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TRPM8 is a cold temperature‐sensitive and non‐selective Ca2+‐channel. Previously we have observed that TRPM8 is endogenously expressed and affects T cell activation process. Now, we report that TRPM8 regulates functions of mitochondria and ER, two important sub‐cellular compartments. Pharmacological modulation of TRPM8 and/or due to TCR‐treatment regulates mitochondrial Ca2+, ATP, membrane potential, cardiolipin level and mitochondrial temperature in a context‐dependent manner. In addition, TRPM8 alters the relative temperature of mitochondria and ER, ER‐mitochondrial contact points, mainly at the immunological synapse (IS), and thus TRPM8 has the potential to affect the overall cellular functions. Our data suggests both, i.e., the presence and enrichment of TRPM8 in the IS of T cells. We suggest that TRPM8 is a crucial regulator of Ca2+‐signalling in T cells and significantly contributes to Ca2+‐buffering by modulating cellular and sub‐cellular organelle functions. These findings are useful to understand the functions of T cells in different pathological conditions.

In eukaryotic cells, hormones and neurotransmitters that engage the phosphoinositide pathway evoke a biphasic increase in intracellular free Ca 2+ concentration: an initial transient release of Ca 2+ from intracellular stores is followed by a sustained phase of Ca 2+ influx. This influx is generally store dependent. Most attention has focused on the link between the endoplasmic reticulum and store‐operated Ca 2+ channels in the plasma membrane. Here, we describe that respiring mitochondria are also essential for the activation of macroscopic store‐operated Ca 2+ currents under physiological conditions of weak intracellular Ca 2+ buffering. We further show that Ca 2+ ‐dependent slow inactivation of Ca 2+ influx, a widespread but poorly understood phenomenon, is regulated by mitochondrial buffering of cytosolic Ca 2+ . Thus, by enabling macroscopic store‐operated Ca 2+ current to activate, and then by controlling its extent and duration, mitochondria play a crucial role in all stages of store‐operated Ca 2+ influx. Store‐operated Ca 2+ entry reflects a dynamic interplay between endoplasmic reticulum, mitochondria and plasma membrane.

The contribution of an impaired astrocytic K+ regulation system to epileptic neuronal hyperexcitability has been increasingly recognized in the last decade. A defective K+ regulation leads to an elevated extracellular K+ concentration ([K+]o). When [K+]o reaches peaks of 10-12 mM, it is strongly associated with seizure initiation during hypersynchronous neuronal activities. On the other hand, reactive astrocytes during a seizure attack restrict influx of K+ across the membrane both passively and actively. In addition to decreased K+ buffering, aberrant Ca2+ signaling and declined glutamate transport have also been observed in astrogliosis in epileptic specimens, precipitating an increased neuronal discharge and induction of seizures. This review aims to provide an overview of experimental findings that implicated astrocytic modulation of extracellular K+ in the mechanism of epileptogenesis.

Transient cytosolic calcium ([Ca(2+)](cyt)) elevation is an ubiquitous denominator of the signaling network when plants are exposed to literally every known abiotic and biotic stress. These stress-induced [Ca(2+)](cyt) elevations vary in magnitude, frequency, and shape, depending on the severity of the stress as well the type of stress experienced. This creates a unique stress-specific calcium \"signature\" that is then decoded by signal transduction networks. While most published papers have been focused predominantly on the role of Ca(2+) influx mechanisms to shaping [Ca(2+)](cyt) signatures, restoration of the basal [Ca(2+)](cyt) levels is impossible without both cytosolic Ca(2+) buffering and efficient Ca(2+) efflux mechanisms removing excess Ca(2+) from cytosol, to reload Ca(2+) stores and to terminate Ca(2+) signaling. This is the topic of the current review. The molecular identity of two major types of Ca(2+) efflux systems, Ca(2+)-ATPase pumps and Ca(2+)/H(+) exchangers, is described, and their regulatory modes are analyzed in detail. The spatial and temporal organization of calcium signaling networks is described, and the importance of existence of intracellular calcium microdomains is discussed. Experimental evidence for the role of Ca(2+) efflux systems in plant responses to a range of abiotic and biotic factors is summarized. Contribution of Ca(2+)-ATPase pumps and Ca(2+)/H(+) exchangers in shaping [Ca(2+)](cyt) signatures is then modeled by using a four-component model (plasma- and endo-membrane-based Ca(2+)-permeable channels and efflux systems) taking into account the cytosolic Ca(2+) buffering. It is concluded that physiologically relevant variations in the activity of Ca(2+)-ATPase pumps and Ca(2+)/H(+) exchangers are sufficient to fully describe all the reported experimental evidence and determine the shape of [Ca(2+)](cyt) signatures in response to environmental stimuli, emphasizing the crucial role these active efflux systems play in plant adaptive responses to environment.

Cancer, the second cause of death worldwide, is characterized by several common criteria, known as the \"cancer hallmarks\" such as unrestrained cell proliferation, cell death resistance, angiogenesis, invasion and metastasis. Calcium permeable channels are proteins present in external and internal biological membranes, diffusing Ca2+ ions down their electrochemical gradient. Numerous physiological functions are mediated by calcium channels, ranging from intracellular calcium homeostasis to sensory transduction. Consequently, calcium channels play important roles in human physiology and it is not a surprise the increasing number of evidences connecting calcium channels disorders with tumor cells growth, survival and migration. Multiple studies suggest that calcium signals are augmented in various cancer cell types, contributing to cancer hallmarks. This review focuses in the role of calcium permeable channels signaling in cancer with special attention to the mechanisms behind the remodeling of the calcium signals. Transient Receptor Potential (TRP) channels and Store Operated Channels (SOC) are the main extracellular Ca2+ source in the plasma membrane of non-excitable cells, while inositol trisphosphate receptors (IP3R) are the main channels releasing Ca2+ from the endoplasmic reticulum (ER). Alterations in the function and/or expression of these calcium channels, as wells as, the calcium buffering by mitochondria affect intracellular calcium homeostasis and signaling, contributing to the transformation of normal cells into their tumor counterparts. Several compounds reported to counteract several cancer hallmarks also modulate the activity and/or the expression of these channels including non-steroidal anti-inflammatory drugs (NSAIDs) like sulindac and aspirin, and inhibitors of polyamine biosynthesis, like difluoromethylornithine (DFMO). The possible role of the calcium permeable channels targeted by these compounds in cancer and their action mechanism will be discussed also in the review.

The bioenergetic system of calcium ([Ca 2+ ]), inositol 1, 4, 5-trisphophate (IP 3 ) and nitric oxide (NO) regulate the diverse mechanisms in neurons. The dysregulation in any or all of the calcium, IP 3 and nitric oxide dynamics may cause neurotoxicity and cell death. Few studies are noted in the literature on the interactions of two systems like [Ca 2+ ] with IP 3 and [Ca 2+ ] with nitric oxide in neuron cells, which gives limited insights into regulatory and dysregulatory processes in neuron cells. But, no study is available on the cross talk in dynamics of three systems [Ca 2+ ], IP 3 and NO in neurons. Thus, the cross talk in the system dynamics of [Ca 2+ ], IP 3 and NO regulation processes in neurons have been studied using mathematical model. The two-way feedback process between [Ca 2+ ] and IP 3 and two-way feedback process between [Ca 2+ ] and NO through cyclic guanosine monophosphate (cGMP) with plasmalemmal [Ca 2+ ]-ATPase (PMCA) have been incorporated in the proposed model. This coupling handles the indirect two-way feedback process between IP 3 and nitric oxide in neuronal cells automatically. The numerical outcomes were acquired by employing the finite element method (FEM) with the Crank-Nicholson scheme (CNS). The present model incorporating the sodium-calcium exchanger (NCX) and voltage-gated calcium channel (VGCC) provides novel insights into the various regulatory and dysregulatory processes due to buffer, IP 3 -receptor, ryanodine receptor, cGMP kinetics through PMCA channel, etc. and their impacts on the interactive spatiotemporal system dynamics of [Ca 2+ ], IP 3 and NO in neurons. It is concluded that the behavior of different crucial mechanisms is quite different for interactions of two systems of [Ca 2+ ] and NO and the interactions of three systems of [Ca 2+ ], IP 3 and nitric oxide in neuronal cell due to mutual regulatory adjustments. The association of several neurological disorders with the alterations in calcium, IP 3 and NO has been explored in neurons.

Background Sodium–glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF. Methods 17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca 2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca 2+ release were recorded by ratiometric microscopy using Ca 2+ -sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca 2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student’s t-test, as applicable. Results Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro , LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca 2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca 2+ ] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium–calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca 2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca 2+ accumulation upon glycolytic inhibition. Conclusion The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca 2+ -mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca 2+ buffer capacity, diastolic Ca 2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.

All life processes depend on the precise spatiotemporal expression of genes, which involves orderly processes including transcription, posttranscriptional processing, translation, and posttranslational modification. Accumulating evidence demonstrates that Ca 2+ is the most critical second messenger that orchestrates nearly all fundamental biological processes vital for maintaining normal physiological functions. Ca 2+ homeostasis/signaling is primarily maintained through Ca 2+ influx, cytoplasmic Ca 2+ release, Ca 2+ store cycling, and binding and release of Ca 2+ buffers. Their coordinated interactions ensure that Ca 2+ concentrations remain within the physiologically appropriate range. Ca 2+ signaling must be appropriately activated or suppressed during cellular signal transduction to support specific functions, and its dysregulation can trigger various pathological conditions. This review summarizes recent progress in Ca 2+ signaling regulatory networks, including the roles of key regulatory elements/toolkits, the functional significance of Ca 2+ signals in different microdomains, and the influence of Ca 2+ signaling on gene expression, along with the underlying mechanisms at various stages of gene expression. The involvement of Ca 2+ , both independently and collaboratively, in the nucleus, cytoplasm, subcellular microdomains such as mitochondria, and the extracellular space, in the multi-level regulation of gene expression, has been extensively studied. This information is essential for understanding the mechanisms underlying gene expression and for advancing the diagnosis and treatment of diseases. Finally, we propose forward-looking recommendations to address current research gaps, aiming to provide valuable references for researchers in this field. Graphical abstract

Calcium ions (Ca2+) serve as a crucial signaling mechanism in almost all cells. The buffers are proteins that bind free Ca2+ to reduce the cell’s Ca2+ concentration. The most studies reported in the past on calcium signaling in various cells have considered the buffer concentration as constant in the cell. However, buffers also diffuse and their concentration varies dynamically in the cells. Almost no work has been reported on interdependent calcium and buffer dynamics in the cells. In the present study, a model is proposed for inter-dependent spatio-temporal dynamics of calcium and buffer by coupling reaction–diffusion equations of Ca2+ and buffer in a hepatocyte cell. Boundary and initial conditions are framed based on the physiological state of the cell. The effect of various parameters viz. inositol 1,4,5-triphosphate receptor (IP3R), diffusion coefficient, SERCA pump and ryanodine receptor (RyR) on spatio-temporal dynamics of calcium and buffer regulating diacylglycerol (DAG) in a normal and obese hepatocyte cell has been studied using finite element simulation. From the results, it is concluded that the dynamics of calcium and buffer impact each other significantly along the spatio-temporal dimensions, thereby affecting the regulation of all the processes including DAG in a hepatocyte cell. The proposed model is more realistic than the existing ones, as the interdependent system dynamics of calcium and buffer have different regulatory impacts as compared to the individual and independent dynamics of these signaling processes in a hepatocyte cell.

The molecular mechanisms leading to saliva secretion are largely established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren’s syndrome (SS) are not fully understood. A major conundrum is the lack of association between the severity of salivary gland immune cell infiltration and glandular hypofunction. SS-like disease was induced by treatment with DMXAA, a small molecule agonist of murine STING. We have previously shown that the extent of salivary secretion is correlated with the magnitude of intracellular Ca 2+ signals (Takano et al., 2021). Contrary to our expectations, despite a significant reduction in fluid secretion, neural stimulation resulted in enhanced Ca 2+ signals with altered spatiotemporal characteristics in vivo. Muscarinic stimulation resulted in reduced activation of the Ca 2+ -activated Cl - channel, TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca 2+ . Super-resolution microscopy revealed a disruption in the colocalization of Inositol 1,4,5-trisphosphate receptor Ca 2+ release channels with TMEM16a, and channel activation was reduced when intracellular Ca 2+ buffering was increased. These data indicate altered local peripheral coupling between the channels. Appropriate Ca 2+ signaling is also pivotal for mitochondrial morphology and bioenergetics. Disrupted mitochondrial morphology and reduced oxygen consumption rate were observed in DMXAA-treated animals. In summary, early in SS disease, dysregulated Ca 2+ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction.