Calcium channel β3 subunit regulates ATP-dependent migration of dendritic cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE224912 | GEO | 2023/09/27
REPOSITORIES: GEO
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Project description:Calcium channel β3 subunit regulates ATP-dependent migration of dendritic cells
| PRJNA933110 | ENA
Project description:Voltage-gated L-type Ca(2+) (Ca(v)1.2) channels in vascular smooth muscle cells are a predominant Ca(2+) influx pathway that mediates arterial tone. Channel biogenesis is accomplished when the pore-forming α(1C) subunit coassembles with regulatory Ca(v)β subunits intracellularly, and the multiprotein Ca(v)1.2 channel complex translocates to the plasma membrane to form functional Ca(2+) channels. We hypothesized that the main Ca(v)β isoform in vascular smooth muscle cells, Ca(v)β3, is required for the upregulation of arterial Ca(v)1.2 channels during the development of hypertension, an event associated with abnormal Ca(2+)-dependent tone. Ca(v)1.2 channel expression and function were compared between second-order mesenteric arteries of C57BL/6 wild-type (WT) and Ca(v)β3(-/-) mice infused with saline (control) or angiotensin II (Ang II) for 2 weeks to induce hypertension. The mesenteric arteries of Ang II-infused WT mice showed increased Ca(v)1.2 channel expression and accentuated Ca(2+)-mediated contractions compared with saline-infused WT mice. In contrast, Ca(v)1.2 channels failed to upregulate in mesenteric arteries of Ang II-infused Ca(v)β3(-/-) mice, and Ca(2+)-dependent reactivity was normal in these arteries. Basal systolic blood pressure was not significantly different between WT and Ca(v)β3(-/-) mice (98 ± 2 and 102 ± 3 mm Hg, respectively), but the Ca(v)β3(-/-) mice showed a blunted pressor response to Ang II infusion. Two weeks after the start of Ang II administration, the systolic blood pressure of Ca(v)β3(-/-) mice averaged 149 ± 4 mm Hg compared with 180 ± 5 mm Hg in WT mice. Thus, the Ca(v)β3 subunit is a critical regulatory protein required to upregulate arterial Ca(v)1.2 channels and fully develop Ang II-dependent hypertension in C57BL/6 mice.
| S-EPMC3748590 | biostudies-literature
Project description:Voltage-gated sodium (Na v ) channels form the basis for the initiation of the action potential in excitable cells by allowing sodium ions to pass through the cell membrane. The Na v channel α subunit is known to function both with and without associated β subunits. There is increasing evidence that these β subunits have multiple roles that include not only influencing the voltage-dependent gating but also the ability to alter the spatial distribution of the pore-forming α subunit. Recent structural data has shown possible ways in which β1 subunits may interact with the α subunit. However, the position of the β1 subunit would not be compatible with a previous trimer structure of the β3 subunit. Furthermore, little is currently known about the dynamic behavior of the β subunits both as individual monomers and as higher order oligomers. Here, we use multiscale molecular dynamics simulations to assess the dynamics of the β3, and the closely related, β1 subunit. These findings reveal the spatio-temporal dynamics of β subunits and should provide a useful framework for interpreting future low-resolution experiments such as atomic force microscopy.
| S-EPMC7103644 | biostudies-literature
Project description:Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAMs). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either pro-tumoral or anti-tumoral signals to glioma cells. Here, we performed bulk RNA-seq and single-cell RNA-seq on GBM patient samples, which revealed increased ATP synthase expression and oxidative phosphorylation (OXPHOS) activity in TAMs located in the tumor core relative to the tumor periphery. Both in vitro and in vivo models displayed similar trends of augmented TAM mitochondrial activity, along with elevated mitochondrial fission, glucose uptake, mitochondrial membrane potential, and extracellular ATP (eATP) production by TAMs in the presence of GBM cells. Tumor-secreted factors, including GM-CSF, induced the increase in TAM eATP production. Elevated eATP in the GBM microenvironment promoted glioma growth and invasion by activating the P2X purinoceptor 7 (P2X7R) on glioma cells. Inhibition of the eATP-P2X7R axis attenuated tumor cell viability in vitro and reduced tumor size and prolonged survival in glioma-bearing mouse models. Overall, this study revealed elevated TAM-derived eATP in GBM and provided the basis for targeting the eATP-P2X7R signaling axis as a therapeutic strategy in GBM.
2024-08-30 | GSE275293 | GEO
Project description:EMT is an early process in metastasis that is associated with up to 90% of cancer-related death. ATP has been known to play some roles in EMT. We previously described that internalization of extracellular ATP (eATP) by cancer cells in vitro and in vivo via macropinocytosis increases intracellular ATP levels, cell proliferation and resistance to anticancer drugs. Recently, we reported eATP also induces EMT and other early metastatic activities independent of TGF-b, a well-known inducer of EMT, in human lung cancer cells. However, exactly how eATP induces EMT at gene expression level is far from understood. In this study, we hypothesize that eATP acts as an inducer and regulator of EMT alternative to TGF-b. Transwell assays revealed that eATP treatment, alone, induced human lung cancer A549 and H1299 cells to invade at rates faster than TGF-b. eATP also induced formation of filopodia-like protrusions faster than TGF-b, and it restored viability of cancer cells treated with TGF-b-neutralizing antibodies. eATP significantly elevated intracellular ATP levels while TGF-b did not. RNA sequencing / western blots revealed that eATP induced changes in expression of genes/proteins involved in EMT similar to but with differences in number and induction time compared with those induced by TGF-b. Metabolomics analysis shows that eATP-induced major metabolic changes are consistent/correlated with those identified at the gene expression level. These differences could be accounted for by the multi-functional and multi-localization properties of eATP and macropinocytosis-internalized eATP, strongly suggesting that eATP is a previously unrecognized master inducer and regulator of EMT.
2022-07-20 | GSE160671 | GEO
Project description:Sequence database searches with the alpha2delta subunit as probe led to the identification of two new genes encoding proteins with the essential properties of this calcium channel subunit. Primary structure comparisons revealed that the novel alpha2delta-2 and alpha2delta-3 subunits share 55.6 and 30.3% identity with the alpha2delta-1 subunit, respectively. The number of putative glycosylation sites and cysteine residues, hydropathicity profiles, and electrophysiological character of the alpha2delta-3 subunit indicates that these proteins are functional calcium channel subunits. Coexpression of alpha2delta-3 with alpha1C and cardiac beta2a or alpha1E and beta3 subunits shifted the voltage dependence of channel activation and inactivation in a hyperpolarizing direction and accelerated the kinetics of current inactivation. The kinetics of current activation were altered only when alpha2delta-1 or alpha2delta-3 was expressed with alpha1C. The effects of alpha2delta-3 on alpha1C but not alpha1E are indistinguishable from the effects of alpha2delta-1. Using Northern blot analysis, it was shown that alpha2delta-3 is expressed exclusively in brain, whereas alpha2delta-2 is found in several tissues. In situ hybridization of mouse brain sections showed mRNA expression of alpha2delta-1 and alpha2delta-3 in the hippocampus, cerebellum, and cortex, with alpha2delta-1 strongly detected in the olfactory bulb and alpha2delta-3 in the caudate putamen.
| S-EPMC6782206 | biostudies-literature
Project description:Purpose: Injuries to the adult central nervous system (CNS) often result in permanent disabilities because neurons lose the ability to regenerate their axon during development. Although the developmental transition from a growing to a transmitting phase may represent one of the first steps in the gradual loss of axon growth and regeneration ability, the molecular mechanisms regulating this process has yet to be identified. The main goal of this study was to dissect the molecular mechanisms mediating the decline in axon growth ability and its relationship with regeneration failure in the adult CNS. To this end, we sequenced the whole transcriptome of dorsal root ganglia (DRG) neurons in both growth competent and incompetent states at different developmental stages, in diverse culture and in vivo experimental conditions.
2016-09-17 | GSE66128 | GEO
Project description:BackgroundCardiomyocyte contraction is initiated by influx of extracellular calcium through voltage-gated calcium channels. These oligomeric channels utilize auxiliary beta subunits to chaperone the pore-forming alpha subunit to the plasma membrane, and to modulate channel electrophysiology 1. Several beta subunit family members are detected by RT-PCR in the embryonic heart. Null mutations in mouse beta2, but not in the other three beta family members, are embryonic lethal at E10.5 due to defects in cardiac contractility 2. However, a drawback of the mouse model is that embryonic heart rhythm is difficult to study in live embryos due to their intra-uterine development. Moreover, phenotypes may be obscured by secondary effects of hypoxia. As a first step towards developing a model for contributions of beta subunits to the onset of embryonic heart rhythm, we characterized the structure and expression of beta2 subunits in zebrafish and other teleosts.ResultsCloning of two zebrafish beta2 subunit genes (beta2.1 and beta2.2) indicated they are membrane-associated guanylate kinase (MAGUK)-family genes. Zebrafish beta2 genes show high conservation with mammals within the SH3 and guanylate kinase domains that comprise the "core" of MAGUK proteins, but beta2.2 is much more divergent in sequence than beta2.1. Alternative splicing occurs at the N-terminus and within the internal HOOK domain. In both beta2 genes, alternative short ATG-containing first exons are separated by some of the largest introns in the genome, suggesting that individual transcript variants could be subject to independent cis-regulatory control. In the Tetraodon nigrovidis and Fugu rubripes genomes, we identified single beta2 subunit gene loci. Comparative analysis of the teleost and human beta2 loci indicates that the short 5' exon sequences are highly conserved. A subset of 5' exons appear to be unique to teleost genomes, while others are shared with mammals. Alternative splicing is temporally and spatially regulated in embryo and adult. Moreover, a different subset of spliced beta2 transcript variants is detected in the embryonic heart compared to the adult.ConclusionThese studies refine our understanding of beta2 subunit diversity arising from alternative splicing, and provide the groundwork for functional analysis of beta2 subunit diversity in the embryonic heart.
| S-EPMC2365960 | biostudies-literature
Project description:The c subunit is an inner mitochondrial membrane (IMM) protein encoded by three nuclear genes. Best known as an integral part of the F0 complex of the ATP synthase, the c subunit is also present in other cytoplasmic compartments in ceroid lipofuscinoses. Under physiological conditions, this 75 residue-long peptide folds into an α-helical hairpin and forms oligomers spanning the lipid bilayer. In addition to its physiological role, the c subunit has been proposed as a key participant in stress-induced IMM permeabilization by the mechanism of calcium-induced permeability transition. However, the molecular mechanism of the c subunit participation in IMM permeabilization is not completely understood. Here we used fluorescence spectroscopy, atomic force microscopy and black lipid membrane methods to gain insights into the structural and functional properties of unmodified c subunit protein that might make it relevant to mitochondrial toxicity. We discovered that c subunit is an amyloidogenic peptide that can spontaneously fold into β-sheets and self-assemble into fibrils and oligomers in a Ca2+-dependent manner. C subunit oligomers exhibited ion channel activity in lipid membranes. We propose that the toxic effects of c subunit might be linked to its amyloidogenic properties and are driven by mechanisms similar to those of neurodegenerative polypeptides such as Aβ and α-synuclein.
| S-EPMC8062469 | biostudies-literature
Project description:A multibillion dollar pharmaceutical industry targets purinergic signaling pathways in humans. However, in contrast, little is known about purinergic signaling in plants. Extracellular adenosine-5’-triphosphate (eATP) acts as a damage-associated molecular pattern (DAMP) in both animals and plants. The first plant eATP receptor, DORN1, was identified in Arabidopsis, defining a new kinase family (P2K) of purinoceptors. Stomates are leaf pores that control gas exchange and, therefore, impact critical functions such as photosynthesis and drought tolerance. Stomates are also the prefer entry point for leaf pathogens. The addition of ATP led to the rapid closure of Arabidopsis leaf stomates resulting in enhanced resistance to the bacterial pathogen Psuedomonas syringae. The data indicate that this response is mediated by eATP recognition by DORN1 followed by direct phosphorylation of the NADPH oxidase RBOHD, resulting in elevated production of reactive oxygen species and stomatal closure. Mutation of the DORN1 phosphorylation sites on RBOHD eliminated the ability of eATP to induce stomatal closure. To date, in contrast to work in animals, purinergic signaling in plants has been viewed as a curiosity without any direct, mechanistic connection to key plant processes. The data presented clearly demonstrates eATP as an important signal controlling stomatal aperture with important implications for the control of plant photosynthesis, water homeostasis, pathogen resistance and ultimately yield.
2018-10-24 | PXD006678 | Pride