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1.
Activation of endo-lysosomal two-pore channels by NAADP and PI(3,5)P2. Five things to know.
Patel, S, Yuan, Y, Gunaratne, GS, Rahman, T, Marchant, JS
Cell calcium. 2022;:102543
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Abstract
Two-pore channels are ancient members of the voltage-gated ion channel superfamily that are expressed predominantly on acidic organelles such as endosomes and lysosomes. Here we review recent advances in understanding how TPCs are activated by their ligands and identify five salient features: (1) TPCs are Ca2+-permeable non-selective cation channels gated by NAADP. (2) NAADP activation is indirect through associated NAADP receptors. (3) TPCs are also Na+-selective channels gated by PI(3,5)P2. (4) PI(3,5)P2 activation is direct through a structurally-resolved binding site. (5) TPCs switch their ion selectivity in an agonist-dependent manner.
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2.
The roles of transmembrane family proteins in the regulation of store-operated Ca2+ entry.
Zhang, N, Pan, H, Liang, X, Xie, J, Han, W
Cellular and molecular life sciences : CMLS. 2022;(2):118
Abstract
Store-operated Ca2+ entry (SOCE) is a major pathway for calcium signaling, which regulates almost every biological process, involving cell proliferation, differentiation, movement and death. Stromal interaction molecule (STIM) and ORAI calcium release-activated calcium modulator (ORAI) are the two major proteins involved in SOCE. With the deepening of studies, more and more proteins are found to be able to regulate SOCE, among which the transmembrane (TMEM) family proteins are worth paying more attention. In addition, the ORAI proteins belong to the TMEM family themselves. As the name suggests, TMEM family is a type of proteins that spans biological membranes including plasma membrane and membrane of organelles. TMEM proteins are in a large family with more than 300 proteins that have been already identified, while the functional knowledge about the proteins is preliminary. In this review, we mainly summarized the TMEM proteins that are involved in SOCE, to better describe a picture of the interaction between STIM and ORAI proteins during SOCE and its downstream signaling pathways, as well as to provide an idea for the study of the TMEM family proteins.
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3.
Decoding the Phosphatase Code: Regulation of Cell Proliferation by Calcineurin.
Masaki, T, Shimada, M
International journal of molecular sciences. 2022;(3)
Abstract
Calcineurin, a calcium-dependent serine/threonine phosphatase, integrates the alterations in intracellular calcium levels into downstream signaling pathways by regulating the phosphorylation states of several targets. Intracellular Ca2+ is essential for normal cellular physiology and cell cycle progression at certain critical stages of the cell cycle. Recently, it was reported that calcineurin is activated in a variety of cancers. Given that abnormalities in calcineurin signaling can lead to malignant growth and cancer, the calcineurin signaling pathway could be a potential target for cancer treatment. For example, NFAT, a typical substrate of calcineurin, activates the genes that promote cell proliferation. Furthermore, cyclin D1 and estrogen receptors are dephosphorylated and stabilized by calcineurin, leading to cell proliferation. In this review, we focus on the cell proliferative functions and regulatory mechanisms of calcineurin and summarize the various substrates of calcineurin. We also describe recent advances regarding dysregulation of the calcineurin activity in cancer cells. We hope that this review will provide new insights into the potential role of calcineurin in cancer development.
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Insight of the role of mitochondrial calcium homeostasis in hepatic insulin resistance.
Dong, Z, Yao, X
Mitochondrion. 2022;:128-138
Abstract
Due to the rapid rise in the prevalence of chronic metabolic disease, more and more clinicians and basic medical researchers focus their eyesight on insulin resistance (IR), an early and central event of metabolic diseases. The occurrence and development of IR are primarily caused by excessive energy intake and reduced energy consumption. Liver is the central organ that controls glucose homeostasis, playing a considerable role in systemic IR. Decreased capacity of oxidative metabolism and mitochondrial dysfunction are being blamed as the direct reason for the development of IR. Mitochondrial Ca2+ plays a fundamental role in maintaining proper mitochondrial function and redox stability. The maintaining of mitochondrial Ca2+ homeostasis requires the cooperation of ion channels in the inner and outer membrane of mitochondria, such as mitochondrial calcium uniporter complex (MCUC) and voltage-dependent anion channels (VDACs). In addition, the crosstalk between the endoplasmic reticulum (ER), lysosome and plasma membrane with mitochondria is also significant for mitochondrial calcium homeostasis, which is responsible for an efficient network of cellular Ca2+ signaling. Here, we review the recent progression in the research about the regulation factors for mitochondrial Ca2+ and how the dysregulation of mitochondrial Ca2+ homeostasis is involved in the pathogenesis of hepatic IR, providing a new perspective for further exploring the role of ion in the onset and development of IR.
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A Review of Current Clinical Concepts in the Pathophysiology, Etiology, Diagnosis, and Management of Hypercalcemia.
Tonon, CR, Silva, TAAL, Pereira, FWL, Queiroz, DAR, Junior, ELF, Martins, D, Azevedo, PS, Okoshi, MP, Zornoff, LAM, de Paiva, SAR, et al
Medical science monitor : international medical journal of experimental and clinical research. 2022;:e935821
Abstract
Calcium is the most abundant extracellular cation in the body, and it is responsible for structural and enzymatic functions. Calcium homeostasis is regulated by 3 factors: calcitonin, vitamin D, and parathyroid hormone (PTH). Hypercalcemia is defined by a serum calcium concentration >10.5 mg/dL, and it is classified into mild, moderate, and severe, depending on calcium values. Most cases are caused by primary hyperparathyroidism and malignancies. Various mechanisms are involved in the pathophysiology of hypercalcemia, such as excessive PTH production, production of parathyroid hormone-related protein (PTHrp), bone metastasis, extrarenal activation of vitamin D, and ectopic PTH secretion. The initial approach is similar in most cases, but a definitive treatment depends on etiology, that is why etiological investigation is mandatory in all cases. The majority of patients are asymptomatic and diagnosed during routine exams; only a small percentage of patients present with severe manifestations which can affect neurological, muscular, gastrointestinal, renal, and cardiovascular systems. Clinical manifestations are related to calcium levels, with higher values leading to more pronounced symptoms. Critically ill patients should receive treatment as soon as diagnosis is made. Initial treatment involves vigorous intravenous hydration and drugs to reduce bone resorption such as bisphosphonates and, more recently, denosumab, in refractory cases; also, corticosteroids and calcitonin can be used in specific cases. This review aims to provide a clinical update on current concepts of the pathophysiology of calcium homeostasis, epidemiology, screening, clinical presentation, diagnosis, and management of hypercalcemia.
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6.
Spatiotemporal regulation of store-operated calcium entry in cancer metastasis.
Lu, F, Li, Y, Lin, S, Cheng, H, Yang, S
Biochemical Society transactions. 2021;(6):2581-2589
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Abstract
The store-operated calcium (Ca2+) entry (SOCE) is the Ca2+ entry mechanism used by cells to replenish depleted Ca2+ store. The dysregulation of SOCE has been reported in metastatic cancer. It is believed that SOCE promotes migration and invasion by remodeling the actin cytoskeleton and cell adhesion dynamics. There is recent evidence supporting that SOCE is critical for the spatial and the temporal coding of Ca2+ signals in the cell. In this review, we critically examined the spatiotemporal control of SOCE signaling and its implication in the specificity and robustness of signaling events downstream of SOCE, with a focus on the spatiotemporal SOCE signaling during cancer cell migration, invasion and metastasis. We further discuss the limitation of our current understanding of SOCE in cancer metastasis and potential approaches to overcome such limitation.
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Coronary artery calcium score: pivotal role as a predictor for detecting coronary artery disease in symptomatic patients.
Cherukuri, L, Birudaraju, D, Budoff, MJ
Coronary artery disease. 2021;(6):578-585
Abstract
Chest pain and dyspnea are common presentations for symptomatic individuals with suspected coronary artery disease (CAD) in the primary care office and cardiology clinics. However, it is imperative to properly diagnose who should undergo further evaluation for cardiac etiologies of chest pain, with either noninvasive or invasive imaging tests. The purpose of this review is to highlight the role of coronary artery calcium (CAC) score as a screening tool for symptomatic patients to detect CAD. The purpose of CAC scoring is to establish the presence and severity of coronary atherosclerosis that can play a vital role in symptomatic patients. The use of CAC testing in symptomatic patients has traditionally been limited due to fundamental concerns, including the occurrence of coronary calcification relatively late in the atherosclerotic process and high prevalence of CAC in the population. Further issue relates to its low specificity for obstructive CAD, as well as demonstration of significant ethnic variability in plaque composition and calcification patterns. CAC testing gained attention as an inexpensive, rapid, reproducible and a well-tolerated alternative to exclude CAD in symptomatic patients and defer further invasive imaging tests. This article will review the available literature in regard to the use of CAC in symptomatic populations.
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8.
Targeting Kca3.1 Channels in Cancer.
Todesca, LM, Maskri, S, Brömmel, K, Thale, I, Wünsch, B, Koch, O, Schwab, A
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2021;(S3):131-144
Abstract
The Kca3.1 channels, previously designated as IK1 or SK4 channels and encoded by the KCNN4 gene, are activated by a rise of the intracellular Ca2+ concentration. These K+ channels are widely expressed in many organs and involved in many pathologies. In particular, Kca3.1 channels have been studied intensively in the context of cancer. They are not only a marker and a valid prognostic tool for cancer patients, but have an important share in driving cancer progression. Their function is required for many characteristic features of the aggressive cancer cell behavior such as migration, invasion and metastasis as well as proliferation and therapy resistance. In the context of cancer, another property of Kca3.1 is now emerging. These channels can be a target for novel small molecule-based imaging probes, as it has been validated in case of fluorescently labeled senicapoc-derivatives. The aim of this review is (i) to give an overview on the role of Kca3.1 channels in cancer progression and in shaping the cancer microenvironment, (ii) discuss the potential of using Kca3.1 targeting drugs for cancer imaging, (iii) and highlight the possibility of combining molecular dynamics simulations to image inhibitor binding to Kca3.1 channels in order to provide a deeper understanding of Kca3.1 channel pharmacology. Alltogether, Kca3.1 is an attractive therapeutic target so that senicapoc, originally developed for the treatment of sickle cell anemia, should be repurposed for the treatment of cancer patients.
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A Calcium Guard in the Outer Membrane: Is VDAC a Regulated Gatekeeper of Mitochondrial Calcium Uptake?
Sander, P, Gudermann, T, Schredelseker, J
International journal of molecular sciences. 2021;(2)
Abstract
Already in the early 1960s, researchers noted the potential of mitochondria to take up large amounts of Ca2+. However, the physiological role and the molecular identity of the mitochondrial Ca2+ uptake mechanisms remained elusive for a long time. The identification of the individual components of the mitochondrial calcium uniporter complex (MCUC) in the inner mitochondrial membrane in 2011 started a new era of research on mitochondrial Ca2+ uptake. Today, many studies investigate mitochondrial Ca2+ uptake with a strong focus on function, regulation, and localization of the MCUC. However, on its way into mitochondria Ca2+ has to pass two membranes, and the first barrier before even reaching the MCUC is the outer mitochondrial membrane (OMM). The common opinion is that the OMM is freely permeable to Ca2+. This idea is supported by the presence of a high density of voltage-dependent anion channels (VDACs) in the OMM, forming large Ca2+ permeable pores. However, several reports challenge this idea and describe VDAC as a regulated Ca2+ channel. In line with this idea is the notion that its Ca2+ selectivity depends on the open state of the channel, and its gating behavior can be modified by interaction with partner proteins, metabolites, or small synthetic molecules. Furthermore, mitochondrial Ca2+ uptake is controlled by the localization of VDAC through scaffolding proteins, which anchor VDAC to ER/SR calcium release channels. This review will discuss the possibility that VDAC serves as a physiological regulator of mitochondrial Ca2+ uptake in the OMM.
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10.
Calcium-calcineurin signaling pathway in Candida albicans: A potential drug target.
Li, W, Shrivastava, M, Lu, H, Jiang, Y
Microbiological research. 2021;:126786
Abstract
Increased morbidity and mortality of candidiasis are a notable threat to the immunocompromised patients. At present, the types of drugs available to treat C. albicans infection are relatively limited. Moreover, the emergence of antifungal drug resistance of C. albicans makes the treatment of C. albicans infection more difficult. The calcium-calcineurin signaling pathway plays a crucial role in the survival and pathogenicity of C. albicans and may act as a potential target against C. albicans. In this review, we summarized functions of the calcium-calcineurin signaling pathway in several biological processes, compared the differences of this signaling pathway between C. albicans and humans, and described anti-C. albicans activity of inhibitors of this signaling pathway. We believe that targeting the calcium-calcineurin signaling pathway is a promising strategy to cope with C. albicans infection.