scholarly journals The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function

2013 ◽  
Vol 202 (1) ◽  
pp. 71-79 ◽  
Author(s):  
Archana Jha ◽  
Malini Ahuja ◽  
József Maléth ◽  
Claudia M. Moreno ◽  
Joseph P. Yuan ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Cell Damage ◽  
Cell Functions ◽  
Dependent Inactivation ◽  
Dependent Cell ◽  
Inhibitory Domain ◽  
Molecular Components ◽  
Full Activation ◽  
Ca2 Channels

Ca2+ influx by store-operated Ca2+ channels (SOCs) mediates all Ca2+-dependent cell functions, but excess Ca2+ influx is highly toxic. The molecular components of SOC are the pore-forming Orai1 channel and the endoplasmic reticulum Ca2+ sensor STIM1. Slow Ca2+-dependent inactivation (SCDI) of Orai1 guards against cell damage, but its molecular mechanism is unknown. Here, we used homology modeling to identify a conserved STIM1(448–530) C-terminal inhibitory domain (CTID), whose deletion resulted in spontaneous clustering of STIM1 and full activation of Orai1 in the absence of store depletion. CTID regulated SCDI by determining access to and interaction of the STIM1 inhibitor SARAF with STIM1 Orai1 activation region (SOAR), the STIM1 domain that activates Orai1. CTID had two lobes, STIM1(448–490) and STIM1(490–530), with distinct roles in mediating access of SARAF to SOAR. The STIM1(448–490) lobe restricted, whereas the STIM1(490–530) lobe directed, SARAF to SOAR. The two lobes cooperated to determine the features of SCDI. These findings highlight the central role of STIM1 in SCDI and provide a molecular mechanism for SCDI of Orai1.

scholarly journals Caspase-1 Mediates Resistance in Murine Melioidosis

2009 ◽  
Vol 77 (4) ◽  
pp. 1589-1595 ◽  
Author(s):  
Katrin Breitbach ◽  
Guang Wen Sun ◽  
Jens Köhler ◽  
Kristin Eske ◽  
Patimaporn Wongprompitak ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Damage ◽  
Bacterial Burden ◽  
Caspase 1 ◽  
In Vivo Experiments ◽  
Cytokine Levels ◽  
Dependent Cell ◽  
Ifn Γ

ABSTRACT The gram-negative rod Burkholderia pseudomallei is the causative agent of melioidosis, a potentially fatal disease which is endemic in tropical and subtropical areas. The bacterium multiplies intracellularly within the cytosol, induces the formation of actin tails, and can spread directly from cell to cell. Recently, it has been shown that B. pseudomallei can induce caspase-1-dependent cell death in macrophages. The aim of the present study was to further elucidate the role of caspase-1 during B. pseudomallei infection. In vivo experiments with caspase-1 −/− mice revealed a high susceptibility to B. pseudomallei challenge. This phenotype was associated with a significantly higher bacterial burden 2 days after infection and decreased gamma interferon (IFN-γ) and interleukin-18 cytokine levels 24 h after infection compared to control animals. caspase-1 −/− bone marrow-derived macrophages (BMM) exhibited strong caspase-3 expression and reduced cell damage compared to wild-type (WT) cells during early B. pseudomallei infection, indicating “classical” apoptosis, whereas WT BMM showed signs of rapid caspase-1-dependent cell death. Moreover, we found that caspase-1 −/− BMM had a strongly increased bacterial burden compared to WT cells 3 h after infection under conditions where no difference in cell death could be observed between both cell populations at this time point. We therefore suggest that caspase-1-dependent rapid cell death might contribute to resistance by reducing the intracellular niche for B. pseudomallei, but, in addition, caspase-1 might also have a role in controlling intracellular replication of B. pseudomallei in macrophages. Moreover, caspase-1-dependent IFN-γ production is likely to contribute to resistance in murine melioidosis.

scholarly journals Arachidonic acid inhibition of L-type calcium (CaV1.3b) channels varies with accessory CaVβ subunits

2009 ◽  
Vol 133 (4) ◽  
pp. 387-403 ◽  
Author(s):  
Mandy L. Roberts-Crowley ◽  
Ann R. Rittenhouse
Keyword(s):  
Arachidonic Acid ◽  
Enzyme Activation ◽  
Membrane Excitability ◽  
Recovery From Inactivation ◽  
293 Cells ◽  
Dependent Inactivation ◽  
Accessory Subunits ◽  
Kinetics Of ◽  
Ca2 Channels

Arachidonic acid (AA) inhibits the activity of several different voltage-gated Ca2+ channels by an unknown mechanism at an unknown site. The Ca2+ channel pore-forming subunit (CaVα1) is a candidate for the site of AA inhibition because T-type Ca2+ channels, which do not require accessory subunits for expression, are inhibited by AA. Here, we report the unanticipated role of accessory CaVβ subunits on the inhibition of CaV1.3b L-type (L-) current by AA. Whole cell Ba2+ currents were measured from recombinant channels expressed in human embryonic kidney 293 cells at a test potential of −10 mV from a holding potential of −90 mV. A one-minute exposure to 10 µM AA inhibited currents with β1b, β3, or β4 58, 51, or 44%, respectively, but with β2a only 31%. At a more depolarized holding potential of −60 mV, currents were inhibited to a lesser degree. These data are best explained by a simple model where AA stabilizes CaV1.3b in a deep closed-channel conformation, resulting in current inhibition. Consistent with this hypothesis, inhibition by AA occurred in the absence of test pulses, indicating that channels do not need to open to become inhibited. AA had no effect on the voltage dependence of holding potential–dependent inactivation or on recovery from inactivation regardless of CaVβ subunit. Unexpectedly, kinetic analysis revealed evidence for two populations of L-channels that exhibit willing and reluctant gating previously described for CaV2 channels. AA preferentially inhibited reluctant gating channels, revealing the accelerated kinetics of willing channels. Additionally, we discovered that the palmitoyl groups of β2a interfere with inhibition by AA. Our novel findings that the CaVβ subunit alters kinetic changes and magnitude of inhibition by AA suggest that CaVβ expression may regulate how AA modulates Ca2+-dependent processes that rely on L-channels, such as gene expression, enzyme activation, secretion, and membrane excitability.

scholarly journals Oligodendrocytes and Microglia: Key Players in Myelin Development, Damage and Repair

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1058
Author(s):  
Ilias Kalafatakis ◽  
Domna Karagogeos
Keyword(s):  
Glial Cell ◽  
Cell Types ◽  
Innate Immune ◽  
Preclinical Models ◽  
Cell Functions ◽  
Pathological Conditions ◽  
Complex Process ◽  
Molecular Components ◽  
The Brain

Oligodendrocytes, the myelin-making cells of the CNS, regulate the complex process of myelination under physiological and pathological conditions, significantly aided by other glial cell types such as microglia, the brain-resident, macrophage-like innate immune cells. In this review, we summarize how oligodendrocytes orchestrate myelination, and especially myelin repair after damage, and present novel aspects of oligodendroglial functions. We emphasize the contribution of microglia in the generation and regeneration of myelin by discussing their beneficial and detrimental roles, especially in remyelination, underlining the cellular and molecular components involved. Finally, we present recent findings towards human stem cell-derived preclinical models for the study of microglia in human pathologies and on the role of microbiome on glial cell functions.

scholarly journals Store-Independent Calcium Entry and Related Signaling Pathways in Breast Cancer

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 994
Author(s):  
Mohamed Chamlali ◽  
Lise Rodat-Despoix ◽  
Halima Ouadid-Ahidouch
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Calcium Entry ◽  
Cell Functions ◽  
Fine Tune ◽  
Ca2 Channels ◽  
In Cells

Known as a key effector in breast cancer (BC) progression, calcium (Ca2+) is tightly regulated to maintain the desired concentration to fine-tune cell functions. Ca2+ channels are the main actors among Ca2+ transporters that control the intracellular Ca2+ concentration in cells. It is well known that the basal Ca2+ concentration is regulated by both store-dependent and independent Ca2+ channels in BC development and progression. However, most of the literature has reported the role of store-dependent Ca2+ entry, and only a few studies are focusing on store-independent Ca2+ entry (SICE). In this review, we aim to summarize all findings on SICE in the BC progression field.

scholarly journals Cooperative and acute inhibition by multiple C-terminal motifs of L-type Ca2+ channels

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Nan Liu ◽  
Yaxiong Yang ◽  
Lin Ge ◽  
Min Liu ◽  
Henry M Colecraft ◽  
...  
Keyword(s):  
Computational Modeling ◽  
Therapeutic Potential ◽  
Regulatory Domain ◽  
New Paradigm ◽  
C Terminus ◽  
Dependent Inactivation ◽  
End Stage ◽  
Lower Limits ◽  
Full Activation ◽  
Ca2 Channels

Inhibitions and antagonists of L-type Ca2+ channels are important to both research and therapeutics. Here, we report C-terminus mediated inhibition (CMI) for CaV1.3 that multiple motifs coordinate to tune down Ca2+ current and Ca2+ influx toward the lower limits determined by end-stage CDI (Ca2+-dependent inactivation). Among IQV (preIQ3-IQ domain), PCRD and DCRD (proximal or distal C-terminal regulatory domain), spatial closeness of any two modules, e.g., by constitutive fusion, facilitates the trio to form the complex, compete against calmodulin, and alter the gating. Acute CMI by rapamycin-inducible heterodimerization helps reconcile the concurrent activation/inactivation attenuations to ensure Ca2+ influx is reduced, in that Ca2+ current activated by depolarization is potently (~65%) inhibited at the peak (full activation), but not later on (end-stage inactivation, ~300 ms). Meanwhile, CMI provides a new paradigm to develop CaV1 inhibitors, the therapeutic potential of which is implied by computational modeling of CaV1.3 dysregulations related to Parkinson’s disease.

The photoreceptor cytoskeleton visualized

1992 ◽  
Vol 50 (1) ◽  
pp. 480-481
Author(s):  
Beth Burnside
Keyword(s):  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Polarization ◽  
Synaptic Proteins ◽  
Cell Functions ◽  
Vertebrate Photoreceptor ◽  
Numerous Cell ◽  
Turn Over

The vertebrate photoreceptor provides a drammatic example of cell polarization. Specialized to carry out phototransduction at its distal end and to synapse with retinal interneurons at its proximal end, this long slender cell has a uniquely polarized morphology which is reflected in a similarly polarized cytoskeleton. Membranes bearing photopigment are localized in the outer segment, a modified sensory cilium. Sodium pumps which maintain the dark current critical to photosensory transduction are anchored along the inner segment plasma membrane between the outer segment and the nucleus.Proximal to the nucleus is a slender axon terminating in specialized invaginating synapses with other neurons of the retina. Though photoreceptor diameter is only 3-8u, its length from the tip of the outer segment to the synapse may be as great as 200μ. This peculiar linear cell morphology poses special logistical problems and has evoked interesting solutions for numerous cell functions. For example, the outer segment membranes turn over by means of a unique mechanism in which new disks are continuously added at the proximal base of the outer segment, while effete disks are discarded at the tip and phagocytosed by the retinal pigment epithelium. Outer segment proteins are synthesized in the Golgi near the nucleus and must be transported north through the inner segment to their sites of assembly into the outer segment, while synaptic proteins must be transported south through the axon to the synapse.The role of the cytoskeleton in photoreceptor motile processes is being intensely investigated in several laboratories.

MicroRNAs in Noise-Induced Hearing Loss and their Regulation by Oxidative Stress and Inflammation

2020 ◽  
Vol 21 (12) ◽  
pp. 1216-1224
Author(s):  
Fatemeh Forouzanfar ◽  
Samira Asgharzade
Keyword(s):  
Oxidative Stress ◽  
Hearing Loss ◽  
Hair Cell ◽  
Noise Exposure ◽  
Cell Damage ◽  
Sensory Cells ◽  
Noise Induced Hearing Loss ◽  
Irreversible Damage ◽  
Open Access Journals

Noise exposure (NE) has been recognized as one of the causes of sensorineural hearing loss (SNHL), which can bring about irreversible damage to sensory hair cells in the cochlea, through the launch of oxidative stress pathways and inflammation. Accordingly, determining the molecular mechanism involved in regulating hair cell apoptosis via NE is essential to prevent hair cell damage. However, the role of microRNAs (miRNAs) in the degeneration of sensory cells of the cochlea during NE has not been so far uncovered. Thus, the main purpose of this study was to demonstrate the regulatory role of miRNAs in the oxidative stress pathway and inflammation induced by NE. In this respect, articles related to noise-induced hearing loss (NIHL), oxidative stress, inflammation, and miRNA from various databases of Directory of Open Access Journals (DOAJ), Google Scholar, PubMed; Library, Information Science & Technology Abstracts (LISTA), and Web of Science were searched and retrieved. The findings revealed that several studies had suggested that up-regulation of miR-1229-5p, miR-451a, 185-5p, 186 and down-regulation of miRNA-96/182/183 and miR-30b were involved in oxidative stress and inflammation which could be used as biomarkers for NIHL. There was also a close relationship between NIHL and miRNAs, but further research is required to prove a causal association between miRNA alterations and NE, and also to determine miRNAs as biomarkers indicating responses to NE.

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