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The relationship between calcium oscillation and cell sensitivity is poorly understood. Calcium oscillation can occur spontaneously or be triggered upon receptor-ligand binding. The cytosolic [Ca 2+ ] increase during calcium oscillation is initiated from Ca 2+ release from the intracellular stores through the phospholipase C (PLC)-derived inositol 1,4,5-trisphosphate (IP 3 ). Here, we show that neutrophil-like HL60 cells lacking PLCγ2 ( plcg2 kd ) exhibit impaired spontaneous calcium oscillation and a diminished calcium response to chemoattractant stimulation. These defects result in reduced membrane targeting of RasGAP CAPRI (calcium-promoted Ras inactivator), and subsequent elevated Ras activations and enhanced downstream signaling, including PI 3 Kγ activation and actin polymerization. Notably, plcg2 kd cells display increased sensitivity and can respond to chemoattractant gradients at a subsensitive concentrations. Taken together, our findings identify PLCγ2 as a key regulator of spontaneous and chemoattractant-induced calcium signaling and demonstrate its essential role in controlling cell sensitivity and chemoattractant concentration range for chemotaxis through CAPRI-dependent Ras signaling.

Stomatal movement is indispensable for plant growth and survival in response to environmental stimuli. Cytosolic Ca2+ elevation plays a crucial role in ABA‐induced stomatal closure during drought stress; however, to what extent the Ca2+ movement across the plasma membrane from the apoplast to the cytosol contributes to this process still needs clarification. Here the authors identify (−)‐catechin gallate (CG) and (−)‐gallocatechin gallate (GCG), components of green tea, as inhibitors of voltage‐dependent K+ channels which regulate K+ fluxes in Arabidopsis thaliana guard cells. In Arabidopsis guard cells CG/GCG prevent ABA‐induced: i) membrane depolarization; ii) activation of Ca2+ permeable cation (ICa) channels; and iii) cytosolic Ca2+ transients. In whole Arabidopsis plants co‐treatment with CG/GCG and ABA suppressed ABA‐induced stomatal closure and surface temperature increase. Similar to ABA, CG/GCG inhibited stomatal closure is elicited by the elicitor peptide, flg22 but has no impact on dark‐induced stomatal closure or light‐ and fusicoccin‐induced stomatal opening, suggesting that the inhibitory effect of CG/GCG is associated with Ca2+‐related signaling pathways. This study further supports the crucial role of ICa channels of the plasma membrane in ABA‐induced stomatal closure. Moreover, CG and GCG represent a new tool for the study of abiotic or biotic stress‐induced signal transduction pathways. Ingredients of green tea affect the growth of Arabidopsis thaliana under drought conditions. Catechin gallates and gallocatechin gallates inhibit plasma membrane‐located K+ channels and prevent Ca2+ entry in Arabidopsis guard cells. These catechin derivates are potent natural chemical regulators controlling plant growth and enabling the study of drought‐induced signaling pathways in guard cells.

Living systems maintain or increase local order by working against the second law of thermodynamics. Thermodynamic consistency is restored as they consume free energy, thereby increasing the net entropy of their environment. Recently introduced estimators for the entropy production rate have provided major insights into the efficiency of important cellular processes. In experiments, however, many degrees of freedom typically remain hidden to the observer, and, in these cases, existing methods are not optimal. Here, by reformulating the problem within an optimization framework, we are able to infer improved bounds on the rate of entropy production from partial measurements of biological systems. Our approach yields provably optimal estimates given certain measurable transition statistics. In contrast to prevailing methods, the improved estimator reveals nonzero entropy production rates even when nonequilibrium processes appear time symmetric and therefore may pretend to obey detailed balance. We demonstrate the broad applicability of this framework by providing improved bounds on the energy consumption rates in a diverse range of biological systems including bacterial flagella motors, growing microtubules, and calcium oscillations within human embryonic kidney cells.

The tricarboxylic acid (TCA) cycle is the main source of cellular energy and participates in many metabolic pathways in cells. Recent reports indicate that dysfunction of TCA cycle-related enzymes causes human diseases, such as neurometabolic disorders and tumors, have attracted increasing interest in their unexplained roles. The diseases which develop as a consequence of loss or dysfunction of TCA cycle-related enzymes are distinct, suggesting that each enzyme has a unique function. This review aims to provide a comprehensive overview of the relationship between each TCA cycle-related enzyme and human diseases. We also discuss their functions in the context of both mitochondrial and extra-mitochondrial (or cytoplasmic) enzymes.

Dynamic Ca 2+ signals reflect acute changes in membrane excitability, and also mediate signaling cascades in chronic processes. In both cases, chronic Ca 2+ imaging is often desired, but challenged by the cytotoxicity intrinsic to calmodulin (CaM)-based GCaMP, a series of genetically-encoded Ca 2+ indicators that have been widely applied. Here, we demonstrate the performance of GCaMP-X in chronic Ca 2+ imaging of cortical neurons, where GCaMP-X by design is to eliminate the unwanted interactions between the conventional GCaMP and endogenous (apo)CaM-binding proteins. By expressing in adult mice at high levels over an extended time frame, GCaMP-X showed less damage and improved performance in two-photon imaging of sensory (whisker-deflection) responses or spontaneous Ca 2+ fluctuations, in comparison with GCaMP. Chronic Ca 2+ imaging of one month or longer was conducted for cultured cortical neurons expressing GCaMP-X, unveiling that spontaneous/local Ca 2+ transients progressively developed into autonomous/global Ca 2+ oscillations. Along with the morphological indices of neurite length and soma size, the major metrics of oscillatory Ca 2+ , including rate, amplitude and synchrony were also examined. Dysregulations of both neuritogenesis and Ca 2+ oscillations became discernible around 2–3 weeks after virus injection or drug induction to express GCaMP in newborn or mature neurons, which were exacerbated by stronger or prolonged expression of GCaMP. In contrast, neurons expressing GCaMP-X were significantly less damaged or perturbed, altogether highlighting the unique importance of oscillatory Ca 2+ to neural development and neuronal health. In summary, GCaMP-X provides a viable solution for Ca 2+ imaging applications involving long-time and/or high-level expression of Ca 2+ probes.

Electromagnetic fields (EMF) are increasing in popularity as a safe and non-invasive therapy. On the one hand, it is widely acknowledged that EMF can regulate the proliferation and differentiation of stem cells, promoting the undifferentiated cells capable of osteogenesis, angiogenesis, and chondroblast differentiation to achieve bone repair purpose. On the other hand, EMF can inhibit tumor stem cells proliferation and promote apoptosis to suppress tumor growth. As an essential second messenger, intracellular calcium plays a role in regulating cell cycle, such as proliferation, differentiation and apoptosis. There is increasing evidence that the modulation of intracellular calcium ion by EMF leads to differential outcomes in different stem cells. This review summarizes the regulation of channels, transporters, and ion pumps by EMF-induced calcium oscillations. It furtherly discusses the role of molecules and pathways activated by EMF-dependent calcium oscillations in promoting bone and cartilage repair and inhibiting tumor stem cells growth.

Mammalian fertilization is triggered by a series of calcium (Ca[sup.2+]) oscillations that are essential for egg activation and successful embryo development. It is widely accepted that Phospholipase C zeta (PLCζ) is the sperm-derived factor that triggers these oscillations, initiating egg activation through the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP[sub.2]) into inositol 1,4,5-trisphosphate (IP[sub.3]) and diacylglycerol (DAG), leading to Ca[sup.2+] release. Several studies have reported a number of PLCζ mutations associated with polyspermy, egg activation failure and early embryonic arrest. Herein, six infertility-linked PLCζ mutations (I120M, L246F, L277P, S350P, A384V and M578T) spanning different domains of PLCζ were selected for characterization through in vivo assessment of their Ca[sup.2+]-oscillation-inducing activities and complementary in silico analysis. Our data revealed that five of the investigated PLCζ mutants exhibited reduced or complete loss of in vivo Ca[sup.2+]-oscillation-inducing activity, with the exception of the L277P, which resulted in increased frequency and duration of Ca[sup.2+] oscillations. Molecular modeling of PLCζ mutants was consistent with the in vivo characterization, revealing that most mutations have a deleterious effect on the structural stability. For the first time, we provide evidence that a gain-of-function PLCζ mutation may be a cause of fertilization failure in humans. Our findings suggest that PLCζ enzymatic activity must operate within an optimal range to ensure successful egg activation and early embryonic development. Additionally, we demonstrate the essential role of all PLCζ domains in maintaining the Ca[sup.2+] oscillation-inducing activity in eggs and the importance of PLCζ functionality in human fertilization.

The transient receptor potential vanilloid 4 (TRPV4) specifically functions as a mechanosensitive ion channel and is responsible for conveying changes in physical stimuli such as mechanical stress, osmotic pressure, and temperature. TRPV4 enables the entry of cation ions, particularly calcium ions, into the cell. Activation of TRPV4 channels initiates calcium oscillations, which trigger intracellular signaling pathways involved in a plethora of cellular processes, including tissue repair. Widely expressed throughout the body, TRPV4 can be activated by a wide array of physicochemical stimuli, thus contributing to sensory and physiological functions in multiple organs. This review focuses on how TRPV4 senses environmental cues and thereby initiates and maintains calcium oscillations, critical for responses to organ injury, tissue repair, and fibrosis. We provide a summary of TRPV4-induced calcium oscillations in distinct organ systems, along with the upstream and downstream signaling pathways involved. In addition, we delineate current animal and disease models supporting TRPV4 research and shed light on potential therapeutic targets for modulating TRPV4-induced calcium oscillation to promote tissue repair while reducing tissue fibrosis.

Calcium (Ca²+) release from intracellular stores, Ca²+ entry across the plasma membrane and their coordination via store-operated Ca²+ entry (SOCE) are critical for receptor-activated Ca²+ oscillations. However, the precise mechanism of Ca²+ oscillations and whether their control loop resides at the plasma membrane or intracellularly remains unresolved. By examining the dynamics of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum (ER)-localized Ca²+ sensor that activates the Orai1 channel on the plasma membrane for SOCE, in mast cells, we found that a significant proportion of cells exhibited STIM1 oscillations with the same periodicity as Ca²+ oscillations. These cortical oscillations, shared with ER–plasma membrane (ER-PM) contact site proteins, were only detectable using total internal reflection fluorescence microscopy. Notably, STIM1 oscillations could occur independently of Ca²+ oscillations. Simultaneous imaging of cytoplasmic Ca²+ and ER Ca²+ with CEPIA1er revealed that receptor activation does not deplete ER Ca²+, whereas receptor activation without extracellular Ca²+ influx induces cyclic ER Ca²+ depletion. However, under such non-physiological conditions, cyclic ER Ca²+ oscillations lead to sustained STIM1 recruitment, indicating that oscillatory Ca²+ release is neither necessary nor sufficient for STIM1 oscillations. Using optogenetic tools to manipulate ER-PM contact site dynamics, we found that persistent ER-PM contact sites reduced the amplitude of Ca²+ oscillations without alteration of oscillation frequency. Together, these findings suggest an active cortical mechanism governs the rapid dissociation of ER-PM contact sites, thereby controlling amplitude of oscillatory Ca²+ dynamics during receptor-induced Ca²+ oscillations.

The transmembrane docking of endoplasmic reticulum (ER) Ca2+-sensing STIM proteins with plasma membrane (PM) Orai Ca2+ channels is a critical but poorly understood step in Ca2+ signal generation. STIM1 protein dimers unfold to expose a discrete STIM–Orai activating region (SOAR1) that tethers and activates Orai1 channels within discrete ER–PM junctions. We reveal that each monomer within the SOAR dimer interacts independently with single Orai1 subunits to mediate cross-linking between Orai1 channels. Superresolution imaging and mobility measured by fluorescence recovery after photobleaching reveal that SOAR dimer cross-linking leads to substantial Orai1 channel clustering, resulting in increased efficacy and cooperativity of Orai1 channel function. A concatenated SOAR1 heterodimer containing one monomer point mutated at its critical Orai1 binding residue (F394H), although fully activating Orai channels, is completely defective in cross-linking Orai1 channels. Importantly, the naturally occurring STIM2 variant, STIM2.1, has an eight-amino acid insert in its SOAR unit that renders it functionally identical to the F394H mutant in SOAR1. Contrary to earlier predictions, the SOAR1–SOAR2.1 heterodimer fully activates Orai1 channels but prevents cross-linking and clustering of channels. Interestingly, combined expression of full-length STIM1 with STIM2.1 in a 5:1 ratio causes suppression of sustained agonist-induced Ca2+ oscillations and protects cells from Ca2+ overload, resulting from high agonist-induced Ca2+ release. Thus, STIM2.1 exerts a powerful regulatory effect on signal generation likely through preventing Orai1 channel cross-linking. Overall, STIM-mediated cross-linking of Orai1 channels is a hitherto unrecognized functional paradigm that likely provides an organizational microenvironment within ER–PM junctions with important functional impact on Ca2+ signal generation.