morphine is a potent analgesic, but its molecular mechanism for tolerance formation is not fully understood. Binding Immunoglobulin Protein (BiP) is an endoplasmic reticulum (ER) chaperone that is central to ER functions. We examined knock-in mice expressing a mutant BiP with the retrieval sequence deleted in order to elucidate physiological BiP functions. We tested thermal antinociceptive effects of morphine on heterozygous mutant BiP mice by a hot plate test. Repeated morphine administration caused the development of morphine tolerance in the wild-type mice. The activation of glycogen synthase kinase 3beta (GSK3beta) was associated with morphine tolerance, since an inhibitor of GSK3beta prevented it. On the other hand, the mutant BiP mice showed less morphine tolerance, and the activation of GSK3beta was suppressed in their brain. These results suggest that BiP may play an important role in the development of morphine tolerance. Furthermore, we found that a chemical chaperone that improves ER Protein folding capacity also attenuated the development of morphine tolerance in wild-type mice, suggesting a possible clinical application of chemical chaperones in preventing morphine tolerance.
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BiP, an endoplasmic reticulum chaperone, modulates the development of morphine antinociceptive tolerance.
Journal of cellular and molecular medicine, 2010Co-Authors: Tamae Dobashi, Hisayo Jin, Naoya Mimura, Serabi Tanabe, Tatsuo Yamamoto, Takashi Nishino, Tomohiko AoeAbstract:Morphine is a potent analgesic, but the molecular mechanism for tolerance formation after repeated use is not fully understood. Binding Immunoglobulin Protein (BiP) is an endoplasmic reticulum (ER) chaperone that is central to ER function. We examined knock-in mice expressing a mutant BiP with the retrieval sequence deleted in order to elucidate physiological processes that are sensitive to BiP functions. We tested the thermal antinociceptive effect of morphine in heterozygous mutant BiP mice in a hot plate test. Paw withdrawal latencies before and after a single administration of morphine were not significantly different between the wild-type and mutant BiP mice. Repeated morphine administration caused the development of morphine tolerance in the wild-type mice. The activation of glycogen synthase kinase 3b (GSK-3b) was associated with morphine tolerance, because an inhibitor of GSK-3β prevented it. On the other hand, the mutant BiP mice showed less morphine tolerance, and the activation of GSK-3b was suppressed in their brain. These results suggest that BiP may play an important role in the development of morphine tolerance. Furthermore, we found that a chemical chaperone which improves ER Protein folding capacity also attenuated the development of morphine tolerance in wild-type mice, suggesting a possible clinical application of chemical chaperones in preventing morphine tolerance.
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Altered quality control in the endoplasmic reticulum causes cortical dysplasia in knock-in mice expressing a mutant BiP.
Molecular and cellular biology, 2007Co-Authors: Naoya Mimura, Hisayo Jin, Haruhiko Koseki, Keita Kimura, Shigemasa Goto, Shigeki Yuasa, Miho Soma, Tomohiko AoeAbstract:Binding Immunoglobulin Protein (BiP) is an endoplasmic reticulum (ER) molecular chaperone that is central to ER function. We examined knock-in mice expressing a mutant BiP in order to elucidate physiological processes that are sensitive to BiP functions during development and adulthood. The mutant BiP lacked the retrieval sequence that normally functions to return BiP to the ER from the secretory pathway. This allowed us to examine the effects of a defect in ER function without completely eliminating BiP function. The homozygous mutant BiP neonates died after birth due to respiratory failure. Besides that, the mutant BiP mice displayed disordered layer formation in the cerebral cortex and cerebellum, a neurological phenotype of reeler mutant-like malformation. Consistent with the phenotype, Cajal-Retzius (CR) cells did not secrete reelin, and the expression of reelin was markedly reduced posttranscriptionally. Furthermore, the reduction in the size of the whole brain and the apparent scattering of CR cells throughout the cortex, which were distinct from the reeler phenotype, were also seen. These findings suggest that the maturation and secretion of reelin in CR cells and other factors related to neural migration may be sensitive to aberrant ER quality control, which may cause various neurological disorders.
Jose Luis Ortegaroldan - One of the best experts on this subject based on the ideXlab platform.
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characterization of the human sigma 1 receptor chaperone domain structure and Binding Immunoglobulin Protein bip interactions
Journal of Biological Chemistry, 2013Co-Authors: Jose Luis Ortegaroldan, Felipe Ossa, Jason R SchnellAbstract:Abstract The sigma-1 receptor (S1R) is a ligand-regulated membrane Protein chaperone involved in the ER stress response. S1R activity is implicated in diseases of the central nervous system including amnesia, schizophrenia, depression, Alzheimer disease, and addiction. S1R has been shown previously to regulate the Hsp70 Binding Immunoglobulin Protein (BiP) and the inositol triphosphate receptor calcium channel through a C-terminal domain. We have developed methods for bacterial expression and reconstitution of the chaperone domain of human S1R into detergent micelles that enable its study by solution NMR spectroscopy. The chaperone domain is found to contain a helix at the N terminus followed by a largely dynamic region and a structured, helical C-terminal region that encompasses a membrane associated domain containing four helices. The helical region at residues ∼198–206 is strongly amphipathic and proposed to anchor the chaperone domain to micelles and membranes. Three of the helices in the C-terminal region closely correspond to previously identified cholesterol and drug recognition sites. In addition, it is shown that the chaperone domain interacts with full-length BiP or the isolated nucleotide Binding domain of BiP, but not the substrate Binding domain, suggesting that the nucleotide Binding domain is sufficient for S1R interactions.
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characterization of the human sigma 1 receptor chaperone domain structure and Binding Immunoglobulin Protein bip interactions
Journal of Biological Chemistry, 2013Co-Authors: Jose Luis Ortegaroldan, Felipe Ossa, Jason R SchnellAbstract:The sigma-1 receptor (S1R) is a ligand-regulated membrane Protein chaperone involved in the ER stress response. S1R activity is implicated in diseases of the central nervous system including amnesia, schizophrenia, depression, Alzheimer disease, and addiction. S1R has been shown previously to regulate the Hsp70 Binding Immunoglobulin Protein (BiP) and the inositol triphosphate receptor calcium channel through a C-terminal domain. We have developed methods for bacterial expression and reconstitution of the chaperone domain of human S1R into detergent micelles that enable its study by solution NMR spectroscopy. The chaperone domain is found to contain a helix at the N terminus followed by a largely dynamic region and a structured, helical C-terminal region that encompasses a membrane associated domain containing four helices. The helical region at residues ∼198–206 is strongly amphipathic and proposed to anchor the chaperone domain to micelles and membranes. Three of the helices in the C-terminal region closely correspond to previously identified cholesterol and drug recognition sites. In addition, it is shown that the chaperone domain interacts with full-length BiP or the isolated nucleotide Binding domain of BiP, but not the substrate Binding domain, suggesting that the nucleotide Binding domain is sufficient for S1R interactions. Background: Sigma-1 receptor is a ligand-regulated membrane Protein chaperone involved in BiP regulation and the ER stress response. Results: The chaperone domain of human sigma-1 receptor is mostly helical with short extended regions. Conclusion: Regions of the sigma-1 receptor chaperone domain implicated in ligand and cholesterol Binding can be mapped to separate helices. Significance: A structural framework for delineating sigma-1 receptor BiP and ligand interactions is presented.