Extended Synaptotagmins 1 and 2 Are Required for Store-Operated Calcium Entry, Cell Migration and Viability in Breast Cancer Cells.

Extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER)-associated proteins that facilitate the tethering of the ER to the plasma membrane (PM), participating in lipid transfer between the membranes and supporting the Orai1-STIM1 interaction at ER-PM junctions. Orai1 and STIM1 are the core proteins of store-operated Ca entry (SOCE), a major mechanism for Ca influx that regulates a variety of cellular functions. Aberrant modulation of SOCE in cells from different types of cancer has been reported to underlie the development of several tumoral features.

SARAF overexpression impairs thrombin-induced Ca homeostasis in neonatal platelets.

Neonatal platelets present a reduced response to the platelet agonist, thrombin (Thr), thus resulting in a deficient Thr-induced aggregation. These alterations are more pronounced in premature newborns. Here, our aim was to uncover the causes underneath the impaired Ca homeostasis described in neonatal platelets.

Thrombotic Alterations under Perinatal Hypoxic Conditions: HIF and Other Hypoxic Markers.

Hypoxia is considered to be a stressful physiological condition, which may occur during labor and the later stages of pregnancy as a result of, among other reasons, an aged placenta. Therefore, when gestation or labor is prolonged, low oxygen supply to the tissues may last for minutes, and newborns may present breathing problems and may require resuscitation maneuvers. As a result, poor oxygen supply to tissues and to circulating cells may last for longer periods of time, leading to life-threatening conditions.

The Ca Sensor STIM in Human Diseases.

The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins that act as Ca sensors in the endoplasmic reticulum (ER) and, upon Ca store discharge, interact with and activate the Orai/CRACs in the plasma membrane. Dysregulation of Ca signaling leads to the pathogenesis of a variety of human diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, and immune disorders.

CAPN1 (Calpain1)-Dependent Cleavage of STIM1 (Stromal Interaction Molecule 1) Results in an Enhanced SOCE (Store-Operated Calcium Entry) in Human Neonatal Platelets.

Background: Altered intracellular Ca homeostasis in neonatal platelets has been previously reported. This study aims to examine the changes in the Ca entry through the store-operated calcium entry (SOCE) mechanism in neonatal platelets.

Methods: Human platelets from either control women, mothers, and neonates were isolated and, following, were fixed after being treated as required.

Correction: Sanchez-Collado et al. Orai2 Modulates Store-Operated Ca Entry and Cell Cycle Progression in Breast Cancer Cells. 2021, , 114.

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New Evidence on Regucalcin, Body Composition, and Walking Ability Adaptations to Multicomponent Exercise Training in Functionally Limited and Frail Older Adults.

Background: Regucalcin, or senescence marker protein-30 (SMP30), is a Ca-binding protein with multiple functions reported in the literature. Physical exercise has been shown to improve aging markers; nevertheless, SMP30 in humans has not been extensively researched. Older adults experience a decline in functional capacity and body composition.

Orai2 Modulates Store-Operated Ca Entry and Cell Cycle Progression in Breast Cancer Cells.

Breast cancer is a heterogeneous disease from the histological and molecular expression point of view, and this heterogeneity determines cancer aggressiveness. Store-operated Ca entry (SOCE), a major mechanism for Ca entry in non-excitable cells, is significantly remodeled in cancer cells and plays an important role in the development and support of different cancer hallmarks. The store-operated CRAC (Ca release-activated Ca) channels are predominantly comprised of Orai1 but the participation of Orai2 and Orai3 subunits has been reported to modulate the magnitude of Ca responses.

PGRMC1 Inhibits Progesterone-Evoked Proliferation and Ca Entry Via STIM2 in MDA-MB-231 Cells.

Progesterone receptor membrane component 1 (PGRMC1) has been shown to regulate some cancer hallmarks. Progesterone (P) evokes intracellular calcium (Ca) changes in the triple-negative breast cancer cell lines (MDA-MB-231, MDA-MB-468, and BT-20) and in other breast cancer cell lines like the luminal MCF7 cells. PGRMC1 expression is elevated in MDA-MB-231 and MCF7 cells as compared to non-tumoral MCF10A cell line, and PGRMC1 silencing enhances P-evoked Ca mobilization.

Arachidonic Acid Attenuates Cell Proliferation, Migration and Viability by a Mechanism Independent on Calcium Entry.

Arachidonic acid (AA) is a phospholipase A2 metabolite that has been reported to mediate a plethora of cellular mechanisms involved in healthy and pathological states such as platelet aggregation, lymphocyte activation, and tissue inflammation. AA has been described to activate Ca entry through the arachidonate-regulated Ca-selective channels (ARC channels). Here, the analysis of the changes in the intracellular Ca homeostasis revealed that, despite MDA-MB-231 cells expressing the ARC channel components Orai1, Orai3, and STIM1, AA does not evoke Ca entry in these cells.

NO1, a New Sigma 2 Receptor/TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines.

(1) Background: The structure of the Sigma 2 receptor/TMEM97 (σ2RTMEM97) has recently been reported. (2, 3) Methods and results: We used genetic and biochemical approaches to identify the molecular mechanism downstream of σ2R/TMEM97. The novel σ2R/TMEM97 fluorescent ligand, NO1, reduced the proliferation and survival of the triple negative breast cancer cell lines (TNBC: MDA-MB-231 and MDA-MB-468 cell lines), due to NO1-induced apoptosis.

Pathophysiological Significance of Store-Operated Calcium Entry in Cardiovascular and Skeletal Muscle Disorders and Angiogenesis.

Store-Operated Ca Entry (SOCE) is an important Ca influx pathway expressed by several excitable and non-excitable cell types. SOCE is recognized as relevant signaling pathway not only for physiological process, but also for its involvement in different pathologies. In fact, independent studies demonstrated the implication of essential protein regulating SOCE, such as STIM, Orai and TRPCs, in different pathogenesis and cell disorders, including cardiovascular disease, muscular dystrophies and angiogenesis.

STIM1 phosphorylation at Y modulates its interaction with SARAF and the activation of SOCE and .

Stromal interaction molecule 1 (STIM1) is one of the key elements for the activation of store-operated Ca entry (SOCE). Hence, identification of the relevant phosphorylatable STIM1 residues with a possible role in the regulation of STIM1 function and SOCE is of interest. By performing a computational analysis, we identified that the Y residue is susceptible to phosphorylation.

TRPC6 Channels Are Required for Proliferation, Migration and Invasion of Breast Cancer Cell Lines by Modulation of Orai1 and Orai3 Surface Exposure.

Transient receptor potential channels convey signaling information from a number of stimuli to a wide variety of cellular functions, mainly by inducing changes in cytosolic Ca concentration. Different members of the TRPC, TRPM and TRPV subfamilies have been reported to play a role in tumorigenesis. Here we show that the estrogen receptor positive and triple negative breast cancer cell lines, MCF7 and MDA-MB-231, respectively, exhibit enhanced expression of the TRPC6 channel as compared to the non-tumoral MCF10A cell line.

Fluorescence-Based Measurements of the CRAC Channel Activity in Cell Populations.

Cytosolic Ca plays an important role in cellular biology, and since its identification as a second messenger, a number of techniques and methods to analyze the changes in cytosolic Ca concentration ([Ca]) induced by physiological agonists have been developed. Changes in [Ca] might be determined in single cells or in cell populations. Measurement in single cells allows to determine changes in [Ca] at a subcellular level but often results in heterogeneous responses among cells.

Flavonoids and Platelet-Derived Thrombotic Disorders.

Thrombotic disorders are characterized by an increase in the probability of the formation of unnecessary thrombi that might be due to the activation of the coagulation cascade or the circulating platelets. Platelets or thrombocytes play an essential role in hemostasis but abnormal platelet function leads to the development of a number of cardiovascular complications, including thrombotic disorders. Under pathological conditions, platelets are associated with the development of different thrombotic disorders, including atherosclerosis, arterial thrombosis and stroke, deep venous thrombosis and pulmonary embolism; therefore, platelets are the target of a number of anti-thrombotic strategies.

Filamin A Modulates Store-Operated Ca Entry by Regulating STIM1 (Stromal Interaction Molecule 1)-Orai1 Association in Human Platelets.

Objective: Here, we provide evidence for the role of FLNA (filamin A) in the modulation of store-operated calcium entry (SOCE).

Approach And Results: SOCE is a major mechanism for calcium influx controlled by the intracellular Ca stores. On store depletion, the endoplasmic reticulum calcium sensor STIM1 (stromal interaction molecule 1) redistributes into puncta at endoplasmic reticulum/plasma membrane junctions, a process supported by the cytoskeleton, where it interacts with the calcium channels; however, the mechanism for fine-tuning SOCE is not completely understood.

New Insights into Adipokines as Potential Biomarkers for Type-2 Diabetes Mellitus.

A large number of studies have been focused on investigating serum biomarkers associated with risk or diagnosis of type-2 diabetes mellitus. In the last decade, promising studies have shown that circulating levels of adipokines could be used as a relevant biomarker for diabetes mellitus progression as well as therapeutic future targets. Here, we discuss the possible use of recently described adipokines, including apelin, omentin-1, resistin, FGF-21, neuregulin-4 and visfatin, as early biomarkers for diabetes.

Involvement of stanniocalcins in the deregulation of glycaemia in obese mice and type 2 diabetic patients.

Stanniocalcins are expressed in the pancreas tissue, and it was suggested a direct correlation between circulating insulin and STC2 concentrations in human. Here, we show a significant correlation between STC1 and both glycaemia and glycosylated haemoglobin among DM2 patients, while DM2 patients who present the greatest glycosylated haemoglobin values exhibited the lowest STC2 expression. However, treatment of patients with antiglycaemic drugs does not significantly modify the expression of both STCs.

TRPs in Pain Sensation.

According to the International Association for the Study of Pain (IASP) pain is characterized as an "unpleasant sensory and emotional experience associated with actual or potential tissue damage". The TRP super-family, compressing up to 28 isoforms in mammals, mediates a myriad of physiological and pathophysiological processes, pain among them. TRP channel might be constituted by similar or different TRP subunits, which will result in the formation of homomeric or heteromeric channels with distinct properties and functions.

FKBP25 and FKBP38 regulate non-capacitative calcium entry through TRPC6.

Non-capacitative calcium entry (NCCE) contributes to cell activation in response to the occupation of G protein-coupled membrane receptors. Thrombin administration to platelets evokes the synthesis of diacylglycerol downstream of PAR receptor activation. Diacylglycerol evokes NCCE through activating TRPC3 and TRPC6 in human platelets.

Role of mTOR1 and mTOR2 complexes in MEG-01 cell physiology.

The function of the mammalian target of rapamycin (mTOR) is upregulated in response to cell stimulation with growing and differentiating factors. Active mTOR controls cell proliferation, differentiation and death. Since mTOR associates with different proteins to form two functional macromolecular complexes, we aimed to investigate the role of the mTOR1 and mTOR2 complexes in MEG-01 cell physiology in response to thrombopoietin (TPO).

Evaluation of the antiaggregant activity of ascorbyl phenolic esters with antioxidant properties.

Beneficial effects of the antioxidant L-ascorbic acid (Asc) in human health are well known. Its particular role in hemostasis deserves further consideration, since it has been described a dose-dependent effect of Asc in platelet activity. Contrary, it has been demonstrated that phenolic compounds have inhibitory effects on platelet aggregation stimulated by the physiological agonist thrombin (Thr).

Store-operated calcium entry: unveiling the calcium handling signalplex.

Store-operated Ca(2+) entry (SOCE) is an important mechanism for Ca(2+) influx in non-excitable cells, also present in excitable cells. The activation of store-operated channels (SOCs) is finely regulated by the filling state of the intracellular agonist-sensitive Ca(2+) compartments, and both, the mechanism of sensing the Ca(2+) stores and the nature and functional properties of the SOCs, have been a matter of intense investigation and debate. The identification of STIM1 as the endoplasmic reticulum Ca(2+) sensor and both Orai1, as the pore-forming subunit of the channels mediating the Ca(2+)-selective store-operated current, and the members of the TRPC subfamily of proteins, as the channels mediating the cation-permeable SOCs, has shed new light on the underlying events.

STIM1 regulates TRPC6 heteromultimerization and subcellular location.

STIM1 (stromal interaction molecule 1) regulates store-operated channels in the plasma membrane, but the regulation of TRPC (transient receptor potential canonical) heteromultimerization and location by STIM1 is poorly understood. STIM1 is a single transmembrane protein that communicates the filling state of the endoplasmic reticulum to store-operated channels. STIM1 has been reported to regulate the activity of all of the TRPC family members, except TRPC7.