Cell Calcium

The Na+ , K+ ATPases play a fundamental role in the homeostatic functions of astrocytes. After a brief historic prologue and discussion of the subunit composition and localization of the astrocytic Na+ , K+ ATPases, the review focuses on the role of the astrocytic Na+ , K+ pumps in extracellular K+ and glutamate homeostasis, intracellular Na+ and Ca2+ homeostasis and signaling, regulation of synaptic transmission and neurometabolic coupling between astrocytes and neurons. Loss-of-function mutations in the gene encoding the astrocytic α2 Na+ , K+ ATPase cause a rare monogenic form of migraine with aura (familial hemiplegic migraine type 2)...

The Transient Receptor Potential Melastatin 2 (TRPM2) channel is a homotetrameric ligand-gated cation channel opened by the binding of cytosolic ADP ribose (ADPR) and Ca2+ . In addition, strong temperature dependence of its activity has lately become a center of attention for both physiological and biophysical studies. TRPM2 temperature sensitivity has been affirmed to play a role in central and peripheral thermosensation, pancreatic insulin secretion, and immune cell function. On the other hand, a number of different underlying mechanisms have been proposed from studies in intact cells...

Several trace metals, including iron, copper, manganese and zinc are essential for normal function of the nervous system. Both deficiency and excessive accumulation of these metals trigger neuropathological developments. The central nervous system (CNS) is in possession of dedicated homeostatic system that removes, accumulates, stores and releases these metals to fulfil nervous tissue demand. This system is mainly associated with astrocytes that act as dynamic reservoirs for trace metals, these being a part of a global system of CNS ionostasis...

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Atrial fibrillation (AF) is common in pulmonary hypertension (PH), whereas the mechanisms and treatments remain to be explored. TRPV2 regulates the structure and function of the cardiovascular system; however, little attention has been given to its role in AF. This study was to determine whether TRPV2 was involved in PH-induced AF and the effects of TRPV2 inhibitor tranilast on AF in rat models of PH. Monocrotaline (MCT) and SU5416/hypoxia (SuHx)-induced PH models were performed to detect atrial electrophysiological parameters...

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Ca2+ signaling is essential for cardiac contractility and excitability in heart function and remodeling. Intriguingly, little is known about the role of a new family of ion channels, the endo-lysosomal non-selective cation "two-pore channel" (TPCs) in heart function. Here we have used double TPC knock-out mice for the 1 and 2 isoforms of TPCs (Tpcn1/2-/- ) and evaluated their cardiac function. Doppler-echocardiography unveils altered left ventricular (LV) systolic function associated with a LV relaxation impairment...

No abstract text is available yet for this article.

Epigenetic mechanisms regulate multiple cell functions like gene expression and chromatin conformation and stability, and its misregulation could lead to several diseases including cancer. Epigenetic drugs are currently under investigation in a broad range of diseases, but the cellular processes involved in regulating epigenetic mechanisms are not fully understood. Calcium (Ca2+ ) signaling regulates several cellular mechanisms such as proliferation, gene expression, and metabolism, among others. Moreover, Ca2+ signaling is also involved in diseases such as neurological disorders, cardiac, and cancer...

Spatio-temporal definition of Ca2+ signals involves the assembly of signaling complexes within the nano-architecture of contact sites between the sarco/endoplasmic reticulum (SR/ER) and the plasma membrane (PM). While the requirement of precise spatial assembly and positioning of the junctional signaling elements is well documented, the role of the nano-scale membrane architecture itself, as an ion-reflecting confinement of the signalling unit, remains as yet elusive. Utilizing the Na+ /Ca2+ Exchanger-1 / SR/ER Ca2+ ATPase-2-mediated ER Ca2+ refilling process as a junctional signalling paradigm, we provide here the first evidence for an indispensable cellular function of the junctional membrane architecture...

Many physiological functions, such as cell differentiation, proliferation, muscle contraction, neurotransmission and fertilisation, are regulated by changes of Ca2+ levels. The major Ca2+ store in cells is the endoplasmic reticulum (ER). Certain cellular processes induce ER store depletion, e.g. by activating IP3 receptors, that in turn induces a store refilling process known as store-operated calcium entry (SOCE). This refilling process entails protein-protein interactions between Ca2+ sensing stromal interaction molecules (STIM) in the ER membrane and Orai proteins in the plasma membrane...

No abstract text is available yet for this article.

Mutations in the small, calcium-sensing, protein calmodulin cause cardiac arrhythmia and can ultimately prove lethal. Here, we report the impact of the G113R variant on the structure and dynamics of the calmodulin molecule, both in the presence and in the absence of calcium. We show that the mutation introduces minor changes into the structure of calmodulin and that it changes the thermostability and thus the degree of foldedness at human body temperature. The mutation also severely impacts the intramolecular mobility of calmodulin, especially in the apo form...

There have been in the last three decades repeated publications indicating that the inositol 1,4,5-trisphosphate receptor (IP3 R) is regulated not only by cytosolic Ca2+ but also by intraluminal Ca2+ . Although most studies indicated that a decreasing intraluminal Ca2+ level led to an inhibition of the IP3 R, a number of publications reported exactly the opposite effect, i.e. an inhibition of the IP3 R by high intraluminal Ca2+ levels. Although intraluminal Ca2+ -binding sites on the IP3 Rs were reported, a regulatory role for them was not demonstrated...

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is frequently caused by mutations in the β-cardiac myosin heavy chain gene (MYH7). Abnormal calcium handling and diastolic dysfunction are archetypical features of HCM caused by MYH7 gene mutations. However, the mechanism of how MYH7 mutations leads to these features remains unclear, which inhibits the development of effective therapies. Initially, cardiomyocytes were generated from induced pluripotent stem cells from an eight-year-old girl diagnosed with HCM carrying a MYH7(C...

Ca2+ /calmodulin-dependent protein kinase kinase (CaMKK) phosphorylates and activates downstream protein kinases, including CaMKI, CaMKIV, PKB/Akt, and AMPK; thus, regulates various Ca2+ -dependent physiological and pathophysiological pathways. Further, CaMKKβ/2 in mammalian species comprises multiple alternatively spliced variants; however, their functional differences or redundancy remain unclear. In this study, we aimed to characterize mouse CaMKKβ/2 splice variants (CaMKKβ-3 and β-3x)...

Calcium is a universal intracellular messenger and proper Ca2+ concentrations ([Ca2+ ]) both in the cytosol and in the lumen of cytoplasmic organelles are essential for cell functions. Ca2+ homeostasis is achieved by a delicate pump/leak balance both at the plasma membrane and at the endomembranes, and improper Ca2+ levels result in malfunction and disease. Selective intraorganellar Ca2+ measurements are best achieved by using targeted genetically encoded Ca2+ indicators (GECIs) but to calibrate the luminal fluorescent signals into accurate [Ca2+ ] is challenging, especially in vivo, due to the difficulty to normalize and calibrate the fluorescent signal in various tissues or conditions...

Neuronal activity and neurochemical stimulation trigger spatio-temporal changes in the cytoplasmic concentration of Na+ ions in astrocytes. These changes constitute the substrate for Na+ signalling and are fundamental for astrocytic excitability. Astrocytic Na+ signals are generated by Na+ influx through neurotransmitter transporters, with primary contribution of glutamate transporters, and through cationic channels; whereas recovery from Na+ transients is mediated mainly by the plasmalemmal Na+ /K+ ATPase...

Ryanodine receptors (RyR) are intracellular Ca2+ channels localized in the endoplasmic reticulum, where they act as critical mediators of Ca2+ -induced Ca2+ calcium release (CICR). In the brain, mammals express in both neurons, and non-neuronal cells, a combination of the three RyR-isoforms (RyR1-3). Pharmacological approaches, which do not distinguish between isoforms, have indicated that RyR-isoforms contribute to brain function. However, isoform-specific manipulations have revealed that RyR-isoforms display different subcellular localizations and are differentially associated with neuronal function...

NCX1, NCX2, and NCX3 gene isoforms and their splice variants are characteristically expressed in different regions of the brain. The tissue-specific splice variants of NCX1-3 isoforms show specific expression profiles in neurons and astrocytes, whereas the relevant NCX isoform/splice variants exhibit diverse allosteric modes of Na+ - and Ca2+ -dependent regulation. In general, overexpression of NCX1-3 genes leads to neuroprotective effects, whereas their ablation gains the opposite results. At this end, the partial contributions of NCX isoform/splice variants to neuroprotective effects remain unresolved...