Dystrophin is a 427kDa sub-membrane cytoskeletal protein, associated with the inner surface membrane and incorporated in a large macromolecular complex of proteins, the dystrophin-associated protein ...complex (DAPC). In addition to dystrophin the DAPC is composed of dystroglycans, sarcoglycans, sarcospan, dystrobrevins and syntrophin. This complex is thought to play a structural role in ensuring membrane stability and force transduction during muscle contraction. The multiple binding sites and domains present in the DAPC confer the scaffold of various signalling and channel proteins, which may implicate the DAPC in regulation of signalling processes. The DAPC is thought for instance to anchor a variety of signalling molecules near their sites of action. The dystroglycan complex may participate in the transduction of extracellular-mediated signals to the muscle cytoskeleton, and β-dystroglycan was shown to be involved in MAPK and Rac1 small GTPase signalling. More generally, dystroglycan is view as a cell surface receptor for extracellular matrix proteins. The adaptor proteins syntrophin contribute to recruit and regulate various signalling proteins such as ion channels, into a macromolecular complex. Although dystrophin and dystroglycan can be directly involved in signalling pathways, syntrophins play a central role in organizing signalplex anchored to the dystrophin scaffold. The dystrophin associated complex, can bind up to four syntrophin through binding domains of dystrophin and dystrobrevin, allowing the scaffold of multiple signalling proteins in close proximity. Multiple interactions mediated by PH and PDZ domains of syntrophin also contribute to build a complete signalplex which may include ion channels, such as voltage-gated sodium channels or TRPC cation channels, together with, trimeric G protein, G protein-coupled receptor, plasma membrane calcium pump, and NOS, to enable efficient and regulated signal transduction and ion transport. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.
Cross talk between dystrophin-associated protein complex and signalling pathway involving sodium and calcium channels, Nitric oxyde synthase, Plasma membrane Calcium ATPase, as well as intracellular pathway depending on trimeric G proteins and Rac1 small GTPases. Display omitted
•Dystrophin is a cytoskeletal protein linked to a macromolecular complex (DAPC).•In DAPC, the dystroglycan complex transduces extracellular-mediated signals.•β-dystroglycan is involved in MAPK and Rac1 small GTPase signalling.•The adaptor protein syntrophin recruits and regulates various signalling proteins.•Syntrophin builds a signalplex including ion channels, G proteins, PMCA and nNOS.
Evaluate how specific morphologic aspects of abdominal aortic aneurysms (AAAs), including asymmetries, curvatures, tortuosities, and angulations, among others can influence the intrinsic ...biomechanical properties of the AAA's wall. This study analyzed the correlation of geometric measurements (1-dimensional, 2-dimensional, and 3-dimensional) of preoperative tomographic images of AAA with uniaxial biomechanical tests of the arterial wall fragments of these AAA obtained in open surgical repair of aneurysms.
It was a multicenter, experimental, and observational study, and initially 54 individuals were selected who underwent open surgical of AAA, with valid biomechanical tests of the anterior wall of the AAA. Seven individuals were excluded because they had poor preoperative quality computed tomography scans and/or artifacts that impeded image segmentation and extraction of AAA geometric indices. The aortic fragments were subjected to uniaxial biomechanical destructive tests to obtain the following data: maximum load, failure stress, failure tension, failure strain energy, strain, and fragment thickness. In the same patients, preoperative computed tomography scans were performed with the extraction of 26 geometric indices, subdivided into 9 1-dimensional indices, 6 2-dimensional indices, and 11 3-dimensional indices. Data were subjected to statistical analysis using SPSS version 28.
Comparing ruptured and unruptured AAA, no statistical difference was observed between the biomechanical and geometric parameters. The fragment thickness of the ruptured AAA was lower than that of the unruptured AAA (P < 0.05). By comparing tomographic geometric indices and biomechanical parameters of the aortic fragments using Pearson's coefficient, positive and linear correlations (P < 0.05) were observed between the geometric variable maximum diameter (Dmax) of the AAA with maximum load (r = 0.408), failure tension (r = 0.372), and failure stress (r = 0.360). Positive and linear correlations were also observed between the variable diameter/height ratio (DHr) and the maximum load (r = 0.360), failure tension (r = 0.354), and failure stress (r = 0.289). The geometric variable DHr was dependent and correlated with Dmax. Simple regression analysis showed that R
varied between 8.3% and 16.7%, and all models were significant (P < 0.05).
Dmax and DHr were linearly and positively correlated with the resistance parameters (maximum load, failure tension, and failure stress) of the AAA fragments. The DHr variable is dependent and correlated with Dmax. There was no correlation between the other geometric indices and the biomechanical parameters of the AAA wall. The asymmetries did not globally influence the biomechanics of AAA wall; however, they may influence regionally. Larger AAAs were stronger than smaller ones. Therefore, such findings may point toward Dmax is still the main geometric parameter, which influences the anterior wall, and possibly globally in the AAA.
The brain of adult mammals, including humans, contains neural stem cells (NSCs) located within specific niches of which the ventricular-subventricular zone (V-SVZ) is the largest one. Under ...physiological conditions, NSCs proliferate, self-renew and produce new neurons and glial cells. Several recent studies established that oncogenic mutations in adult NSCs of the V-SVZ are responsible for the emergence of malignant primary brain tumors called glioblastoma. These aggressive tumors contain a small subpopulation of cells, the glioblastoma cancer stem cells (GSCs), that are endowed with proliferative and self-renewal abilities like NSCs from which they may arise. GSCs are thus considered as the cells that initiate and sustain tumor growth and, because of their resistance to current treatments, provoke tumor relapse. A growing body of studies supports that Ca2+ signaling controls a variety of processes in NSCs and GSCs. Ca2+ is a ubiquitous second messenger whose fluctuations of its intracellular concentrations are handled by channels, pumps, exchangers and Ca2+ binding proteins. The concerted action of the Ca2+ toolkit components encodes specific Ca2+ signals with defined spatio-temporal characteristics that determine the cellular responses. In this review, after a general overview of the adult brain NSCs and GSCs, we focus on the multiple roles of Ca2+ toolkit in NSCs and discuss how GSCs hijack these mechanisms to promote tumor growth. Extensive knowledge of the role of Ca2+ toolkit in the management of essential functions in healthy and pathological stem cells of the adult brain should help to identify promising targets for clinical applications.
Neural stem cells (NSCs) persist in specific brain germinative niches and sustain neurogenesis throughout life in adult mammals. In addition to the two major stem cell niches in the subventricular ...zone and the hippocampal dentate gyrus, the area postrema located in the brainstem has been identified as a neurogenic zone as well. NSCs are regulated by signals from the microenvironment that adjust stem cell response to the needs of the organism. Evidence accumulated over the past decade indicates that Ca
channels play pivotal functions in NSC maintenance. In this study, we explored in area postrema NSCs the presence and roles of a subset of Ca
channels, the store-operated Ca
channels (SOCs) that have the capacity to transduce extracellular signals into Ca
signals. Our data show that NSCs derived from the area postrema express TRPC1 and Orai1, known to form SOCs, as well as their activator STIM1. Ca
imaging indicated that NSCs exhibit store-operated Ca
entries (SOCEs). Pharmacological blockade of SOCEs with SKF-96365, YM-58483 (also known as BTP2) or GSK-7975A resulted in decreased NSC proliferation and self-renewal, indicating a major role for SOCs in maintaining NSC activity within the area postrema. Furthermore, our results show that leptin, an adipose tissue-derived hormone whose ability to control energy homeostasis is dependent on the area postrema, decreased SOCEs and reduced self-renewal of NSCs in the area postrema. As aberrant SOC function has been linked to an increasing number of diseases, including brain disorders, our study opens new perspectives for NSCs in brain pathophysiology.
Abstract
It is generally accepted that voltage-gated Ca
2+
channels, CaV, regulate Ca
2+
homeostasis in excitable cells following plasma membrane depolarization. Here, we show that the Ca
2+
protein ...α1D of CaV1.3 channel is overexpressed in colorectal cancer biopsies compared to normal tissues. Gene silencing experiments targeting α1D reduced the migration and the basal cytosolic Ca
2+
concentration of HCT116 colon cancer cell line and modified the cytosolic Ca
2+
oscillations induced by the sodium/calcium exchanger NCX1/3 working in its reverse mode. Interestingly, NCX1/3 regulated membrane potential of HCT116 cells only when α1D was silenced, and blocking NCX1/3 increased cytosolic Ca
2+
concentration and cell migration. However, membrane depolarization did not induce an increase in intracellular Ca
2+
. Patch-clamp experiments clearly showed that the inward Ca
2+
current was absent. Finally, flow cytometry and immunofluorescence studies showed that α1D protein was localized at the plasma membrane, in cytosol and cell nuclei. Altogether, we uncover a novel signaling pathway showing that α1D is involved in the regulation of Ca
2+
homeostasis and cell migration by a mechanism independent of its plasma membrane canonical function but that involved plasma membrane Na
+
/Ca
2+
exchanger.
Glioblastoma is the most frequent and deadly form of primary brain tumors. Despite multimodal treatment, more than 90% of patients experience tumor recurrence. Glioblastoma contains a small ...population of cells, called glioblastoma stem cells (GSC) that are highly resistant to treatment and endowed with the ability to regenerate the tumor, which accounts for tumor recurrence. Transcriptomic studies disclosed an enrichment of calcium (Ca2+) signaling transcripts in GSC. In non-excitable cells, store-operated channels (SOC) represent a major route of Ca2+ influx. As SOC regulate the self-renewal of adult neural stem cells that are possible cells of origin of GSC, we analyzed the roles of SOC in cultures of GSC previously derived from five different glioblastoma surgical specimens. Immunoblotting and immunocytochemistry experiments showed that GSC express Orai1 and TRPC1, two core SOC proteins, along with their activator STIM1. Ca2+ imaging demonstrated that SOC support Ca2+ entries in GSC. Pharmacological inhibition of SOC-dependent Ca2+ entries decreased proliferation, impaired self-renewal, and reduced expression of the stem cell marker SOX2 in GSC. Our data showing the ability of SOC inhibitors to impede GSC self-renewal paves the way for a strategy to target the cells considered responsible for conveying resistance to treatment and tumor relapse.
The study of calcium channels in molecular mechanisms of cancer transformation is still a novel area of research. Several studies, mostly conducted on cancer cell lines, however support the idea that ...a diversity of plasma membrane channels participates in the remodeling of Ca2+ homeostasis, which regulates various cancer hallmarks such as uncontrolled multiplication and increase in migration and invasion abilities. However few is still understood concerning the intracellular signaling cascades mobilized by calcium influx participating to cancer cell behavior. This review intends to gather some of these pathways dependent on plasma membrane calcium channels and described in prostate, breast and lung cancer cell lines. In these cancer cell types, the calcium channels involved in calcium signaling pathways promoting cancer behaviors are mostly non-voltage activated calcium channels and belong to the TRP superfamily (TRPC, TPRPV and TRPM families) and the Orai family. TRP and Orai channels are part of many signaling cascades involving the activation of transmembrane receptors by extracellular ligand from the tumor environment. TRPV can sense changes in the physical and chemical environment of cancer cells and TRPM7 are stretch activated and sensitive to cholesterol. Changes in activation and or expression of plasma-membrane calcium channels affect calcium-dependent signaling processes relevant to tumorigenesis. The studies cited in this review suggest that an increase in plasma membrane calcium channel expression and/or activity sustain an elevated calcium entry (constitutive or under the control of extracellular signals) promoting higher cell proliferation and migration in most cases. A variety of non-voltage-operated calcium channels display change expression and/or activity in a same cancer type and cooperate to the same process relevant to cancer cell behavior, or can be involved in a different sequence of events during the tumorigenesis. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
Display omitted
Dystrophin is a 427kDa sub-membrane cytoskeletal protein, associated with the inner surface membrane and incorporated in a large macromolecular complex of proteins, the dystrophin-associated protein ...complex (DAPC). In addition to dystrophin the DAPC is composed of dystroglycans, sarcoglycans, sarcospan, dystrobrevins and syntrophin. This complex is thought to play a structural role in ensuring membrane stability and force transduction during muscle contraction. The multiple binding sites and domains present in the DAPC confer the scaffold of various signalling and channel proteins, which may implicate the DAPC in regulation of signalling processes. The DAPC is thought for instance to anchor a variety of signalling molecules near their sites of action. The dystroglycan complex may participate in the transduction of extracellular-mediated signals to the muscle cytoskeleton, and β-dystroglycan was shown to be involved in MAPK and Rac1 small GTPase signalling. More generally, dystroglycan is view as a cell surface receptor for extracellular matrix proteins. The adaptor proteins syntrophin contribute to recruit and regulate various signalling proteins such as ion channels, into a macromolecular complex. Although dystrophin and dystroglycan can be directly involved in signalling pathways, syntrophins play a central role in organizing signalplex anchored to the dystrophin scaffold. The dystrophin associated complex, can bind up to four syntrophin through binding domains of dystrophin and dystrobrevin, allowing the scaffold of multiple signalling proteins in close proximity. Multiple interactions mediated by PH and PDZ domains of syntrophin also contribute to build a complete signalplex which may include ion channels, such as voltage-gated sodium channels or TRPC cation channels, together with, trimeric G protein, G protein-coupled receptor, plasma membrane calcium pump, and NOS, to enable efficient and regulated signal transduction and ion transport. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.
Calcium mishandling in Duchenne muscular dystrophy (DMD) suggested that dystrophin, a membrane-associated cytoskeleton protein, may regulate calcium-signalling cascades such as calcium entries. ...Calcium overload in human DMD myotubes is dependent on their contractile activity suggesting the involvement of channels being activated during contraction and/or calcium release. Forced expression of mini-dystrophin in dystrophin-deficient myotubes, reactivates appropriate sarcolemmal expression of dystrophin-associated proteins and restores normal calcium handling in the cytosol. Furthermore, the recombinant mini-dystrophin reduced the store-operated calcium influx across the sarcolemma, and the mitochondrial calcium uptake during this influx. A slow component of calcium release dependent on IP3R, as well as the production of IP3, were also reduced to normal levels by expression of mini-dystrophin. Our studies provide a new model for the convergent regulation of transmembrane calcium influx and IP3-dependent calcium release by the dystrophin-based cytoskeleton (DBC). We also suggest molecular association of such channels with DBC which may provide the scaffold for assembling a multiprotein-signalling complex that modulates the channel activity. This suggests that the loss of this molecular association could participate in the alteration of calcium homeostasis observed in DMD muscle cells.
Previously, we demonstrated that loss of SEMA3F, a secreted semaphorin encoded in 3p21.3, is associated with higher stages in lung cancer and primary tumor cells studied with anti-vascular ...endothelial growth factor (VEGF) and SEMA3F antibodies. In vitro, SEMA3F inhibits cell spreading; this activity is opposed by VEGF. These results suggest that VEGF and SEMA3F compete for binding to their common neuropilin receptor. In the present report, we investigated the attractive/repulsive effects of SEMA3F on cell migration when cells were grown in a threedimensional system and exposed to a SEMA3F gradient. In addition, we adapted the neurobiologic stripe assay to analyze the migration of tumor cells in response to SEMA3F. In the motile breast cancer cell line C100, which expresses both neuropilin-1 (NRPi) and neuropilin-2 (NRP2) receptors, SEMA3F had a repulsive effect, which was blocked by anti-NRP2 antibody. In less motile MCF7 cells, which express only NRPi, SEMA3F inhibited cell contacts with loss of membrane-associated E-cadherin and β-catenin without motility induction. Cell spreading and proliferation were reduced. These results support the concept that in a first step during tumorigenesis, normal tissues expressing SEMA3F would try to prevent tumor cells from spreading and attaching to the stroma for further implantation.
PDF
