Cell calcium最新文献

NMDA receptors are Ca²⁺-permeable ligand-gated ion channels that mediate fast excitatory transmission in the central nervous system. NMDA receptors regulate the proliferation and differentiation of neural progenitor cells and also play critical roles in neural plasticity, memory, and learning. In addition to their physiological role, NMDA receptors are also involved in glutamate-mediated excitotoxicity, which results from excessive glutamate stimulation, leading to Ca²⁺ overload, and ultimately to neuronal death. Thus, NMDA receptor-mediated excitotoxicity has been linked to several neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, dementia, and stroke. Interestingly, in addition to its effects on cell death, aberrant expression or activation of NMDA receptors is also involved in pathological cellular proliferation, and is implicated in the invasion and proliferation of various types of cancer. These disorders are thought to be related to the contribution of NMDA receptors to cell proliferation and cell death through cell cycle modulation. This review aims to discuss the evidence implicating NMDA receptor activity in cell cycle regulation and the link between aberrant NMDA receptor activity and the development of neurodegenerative diseases and cancer due to cell cycle dysregulation. The information presented here will provide insights into the signaling pathways and the contribution of NMDA receptors to these diseases, and suggests that NMDA receptors are promising targets for the prevention and treatment of these diseases, which are leading causes of death and disability worldwide.

In skeletal muscle (SM), inward Ca²⁺-currents have no apparent role in excitation-contraction coupling (e-c coupling), however the Ca²⁺-channel blocker can affect twitch and tetanic muscle in mammalian SM. Experiments were conducted to study how diltiazem (DLZ) facilitates e-c coupling and inhibits contraction. 1) In complete Extensor Digitorum Longus (EDL) muscle and single intact fibres, 0.03 mM DLZ causes twitch potentiation and decreases force during tetanic activity, with increased fatigue. 2) In split open fibres isolated from EDL fibres, DLZ inhibits sarcoplasmic reticulum (SR) Ca²⁺-loading in a dose-dependent manner and has a potentiating effect on caffeine-induced SR Ca²⁺-release. 3) In isolated light SR (LSR) vesicles, SERCA1 hydrolytic activity is not affected by DLZ up to 0.2 mM. However, ATP-dependent Ca²⁺-uptake was inhibited in a dose-dependent manner at a concentration where e-c coupling is changed. 4) The passive Ca²⁺-efflux from LSR was reduced by half with 0.03 mM diltiazem, indicating that SR leaking does not account for the decreased Ca²⁺-uptake. 5) The denaturation profile of the SERCA Ca²⁺-binding domain has lower thermal stability in the presence of DLZ in a concentration-dependent manner, having no effect on the nucleotide-binding domain. We conclude that the effect of DLZ on SM is exerted by crossing the sarcolemma and interacting directly with the SERCA Ca²⁺-binding domain, affecting SR Ca²⁺-loading during relaxation, which has a consequence on SM contractility. Diltiazem effect on SM could be utilized as a tool to understand SM e-c coupling and muscle fatigue.

Chloride ions (Cl⁻) play a pivotal role in synaptic inhibition in the central nervous system, primarily mediated through ionotropic mechanisms. A recent breakthrough emphathizes the significant influence of astrocytic intracellular chloride concentration ([Cl⁻]_i) regulation, a field still in its early stages of exploration. Typically, the [Cl⁻]_i in most animal cells is maintained at lower levels than the extracellular chloride [Cl⁻]_o, a critical balance to prevent cell swelling due to osmotic pressure. Various Cl⁻ transporters are expressed differently across cell types, fine-tuning the [Cl⁻]_i, while Cl⁻ gradients are utilised by several families of Cl⁻ channels. Although the passive distribution of ions within cells is governed by basic biophysical principles, astrocytes actively expend energy to sustain [Cl⁻]_i at much higher levels than those achieved passively, and much higher than neuronal [Cl⁻]_i. Beyond the role in volume regulation, astrocytic [Cl⁻]_i is dynamically linked to brain states and influences neuronal signalling in actively behaving animals. As a vital component of brain function, astrocytic [Cl⁻]_i also plays a role in the development of disorders where inhibitory transmission is disrupted. This review synthesises the latest insights into astrocytic [Cl⁻]_i, elucidating its role in modulating brain function and its implications in various pathophysiological conditions.

The necroptotic effector molecule MLKL accumulates in neurons over the lifespan of mice, and its downregulation has the potential to improve cognition through neuroinflammation, and changes in the abundance of synaptic proteins and enzymes in the central nervous system. Notwithstanding, direct evidence of cell-autonomous effects of MLKL expression on neuronal physiology and metabolism are lacking. Here, we tested whether the overexpression of MLKL in the absence of cell death in the neuronal cell line Neuro-2a recapitulates some of the hallmarks of aging at the cellular level. Using genetically-encoded fluorescent biosensors, we monitored the cytosolic and mitochondrial Ca²⁺ levels, along with the cytosolic concentrations of several metabolites involved in energy metabolism (lactate, glucose, ATP) and oxidative stress (oxidized/reduced glutathione). We found that MLKL overexpression marginally decreased cell viability, however, it led to reduced cytosolic and mitochondrial Ca²⁺ elevations in response to Ca²⁺ influx from the extracellular space. On the contrary, Ca²⁺ signals were elevated after mobilizing Ca²⁺ from the endoplasmic reticulum. Transient elevations in cytosolic Ca²⁺, mimicking neuronal stimulation, lead to higher lactate levels and lower glucose concentrations in Neuro-2a cells when overexpressing MLKL, which suggest enhanced neuronal glycolysis. Despite these alterations, energy levels and glutathione redox state in the cell bodies remained largely preserved after inducing MLKL overexpression for 24–48 h. Taken together, our proof-of-concept experiments are consistent with the hypothesis that MLKL overexpression in the absence of cell death contributes to both Ca²⁺ and metabolic dyshomeostasis, which are cellular hallmarks of brain aging.

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). On the other hand, the α2 Na⁺, K⁺ ATPase is upregulated in spinal cord and brain samples from amyotrophic lateral sclerosis and Alzheimer disease patients, respectively. In the last part, the review focuses on i) the migraine relevant phenotypes shown by familial hemiplegic migraine type 2 knock-in mice with 50 % reduced expression of the astrocytic α2 Na⁺, K⁺ ATPase and the insights into the pathophysiology of migraine obtained from these genetic mouse models, and ii) the evidence that upregulation of the astrocytic α2 Na⁺, K⁺ ATPase in mouse models of amyotrophic lateral sclerosis and Alzheimer disease promotes neuroinflammation and contributes to progressive neurodegeneration.

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. This review summarizes available information on TRPM2 temperature sensitivity, with a focus on recent mechanistic insight obtained in a cell-free system. Those biophysical results outline TRPM2 as a channel with an intrinsically endothermic opening transition, a temperature threshold strongly modulated by cytosolic agonist concentrations, and a response steepness greatly enhanced through a positive feedback loop generated by Ca²⁺ influx through the channel's pore. Complex observations in intact cells and apparent discrepancies between studies using in vivo and in vitro models are discussed and interpreted in light of the intrinsic biophysical properties of the channel protein.

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. Here we overview physiological and pathophysiological aspects of astrocyte-cantered trace metals regulation.

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. Daily tranilast (a TRPV2 inhibitor) or saline was given starting 1 day before PH establishment. PH increased the susceptibility to AF, with TRPV2 up-regulated in the right atria. Compared to PH rats, tranilast reduced AF inducibility and the prolongations of ERP and APD; mitigated cardiopulmonary remodeling and the increases in P-wave duration and P-R interval; partially reversed the down-regulation of ion channels such as Cav1.2, Nav1.5, Kv4.3, Kv4.2, Kv1.5, Kir2.1, Kir3.1, Kir3.4 as well as connexin (Cx) 40 and Cx43; improved right atrial (RA) fibrosis, enlargement, and myocardial hypertrophy; decreased the accumulation of inflammatory cells; down-regulated inflammatory indicators such as TNF-α, IL-1β, CXCL1, and CXCL2; and inhibited the activation of the PI3K-AKT-NF-κB signaling pathway. Our results reveal that TRPV2 participates in PH-induced AF, and TRPV2 inhibitor tranilast prevents PH-induced RA remodeling. TRPV2 might be a promising target for PH-induced AF.