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The Journal of Physiology Jun 2016Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are contact sites between the ER and the PM; the distance between the two organelles in the junctions is below... (Review)
Review
Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are contact sites between the ER and the PM; the distance between the two organelles in the junctions is below 40 nm and the membranes are connected by protein tethers. A number of molecular tools and technical approaches have been recently developed to visualise, modify and characterise properties of ER-PM junctions. The junctions serve as the platforms for lipid exchange between the organelles and for cell signalling, notably Ca(2+) and cAMP signalling. Vice versa, signalling events regulate the development and properties of the junctions. Two Ca(2+) -dependent mechanisms of de novo formation of ER-PM junctions have been recently described and characterised. The junction-forming proteins and lipids are currently the focus of vigorous investigation. Junctions can be relatively short-lived and simple structures, forming and dissolving on the time scale of a few minutes. However, complex, sophisticated and multifunctional ER-PM junctions, capable of attracting numerous protein residents and other cellular organelles, have been described in some cell types. The road from simplicity to complexity, i.e. the transformation from simple 'nascent' ER-PM junctions to advanced stable multiorganellar complexes, is likely to become an attractive research avenue for current and future junctologists. Another area of considerable research interest is the downstream cellular processes that can be activated by specific local signalling events in the ER-PM junctions. Studies of the cell physiology and indeed pathophysiology of ER-PM junctions have already produced some surprising discoveries, likely to expand with advances in our understanding of these remarkable organellar contact sites.
Topics: Animals; Cell Membrane; Endoplasmic Reticulum; Humans; Intercellular Junctions
PubMed: 26939537
DOI: 10.1113/JP271142 -
Expert Review of Gastroenterology &... Sep 2016The accumulation of unfolded protein in the endoplasmic reticulum (ER) initiates an unfolded protein response (UPR) via three signal transduction cascades, which involve... (Review)
Review
INTRODUCTION
The accumulation of unfolded protein in the endoplasmic reticulum (ER) initiates an unfolded protein response (UPR) via three signal transduction cascades, which involve protein kinase RNA-like ER kinase (PERK), inositol requiring enzyme-1α (IRE1α) and activating transcription factor-6α (ATF6α). An ER stress response is observed in nearly all physiologies related to acute and chronic liver disease and therapeutic targeting of the mechanisms implicated in UPR signaling have attracted considerable attention.
AREAS COVERED
This review focuses on the correlation between ER stress and liver disease and the possible targets which may drive the potential for novel therapeutic intervention. Expert Commentary: We describe pathways which are involved in UPR signaling and their potential correlation with various liver diseases and underlying mechanisms which may present opportunities for novel therapeutic strategies are discussed.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Liver Diseases; Molecular Targeted Therapy; Signal Transduction; Unfolded Protein Response
PubMed: 27093595
DOI: 10.1080/17474124.2016.1179575 -
Reviews in the Neurosciences 2012The endoplasmic reticulum (ER), an important cellular organelle in eukaryotic cells, becomes dysfunctional following exposure to harmful stimuli. These stimuli can cause... (Review)
Review
The endoplasmic reticulum (ER), an important cellular organelle in eukaryotic cells, becomes dysfunctional following exposure to harmful stimuli. These stimuli can cause the ER stress response, which induces cell apoptosis due to changes in ER protein levels such as glucose-regulated protein. Current studies indicate that ER stress is closely related to the occurrence and development of neurodegenerative disorders, e.g., prion diseases. The pathogenic agent known as the misfolded prion protein may cause an imbalance in ER homeostasis and commit the neuron to a pathway of apoptosis; however, the specific mechanisms are still under intensive investigation. This review summarizes current research investigating the relationship between ER stress and prion diseases. These findings will aid in the development of novel strategies for diagnosis and therapies for prion and other neurodegenerative diseases.
Topics: Animals; Apoptosis; Endoplasmic Reticulum; Humans; Prion Diseases; Stress, Physiological
PubMed: 22718614
DOI: 10.1515/rns.2011.062 -
Experimental Diabetes Research 2012The endoplasmic reticulum (ER) is an organelle entrusted with lipid synthesis, calcium homeostasis, protein folding, and maturation. Perturbation of ER-associated... (Review)
Review
The endoplasmic reticulum (ER) is an organelle entrusted with lipid synthesis, calcium homeostasis, protein folding, and maturation. Perturbation of ER-associated functions results in an evolutionarily conserved cell stress response, the unfolded protein response (UPR) that is also called ER stress. ER stress is aimed initially at compensating for damage but can eventually trigger cell death if ER stress is excessive or prolonged. Now the ER stress has been associated with numerous diseases. For instance, our recent studies have demonstrated the important role of ER stress in diabetes-induced cardiac cell death. It is known that apoptosis has been considered to play a critical role in diabetic cardiomyopathy. Therefore, this paper will summarize the information from the literature and our own studies to focus on the pathological role of ER stress in the development of diabetic cardiomyopathy. Improved understanding of the molecular mechanisms underlying UPR activation and ER-initiated apoptosis in diabetic cardiomyopathy will provide us with new targets for drug discovery and therapeutic intervention.
Topics: Animals; Diabetic Cardiomyopathies; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Heart; Homeostasis; Humans; Models, Biological; Myocardium; Unfolded Protein Response
PubMed: 22144992
DOI: 10.1155/2012/827971 -
The FEBS Journal Jan 2020The endoplasmic reticulum (ER) is a multifunctional organelle that constitutes the entry into the secretory pathway. The ER contributes to the maintenance of cellular... (Review)
Review
The endoplasmic reticulum (ER) is a multifunctional organelle that constitutes the entry into the secretory pathway. The ER contributes to the maintenance of cellular calcium homeostasis, lipid synthesis and productive secretory, and transmembrane protein folding. Physiological, chemical, and pathological factors that compromise ER homeostasis lead to endoplasmic reticulum stress (ER stress). To cope with this situation, cells activate an adaptive signaling pathway termed the unfolded protein response (UPR) that aims at restoring ER homeostasis. The UPR is transduced through post-translational, translational, post-transcriptional, and transcriptional mechanisms initiated by three ER-resident sensors, inositol-requiring protein 1α, activating transcription factor 6α, and PRKR-like endoplasmic reticulum kinase. Determining the in and out of ER homeostasis control and UPR activation still represents a challenge for the community. Hence, standardized criteria and methodologies need to be proposed for monitoring ER homeostasis and ER stress in different model systems. Here, we summarize the pathways that are activated during ER stress and provide approaches aimed at assess ER homeostasis and stress in vitro and in vivo mammalian systems that can be used by researchers to plan and interpret experiments. We recommend the use of multiple assays to verify ER stress because no individual assay is guaranteed to be the most appropriate one.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Humans; Signal Transduction; Unfolded Protein Response
PubMed: 31647176
DOI: 10.1111/febs.15107 -
Intertwined and Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, and Diseases.Cells Sep 2021The endoplasmic reticulum (ER) is an organelle that is responsible for many essential subcellular processes. Interconnected narrow tubules at the periphery and thicker... (Review)
Review
The endoplasmic reticulum (ER) is an organelle that is responsible for many essential subcellular processes. Interconnected narrow tubules at the periphery and thicker sheet-like regions in the perinuclear region are linked to the nuclear envelope. It is becoming apparent that the complex morphology and dynamics of the ER are linked to its function. Mutations in the proteins involved in regulating ER structure and movement are implicated in many diseases including neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS). The ER is also hijacked by pathogens to promote their replication. Bacteria such as and as well as the Zika virus, bind to ER morphology and dynamics-regulating proteins to exploit the functions of the ER to their advantage. This review covers our understanding of ER morphology, including the functional subdomains and membrane contact sites that the organelle forms. We also focus on ER dynamics and the current efforts to quantify ER motion and discuss the diseases related to ER morphology and dynamics.
Topics: Animals; Cytoskeleton; Endoplasmic Reticulum; Humans; Lipids; Membrane Proteins; Microtubules; Mitochondria; Mitochondrial Membranes; Nuclear Envelope; Structure-Activity Relationship
PubMed: 34571990
DOI: 10.3390/cells10092341 -
Canadian Journal of Physiology and... Sep 2012The endoplasmic reticulum has an intricate network of pathways built to deal with the secretory and integral membrane protein synthesis demands of the cell, as well as... (Review)
Review
The endoplasmic reticulum has an intricate network of pathways built to deal with the secretory and integral membrane protein synthesis demands of the cell, as well as adaptive responses set up for the endoplasmic reticulum to rely on when stressed. These pathways are both essential and complex, and because of these 2 factors, several situations can lead to a dysfunctional endoplasmic reticulum and result in a dysfunctional cell with the potential to contribute to the progression of disease. The endoplasmic reticulum has been implicated in several metabolic, neurodegenerative, inflammatory, autoimmune, and renal diseases and disorders, and in particular, cardiovascular diseases. The role of the endoplasmic reticulum in cardiovascular disease shows how the change in function of a particular microscopic organelle can lead to macroscopic changes in the form of disease.
Topics: Animals; Apoptosis; Autophagy; Benzimidazoles; Benzoates; Cardiovascular Diseases; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Heart; Humans; Organogenesis; Solanaceous Alkaloids; Telmisartan; Treatment Outcome; Unfolded Protein Response
PubMed: 22897133
DOI: 10.1139/y2012-058 -
Cellular & Molecular Biology Letters 2006Cell death is an essential event in normal life and development, as well as in the pathophysiological processes that lead to disease. It has become clear that each of... (Review)
Review
Cell death is an essential event in normal life and development, as well as in the pathophysiological processes that lead to disease. It has become clear that each of the main cellular organelles can participate in cell death signalling pathways, and recent advances have highlighted the importance of the endoplasmic reticulum (ER) in cell death processes. In cells, the ER functions as the organelle where proteins mature, and as such, is very responsive to extracellular-intracellular changes of environment. This short overview focuses on the known pathways of programmed cell death triggering from or involving the ER.
Topics: Animals; Apoptosis; Endoplasmic Reticulum; Humans; Oxidative Stress; Protein Folding; Signal Transduction
PubMed: 16977377
DOI: 10.2478/s11658-006-0040-4 -
Synapse (New York, N.Y.) Jun 2021Alzheimer's disease (AD) is the leading cause of dementia and is incurable. The widely accepted amyloid hypothesis failed to produce efficient clinical therapies. In... (Review)
Review
Alzheimer's disease (AD) is the leading cause of dementia and is incurable. The widely accepted amyloid hypothesis failed to produce efficient clinical therapies. In contrast, there is increasing evidence suggesting that the disruption of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) is a critical upstream event of AD pathogenesis. Here, we review MAM's role in some AD symptoms such as plaque formation, tau hyperphosphorylation, synaptic loss, aberrant lipid synthesis, disturbed calcium homeostasis, and abnormal autophagy. At last, we proposed that MAM plays a central role in familial AD (FAD) and sporadic AD (SAD).
Topics: Alzheimer Disease; Endoplasmic Reticulum; Humans; Mitochondria
PubMed: 33559220
DOI: 10.1002/syn.22196 -
Antioxidants & Redox Signaling Oct 2018Properly controlled intracellular Ca dynamics is crucial for regulation of neuronal function and survival in the central nervous system. The endoplasmic reticulum (ER),... (Review)
Review
SIGNIFICANCE
Properly controlled intracellular Ca dynamics is crucial for regulation of neuronal function and survival in the central nervous system. The endoplasmic reticulum (ER), a major intracellular Ca store, plays a critical role as a source and sink for neuronal Ca. Recent Advances: Accumulating evidence indicates that disrupted ER Ca signaling is involved in neuronal cell death under various pathological conditions, providing novel insight into neurodegenerative disease mechanisms.
CRITICAL ISSUES
We summarize current knowledge concerning the relationship between abnormal ER Ca dynamics and neuronal cell death. We also introduce recent technical advances for probing ER intraluminal Ca dynamics with unprecedented spatiotemporal resolution.
FUTURE DIRECTIONS
Further studies on ER Ca signaling are expected to provide progress for unmet medical needs in neurodegenerative disease. Antioxid. Redox Signal. 29, 1147-1157.
Topics: Animals; Calcium; Calcium Signaling; Cell Death; Endoplasmic Reticulum; Humans; Neurodegenerative Diseases; Neurons
PubMed: 29361832
DOI: 10.1089/ars.2018.7498