Hypoxia. 4. Hypoxia and ion channel function

The ability to sense and respond to oxygen deprivation is required for survival; thus, understanding the mechanisms by which changes in oxygen are linked to cell viability and function is of great importance. Ion channels play a critical role in regulating cell function in a wide variety of biological processes, including neuronal transmission, control of ventilation, cardiac contractility, and control of vasomotor tone. Since the 1988 discovery of oxygen-sensitive potassium channels in chemoreceptors, the effect of hypoxia on an assortment of ion channels has been studied in an array of cell types. In this review, we describe the effects of both acute and sustained hypoxia (continuous and intermittent) on mammalian ion channels in several tissues, the mode of action, and their contribution to diverse cellular processes.

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Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond

Cells ◽

10.3390/cells10102722 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2722

Author(s):

Elena Conte ◽

Paola Imbrici ◽

Paola Mantuano ◽

Maria Coppola ◽

Giulia Maria Camerino ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Function ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Critical Role ◽

Protein A ◽

Cell Types ◽

Muscle Diseases ◽

Cellular Processes ◽

And Function

Intracellular Ca2+ ions represent a signaling mediator that plays a critical role in regulating different muscular cellular processes. Ca2+ homeostasis preservation is essential for maintaining skeletal muscle structure and function. Store-operated Ca2+ entry (SOCE), a Ca2+-entry process activated by depletion of intracellular stores contributing to the regulation of various function in many cell types, is pivotal to ensure a proper Ca2+ homeostasis in muscle fibers. It is coordinated by STIM1, the main Ca2+ sensor located in the sarcoplasmic reticulum, and ORAI1 protein, a Ca2+-permeable channel located on transverse tubules. It is commonly accepted that Ca2+ entry via SOCE has the crucial role in short- and long-term muscle function, regulating and adapting many cellular processes including muscle contractility, postnatal development, myofiber phenotype and plasticity. Lack or mutations of STIM1 and/or Orai1 and the consequent SOCE alteration have been associated with serious consequences for muscle function. Importantly, evidence suggests that SOCE alteration can trigger a change of intracellular Ca2+ signaling in skeletal muscle, participating in the pathogenesis of different progressive muscle diseases such as tubular aggregate myopathy, muscular dystrophy, cachexia, and sarcopenia. This review provides a brief overview of the molecular mechanisms underlying STIM1/Orai1-dependent SOCE in skeletal muscle, focusing on how SOCE alteration could contribute to skeletal muscle wasting disorders and on how SOCE components could represent pharmacological targets with high therapeutic potential.

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Modelling the Human Placental Interface In Vitro—A Review

Micromachines ◽

10.3390/mi12080884 ◽

2021 ◽

Vol 12 (8) ◽

pp. 884

Author(s):

Marta Cherubini ◽

Scott Erickson ◽

Kristina Haase

Keyword(s):

Drug Testing ◽

Cell Types ◽

In Vitro Models ◽

Placental Development ◽

Scientific Challenge ◽

Induced Pluripotent ◽

And Function ◽

And Control

Acting as the primary link between mother and fetus, the placenta is involved in regulating nutrient, oxygen, and waste exchange; thus, healthy placental development is crucial for a successful pregnancy. In line with the increasing demands of the fetus, the placenta evolves throughout pregnancy, making it a particularly difficult organ to study. Research into placental development and dysfunction poses a unique scientific challenge due to ethical constraints and the differences in morphology and function that exist between species. Recently, there have been increased efforts towards generating in vitro models of the human placenta. Advancements in the differentiation of human induced pluripotent stem cells (hiPSCs), microfluidics, and bioprinting have each contributed to the development of new models, which can be designed to closely match physiological in vivo conditions. By including relevant placental cell types and control over the microenvironment, these new in vitro models promise to reveal clues to the pathogenesis of placental dysfunction and facilitate drug testing across the maternal–fetal interface. In this minireview, we aim to highlight current in vitro placental models and their applications in the study of disease and discuss future avenues for these in vitro models.

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CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

Journal of Experimental Medicine ◽

10.1084/jem.20081811 ◽

2009 ◽

Vol 206 (2) ◽

pp. 421-434 ◽

Cited By ~ 160

Author(s):

Randall H. Friedline ◽

David S. Brown ◽

Hai Nguyen ◽

Hardy Kornfeld ◽

JinHee Lee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cell Function ◽

Cytotoxic T Lymphocyte ◽

Critical Role ◽

Lymphoproliferative Disease ◽

In Trans ◽

And Function

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3+ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3+ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3+ regulatory T cell function in vivo.

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Abstract P351: The Post-transcriptional Regulations Of Centrosomal Plp Mrna In Drosophila

Circulation Research ◽

10.1161/res.129.suppl_1.p351 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Junnan Fang

Keyword(s):

Translational Control ◽

Rna Binding ◽

Rna Binding Proteins ◽

Cell Types ◽

Mrna Localization ◽

Rna Localization ◽

Embryonic Lethality ◽

Cellular Processes ◽

Pericentriolar Material ◽

And Function

Centrosomes, functioning as microtubule organizing centers, are composed of a proteinaceous matrix of pericentriolar material (PCM) that surrounds a pair of centrioles. Drosophila Pericentrin (Pcnt)-like protein (PLP) is a key component of the centrosome that serves as a scaffold for PCM assembly. The disruption of plp in Drosophila results in embryonic lethality, while the deregulation of Pcnt in humans is associated with MOPD II and Trisomy 21.We recently found plp mRNA localizes to Drosophila embryonic centrosomes. While RNA is known to associate with centrosomes in diverse cell types, the elements required for plp mRNA localization to centrosomes remains completely unknown. Additionally, how plp translation is regulated to accommodate rapid cell divisions during early embryogenesis is unclear. RNA localization coupled with translational control is a conserved mechanism that functions in diverse cellular processes. Control of mRNA localization and translation is mediated by RNA-binding proteins (RBPs). We find PLP protein expression is specifically promoted by an RNA-binding protein, Orb, during embryogenesis; moreover, plp mRNA interacts with Orb. Importantly, we find overexpression of full-length PLP can rescue cell division defects and embryonic lethality caused by orb depletion. We aim to uncover the mechanisms underlying embryonic plp mRNA localization and function and how Orb regulates plp translation.

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Form and Function in Cells of the Brain

The Neuron ◽

10.1093/med/9780199773893.003.0002 ◽

2015 ◽

pp. 23-38

Author(s):

Irwin B. Levitan ◽

Leonard K. Kaczmarek

Keyword(s):

Axonal Transport ◽

Molecular Motors ◽

Critical Role ◽

Neuronal Cell ◽

Cell Types ◽

Neuronal Cell Body ◽

Long Distance ◽

Form And Function ◽

And Function ◽

The Brain

This chapter examines unique mechanisms that the neuron has evolved to establish and maintain the form required for its specialized signaling functions. Unlike some other organs, the brain contains a variety of cell types including several classes of glial cells, which play a critical role in the formation of the myelin sheath around axons and may be involved in immune responses, synaptic transmission, and long-distance calcium signaling in the brain. Neurons share many features in common with other cells (including glia), but they are distinguished by their highly asymmetrical shapes. The neuronal cytoskeleton is essential for establishing this cell shape during development and for maintaining it in adulthood. The process of axonal transport moves vesicles and other organelles to regions remote from the neuronal cell body. Proteins such as kinesin and dynein, called molecular motors, make use of the energy released by hydrolysis of ATP to drive axonal transport.

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Human Neural Stem Cell Systems to Explore Pathogen-Related Neurodevelopmental and Neurodegenerative Disorders

Cells ◽

10.3390/cells9081893 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1893

Author(s):

Matteo Baggiani ◽

Maria Teresa Dell’Anno ◽

Mauro Pistello ◽

Luciano Conti ◽

Marco Onorati

Keyword(s):

Extended Period ◽

Cell Types ◽

Coxsackie Virus ◽

Long Term Effects ◽

Cellular Processes ◽

Normal Human ◽

Neuronal Lineage ◽

Simplex Virus ◽

And Function ◽

New Evidence

Building and functioning of the human brain requires the precise orchestration and execution of myriad molecular and cellular processes, across a multitude of cell types and over an extended period of time. Dysregulation of these processes affects structure and function of the brain and can lead to neurodevelopmental, neurological, or psychiatric disorders. Multiple environmental stimuli affect neural stem cells (NSCs) at several levels, thus impairing the normal human neurodevelopmental program. In this review article, we will delineate the main mechanisms of infection adopted by several neurotropic pathogens, and the selective NSC vulnerability. In particular, TORCH agents, i.e., Toxoplasma gondii, others (including Zika virus and Coxsackie virus), Rubella virus, Cytomegalovirus, and Herpes simplex virus, will be considered for their devastating effects on NSC self-renewal with the consequent neural progenitor depletion, the cellular substrate of microcephaly. Moreover, new evidence suggests that some of these agents may also affect the NSC progeny, producing long-term effects in the neuronal lineage. This is evident in the paradigmatic example of the neurodegeneration occurring in Alzheimer’s disease.

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Generation of Free Radicals and Messenger Function

Canadian Journal of Applied Physiology ◽

10.1139/h95-021 ◽

1995 ◽

Vol 20 (3) ◽

pp. 280-288 ◽

Cited By ~ 6

Author(s):

John C. Carlson ◽

Masaaki Sawada

Keyword(s):

Free Radicals ◽

Cell Function ◽

Control Cell ◽

Muscle Cells ◽

Cell Types ◽

Signal Pathways ◽

Cellular Processes ◽

Toxic Agents ◽

Intracellular Messengers ◽

Antioxidant Mechanisms

Free radicals are toxic agents that are produced as by-products of metabolic activity. A number of antioxidant mechanisms work to protect cells from damage. Recent evidence indicates, however, that free radicals and related oxidants such as hydrogen peroxide may also have a beneficial role, working as messengers to control cell function. These agents are generated in response to agonists, production is regulated by intracellular signal pathways, and they appear to be used to control particular cellular processes. Free radicals may perform these functions in a number of cell types. Also, they are produced in muscles and there is evidence that they may work as messengers in smooth muscle cells. Key words: phospholipases, intracellular messengers, regulation of function, muscle cells

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The gene coding for secreted phosphoprotein1/osteopontin is the most overexpressed gene in cholangiocarcinoma—detected by oligonucleotide arrays and LightCycler analysis

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10036 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10036-10036

Author(s):

H. G. Hass ◽

J. Jobst ◽

O. Nehls ◽

A. Frilling ◽

J. T. Hartmann ◽

...

Keyword(s):

Cell Function ◽

Immune Cell ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cell Types ◽

Cell Phenotype ◽

Oligonucleotide Arrays ◽

Surface Receptors ◽

Malignant Liver ◽

And Control

10036 Background: Cholangiocarcinomas (CCC) are the second most common primary hepatic malignancy with a still poor prognosis and arise from biliary epithelia or cholangiocytes. Until now, less is known about the molecular pathways leeding to CCC. Methods: Oligonucleotide arrays were used to analyze gene expression profiles of 8 intrahepatic CCCs. After isolation of tRNA and transcription into cDNA, biotin-labelled cRNA probes were hybridized to GeneArrays (Affymetrix U 133A) containing probes of more than 22.000 genes/ESTs. For two-dimensional cluster analysis we used special software programs (Genexplore, GeneSpring). Dysregulated genes were determined by presence in more than 70% and a 2-fold change in relation to the corresponding non-malignant liver tissue. Lightcycler analysis were performed to validate the expression datas of dysregulated genes. Results: A total of 694 dysregulated genes (330 up-/364 down-regulated, compared with corresponding non-malignant tissue) were detected. As the gene with the highest and most consistent upregulation we were able to identify osteopontin (OPN) with an average 5-fold overexpression in all CCC tissues. OPN is an acidic phosphoprotein that is secreted by osteoblasts, macrophages and many other cell types and binds to a variety of cell surface receptors (integrins/CD44). OPN is multifunctional, with activities in cell migration, regulation of bone metabolism, immune cell function and control of tumor cell phenotype. Elevated OPN levels were seen in different tumors but until now no data exist about the expression in CCCs. As one possible interaction in human carcinogenesis, OPN has recently been shown to be a novel substrate for some MMPs, which play an importand role in tumor invasion and metastasis. Conclusions: This is the first report about an overexpression of OPN in CCC and our data indicate an important role in cholangiocarcinogenesis. Further studies are needed to illucidate the moleculargenetic mechanisms of OPN interactions in CCC. No significant financial relationships to disclose.

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TMEM266 is a functional voltage sensor regulated by extracellular Zn2+

eLife ◽

10.7554/elife.42372 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 3

Author(s):

Ferenc Papp ◽

Suvendu Lomash ◽

Orsolya Szilagyi ◽

Erika Babikow ◽

Jaime Smith ◽

...

Keyword(s):

Ion Channels ◽

Unknown Function ◽

Conformational Transition ◽

Voltage Sensor ◽

Structural Rearrangements ◽

Future Studies ◽

Proton Channels ◽

Cellular Processes ◽

Electrical Signaling ◽

And Control

Voltage-activated ion channels contain S1-S4 domains that sense membrane voltage and control opening of ion-selective pores, a mechanism that is crucial for electrical signaling. Related S1-S4 domains have been identified in voltage-sensitive phosphatases and voltage-activated proton channels, both of which lack associated pore domains. hTMEM266 is a protein of unknown function that is predicted to contain an S1-S4 domain, along with partially structured cytoplasmic termini. Here we show that hTMEM266 forms oligomers, undergoes both rapid (µs) and slow (ms) structural rearrangements in response to changes in voltage, and contains a Zn2+ binding site that can regulate the slow conformational transition. Our results demonstrate that the S1-S4 domain in hTMEM266 is a functional voltage sensor, motivating future studies to identify cellular processes that may be regulated by the protein. The ability of hTMEM266 to respond to voltage on the µs timescale may be advantageous for designing new genetically encoded voltage indicators.

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GM-CSF: Orchestrating the Pulmonary Response to Infection

Frontiers in Pharmacology ◽

10.3389/fphar.2021.735443 ◽

2022 ◽

Vol 12 ◽

Author(s):

Thomas S. McCormick ◽

Rana B. Hejal ◽

Luis O. Leal ◽

Mahmoud A. Ghannoum

Keyword(s):

Infectious Diseases ◽

Respiratory Infections ◽

Critical Role ◽

Alveolar Epithelium ◽

Cell Types ◽

Adjunctive Treatment ◽

Gm Csf ◽

Lung Physiology ◽

Pulmonary Immune System ◽

And Function

This review summarizes the structure and function of the alveolar unit, comprised of alveolar macrophage and epithelial cell types that work in tandem to respond to infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) helps to maintain the alveolar epithelium and pulmonary immune system under physiological conditions and plays a critical role in restoring homeostasis under pathologic conditions, including infection. Given the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and global spread of coronavirus disease 2019 (COVID-19), with subsequent acute respiratory distress syndrome, understanding basic lung physiology in infectious diseases is especially warranted. This review summarizes clinical and preclinical data for GM-CSF in respiratory infections, and the rationale for sargramostim (yeast-derived recombinant human [rhu] GM-CSF) as adjunctive treatment for COVID-19 and other pulmonary infectious diseases.

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