scholarly journals Evidence That ITPR2-Mediated Intracellular Calcium Release in Oligodendrocytes Regulates the Development of Carbonic Anhydrase II + Type I/II Oligodendrocytes and the Sizes of Myelin Fibers

2021 ◽  
Vol 15 ◽  
Author(s):  
Ruyi Mei ◽  
Linyu Huang ◽  
Mengyuan Wu ◽  
Chunxia Jiang ◽  
Aifen Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Calcium Release ◽  
Developmental Process ◽  
Small Diameter ◽  
Normal Brain ◽  
Type I ◽  
Release Channel ◽  
Different Types ◽  
Compound Action Potentials ◽  
Intracellular Ca

Myelination of neuronal axons in the central nervous system (CNS) by oligodendrocytes (OLs) enables rapid saltatory conductance and axonal integrity, which are crucial for normal brain functioning. Previous studies suggested that different subtypes of oligodendrocytes in the CNS form different types of myelin determined by the diameter of axons in the unit. However, the molecular mechanisms underlying the developmental association of different types of oligodendrocytes with different fiber sizes remain elusive. In the present study, we present the evidence that the intracellular Ca2+ release channel associated receptor (Itpr2) contributes to this developmental process. During early development, Itpr2 is selectively up-regulated in oligodendrocytes coinciding with the initiation of myelination. Functional analyses in both conventional and conditional Itpr2 mutant mice revealed that Itpr2 deficiency causes a developmental delay of OL differentiation, resulting in an increased percentage of CAII+ type I/II OLs which prefer to myelinate small-diameter axons in the CNS. The increased percentage of small caliber myelinated axons leads to an abnormal compound action potentials (CAP) in the optic nerves. Together, these findings revealed a previously unrecognized role for Itpr2-mediated calcium signaling in regulating the development of different types of oligodendrocytes.

scholarly journals Regulation of intracellular Ca<sup>2+</sup> concentration and meat quality in pigs

2003 ◽  
Vol 46 (5) ◽  
pp. 445-454
Author(s):  
U. Küchenmeister ◽  
G. Kuhn
Keyword(s):  
Energy Metabolism ◽  
Meat Quality ◽  
Calcium Release ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Cellular Processes ◽  
Wide Variability ◽  
Intracellular Ca ◽  
Energy Consuming

Abstract. The meat quality of pigs is essentially dependent on the rate and intensity of energy metabolism after slaughter. The major cellular processes in muscle cells are regulated by the Ca2+ concentration in the cytoplasm, stimulating different energy consuming ATPases. The most essential regulator of the Ca2+ concentration is the sarcoplasmic reticulum (SR) with its membranes, the SR Ca2+ ATPase (Ca2+ pump), and the calcium release channel (CRC). Defects of one or more of these elements will be of influence on the metabolism and ultimately on the meat quality. This is widely investigated in pigs with a mutated CRC. However, pigs without a mutation in the CRC also show a wide variability in their meat quality, dependent on other factors e.g. stress or season of the year. The variability in meat quality in these "normal" pigs is at least partly a result of differences in SR Ca2+ transport and the resulting metabolism.

A model of graded calcium release and L-type Ca2+ channel inactivation in cardiac muscle

2004 ◽  
Vol 286 (3) ◽  
pp. H1154-H1169 ◽  
Author(s):  
Vladimir E. Bondarenko ◽  
Glenna C. L. Bett ◽  
Randall L. Rasmusson
Keyword(s):  
Molecular Mechanisms ◽  
Calcium Release ◽  
Ventricular Myocytes ◽  
Ryanodine Receptors ◽  
Quantitative Description ◽  
Channel Current ◽  
Channel Inactivation ◽  
Transmembrane Voltage ◽  
Intracellular Ca ◽  
Junctional Sarcoplasmic Reticulum

We have developed a model of Ca2+ handling in ferret ventricular myocytes. This model includes a novel L-type Ca2+ channel, detailed intracellular Ca2+ movements, and graded Ca2+-induced Ca2+ release (CICR). The model successfully reproduces data from voltage-clamp experiments, including voltage- and time-dependent changes in intracellular Ca2+ concentration ([Ca2+]i), L-type Ca2+ channel current ( ICaL) inactivation and recovery kinetics, and Ca2+ sparks. The development of graded CICR is critically dependent on spatial heterogeneity and the physical arrangement of calcium channels in opposition to ryanodine-sensitive release channels. The model contains spatially distinct subsystems representing the subsarcolemmal regions where the junctional sarcoplasmic reticulum (SR) abuts the T-tubular membrane and where the L-type Ca2+ channels and SR ryanodine receptors (RyRs) are localized. There are eight different types of subsystems in our model, with between one and eight L-type Ca2+ channels distributed binomially. This model exhibits graded CICR and provides a quantitative description of Ca2+ dynamics not requiring Monte-Carlo simulations. Activation of RyRs and release of Ca2+ from the SR depend critically on Ca2+ entry through L-type Ca2+ channels. In turn, Ca2+ channel inactivation is critically dependent on the release of stored intracellular Ca2+. Inactivation of ICaL depends on both transmembrane voltage and local [Ca2+]i near the channel, which results in distinctive inactivation properties. The molecular mechanisms underlying many ICaL gating properties are unclear, but [Ca2+]i dynamics clearly play a fundamental role.

scholarly journals Phosphorylation-Dependent Interactome of Ryanodine Receptor Type 2 in the Heart

Proteomes ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 27
Author(s):  
David Y. Chiang ◽  
Satadru Lahiri ◽  
Guoliang Wang ◽  
Jason Karch ◽  
Meng C. Wang ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
Affinity Purification ◽  
Receptor Type ◽  
Mouse Heart ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Western Blots

Hyperphosphorylation of the calcium release channel/ryanodine receptor type 2 (RyR2) at serine 2814 (S2814) is associated with multiple cardiac diseases including atrial fibrillation and heart failure. Despite recent advances, the molecular mechanisms driving pathological changes associated with RyR2 S2814 phosphorylation are still not well understood. Methods: Using affinity-purification coupled to mass spectrometry (AP-MS), we investigated the RyR2 interactome in ventricles from wild-type (WT) mice and two S2814 knock-in mutants: the unphosphorylated alanine mutant (S2814A) and hyperphosphorylated mimic aspartic acid mutant (S2814D). Western blots were used for validation. Results: In WT mouse ventricular lysates, we identified 22 proteins which were enriched with RyR2 pull-down relative to both IgG control and no antibody (beads-only) pull-downs. Parallel AP-MS using WT, S2814A, and S2814D mouse ventricles identified 72 proteins, with 20 being high confidence RyR2 interactors. Of these, 14 had an increase in their binding to RyR2 S2814A but a decrease in their binding to RyR2 S2814D. We independently validated three protein hits, Idh3b, Aifm1, and Cpt1b, as RyR2 interactors by western blots and showed that Aifm1 and Idh3b had significantly decreased binding to RyR2 S2814D compared to WT and S2814A, consistent with MS findings. Conclusion: By applying state-of-the-art proteomic approaches, we discovered a number of novel RyR2 interactors in the mouse heart. In addition, we found and defined specific alterations in the RyR2 interactome that were dependent on the phosphorylation status of RyR2 at S2814. These findings yield mechanistic insights into RyR2 regulation which may guide future drug designs.

scholarly journals David Herman Maclennan. 3 July 1937—24 June 2020

2021 ◽  
Author(s):  
Reinhart Reithmeier
Keyword(s):  
Muscle Contraction ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
New Technologies ◽  
Muscle Disease ◽  
Mitochondrial Atpase ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Isolation And Characterization ◽  
The University

David Herman MacLennan, one of Canada's foremost biomedical scientists, was known internationally for his research on the molecular mechanism of muscle contraction in human health and disease. David was born on 3 July 1937 in Swan River, Manitoba, and grew up in farm country. After obtaining a BS (Agriculture) in plant science from the University of Manitoba in 1959, David completed his MSc (1961) and PhD (1963) in biology at Purdue. A post-doctoral fellowship at the Enzyme Institute at the University of Wisconsin followed, where he was appointed as an assistant professor (1964–1968). At Wisconsin David published a series of elegant papers on the isolation and characterization of the mitochondrial ATPase and protein components of the electron transfer system. In 1969 he was recruited back to Canada as an associate professor in the Banting and Best Department of Medical Research at the University of Toronto, where he spent the rest of his illustrious career. Here, David shifted his focus to determine how calcium regulates muscle contraction, with a focus on the role of the sarcoplasmic reticulum (SR). David was a scientist who knew where a field was going and he often got there first, incorporating new technologies along the way. His early discovery of the Ca 2+ ATPase pump that controls calcium uptake into the SR was the key to muscle relaxation. His lab systematically characterized the components of the SR, including the ryanodine receptor which acts as a calcium release channel to allow muscle contraction. David's discoveries of these molecular mechanisms and their application to debilitating muscle disease are an inspiring scientific legacy. Although David published hundreds of papers, many cited hundreds of times, gave hundreds of invited seminars and won many prestigious awards, including Fellow of the Royal Society of London in 1994, his greatest legacy is the people he trained, many of whom went on to leadership positions in research and at universities around the world.

Sarcoplasmic reticulum calcium leak and cardiac arrhythmias

2007 ◽  
Vol 35 (5) ◽  
pp. 952-956 ◽  
Author(s):  
M.G. Chelu ◽  
X.H.T. Wehrens
Keyword(s):  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Arrhythmias ◽  
Ventricular Arrhythmias ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Incomplete Closure ◽  
Sarcoplasmic Reticulum Calcium

Ventricular arrhythmias deteriorating into sudden cardiac death are a major cause of mortality worldwide. The recent linkage of a genetic form of cardiac arrhythmia to mutations in the gene encoding RyR2 (ryanodine receptor 2) has uncovered an important role of this SR (sarcoplasmic reticulum) calcium release channel in triggering arrhythmias. Mutant RyR2 channels give rise to spontaneous release of calcium (Ca2+) from the SR during diastole, which enhances the probability of ventricular arrhythmias. Several molecular mechanisms have been proposed to explain the gain-of-function phenotype observed in mutant RyR2 channels. Despite considerable differences between the models discussed in the present review, each predicts spontaneous diastolic Ca2+ leak from the SR due to incomplete closure of the RyR2 channel. Enhanced SR Ca2+ leak is also observed in common structural diseases of the heart, such as heart failure. In heart failure, defective channel regulation in the absence of inherited mutations may also increase SR Ca2+ leak and initiate cardiac arrhythmias. Therefore inhibition of diastolic Ca2+ leak through SR Ca2+ release channels has emerged as a new and promising therapeutic target for cardiac arrhythmias.

scholarly journals Molecular Mechanism and Current Therapies for Catecholaminergic Polymorphic Ventricular Tachycardia

2021 ◽  
Author(s):  
Bin Liu ◽  
Brian D. Tow ◽  
Ingrid M. Bonilla
Keyword(s):  
Ventricular Tachycardia ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
Heart Diseases ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Release Channel ◽  
Current Therapies ◽  
Cardiac Disorders

The rhythmic contraction of the heart relies on tightly regulated calcium (Ca) release from the sarcoplasmic reticulum (SR) Ca release channel, Ryanodine receptor (RyR2). Genetic mutations in components of the calcium release unit such as RyR2, cardiac calsequestrin and other proteins have been shown to cause a genetic arrhythmic syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT). This book chapter will focus on the following: (1) to describing CPVT as a stress-induced cardiac arrhythmia syndrome and its genetic causes. (2) Discussing the regulation of SR Ca release, and how dysregulation of Ca release contributes to arrhythmogenesis. (3) Discussing molecular mechanisms of CPVT with a focus on impaired Ca signaling refractoriness as a unifying mechanism underlying different genetic forms of CPVT. (4) Discussing pharmacological approaches as CPVT treatments as well as other potential future therapies. Since dysregulated SR Ca release has been implicated in multiple cardiac disorders including heart failure and metabolic heart diseases, knowledge obtained from CPVT studies will also shed light on the development of therapeutic approaches for these devastating cardiac dysfunctions as a whole.

scholarly journals “Ryanopathies” and RyR2 dysfunctions: can we further decipher them using in vitro human disease models?

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Yvonne Sleiman ◽  
Alain Lacampagne ◽  
Albano C. Meli
Keyword(s):  
Intracellular Calcium ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Current Knowledge ◽  
Cell Types ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Cellular Environment ◽  
Intracellular Ca

AbstractThe regulation of intracellular calcium (Ca2+) homeostasis is fundamental to maintain normal functions in many cell types. The ryanodine receptor (RyR), the largest intracellular calcium release channel located on the sarco/endoplasmic reticulum (SR/ER), plays a key role in the intracellular Ca2+ handling. Abnormal type 2 ryanodine receptor (RyR2) function, associated to mutations (ryanopathies) or pathological remodeling, has been reported, not only in cardiac diseases, but also in neuronal and pancreatic disorders. While animal models and in vitro studies provided valuable contributions to our knowledge on RyR2 dysfunctions, the human cell models derived from patients’ cells offer new hope for improving our understanding of human clinical diseases and enrich the development of great medical advances. We here discuss the current knowledge on RyR2 dysfunctions associated with mutations and post-translational remodeling. We then reviewed the novel human cellular technologies allowing the correlation of patient’s genome with their cellular environment and providing approaches for personalized RyR-targeted therapeutics.

Methionine-Specific Staining of Collagen

1982 ◽  
Vol 40 ◽  
pp. 294-295
Author(s):  
E.M. Kuhn ◽  
K.D. Marenus ◽  
M. Beer
Keyword(s):  
Amino Acids ◽  
Collagen Fibers ◽  
Type Iii Collagen ◽  
Type I ◽  
Electron Microscopic ◽  
Good Correspondence ◽  
Specific Staining ◽  
Type Iii ◽  
Different Types ◽  
Sulfur Containing

Fibers composed of different types of collagen cannot be differentiated by conventional electron microscopic stains. We are developing staining procedures aimed at identifying collagen fibers of different types.Pt(Gly-L-Met)Cl binds specifically to sulfur-containing amino acids. Different collagens have methionine (met) residues at somewhat different positions. A good correspondence has been reported between known met positions and Pt(GLM) bands in rat Type I SLS (collagen aggregates in which molecules lie adjacent to each other in exact register). We have confirmed this relationship in Type III collagen SLS (Fig. 1).

Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

2019 ◽  
Vol 14 (3) ◽  
pp. 219-225 ◽  
Author(s):  
Cong Tang ◽  
Guodong Zhu
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transmembrane Receptors ◽  
Biological Responses ◽  
Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

scholarly journals Immunomodulatory Effects of Radiotherapy

2020 ◽  
Vol 21 (21) ◽  
pp. 8151
Author(s):  
Sharda Kumari ◽  
Shibani Mukherjee ◽  
Debapriya Sinha ◽  
Salim Abdisalaam ◽  
Sunil Krishnan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Carbon Particle ◽  
Dna Lesions ◽  
X Rays ◽  
Adaptive Immune ◽  
High Let Radiation ◽  
Different Types ◽  
High Let ◽  
Radiation Induced ◽  
Tumor Death

Radiation therapy (RT), an integral component of curative treatment for many malignancies, can be administered via an increasing array of techniques. In this review, we summarize the properties and application of different types of RT, specifically, conventional therapy with x-rays, stereotactic body RT, and proton and carbon particle therapies. We highlight how low-linear energy transfer (LET) radiation induces simple DNA lesions that are efficiently repaired by cells, whereas high-LET radiation causes complex DNA lesions that are difficult to repair and that ultimately enhance cancer cell killing. Additionally, we discuss the immunogenicity of radiation-induced tumor death, elucidate the molecular mechanisms by which radiation mounts innate and adaptive immune responses and explore strategies by which we can increase the efficacy of these mechanisms. Understanding the mechanisms by which RT modulates immune signaling and the key players involved in modulating the RT-mediated immune response will help to improve therapeutic efficacy and to identify novel immunomodulatory drugs that will benefit cancer patients undergoing targeted RT.

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