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Physiological Reviews Oct 2023Calcium signaling underlies much of physiology. Almost all the Ca in the cytoplasm is bound to buffers, with typically only ∼1% being freely ionized at resting levels... (Review)
Review
Calcium signaling underlies much of physiology. Almost all the Ca in the cytoplasm is bound to buffers, with typically only ∼1% being freely ionized at resting levels in most cells. Physiological Ca buffers include small molecules and proteins, and experimentally Ca indicators will also buffer calcium. The chemistry of interactions between Ca and buffers determines the extent and speed of Ca binding. The physiological effects of Ca buffers are determined by the kinetics with which they bind Ca and their mobility within the cell. The degree of buffering depends on factors such as the affinity for Ca, the Ca concentration, and whether Ca ions bind cooperatively. Buffering affects both the amplitude and time course of cytoplasmic Ca signals as well as changes of Ca concentration in organelles. It can also facilitate Ca diffusion inside the cell. Ca buffering affects synaptic transmission, muscle contraction, Ca transport across epithelia, and the killing of bacteria. Saturation of buffers leads to synaptic facilitation and tetanic contraction in skeletal muscle and may play a role in inotropy in the heart. This review focuses on the link between buffer chemistry and function and how Ca buffering affects normal physiology and the consequences of changes in disease. As well as summarizing what is known, we point out the many areas where further work is required.
Topics: Humans; Calcium; Buffers; Cytoplasm; Heart; Synaptic Transmission; Calcium Signaling
PubMed: 37326298
DOI: 10.1152/physrev.00042.2022 -
Nature Neuroscience Nov 2023The participation of astrocytes in brain computation was hypothesized in 1992, coinciding with the discovery that these cells display a form of intracellular Ca... (Review)
Review
The participation of astrocytes in brain computation was hypothesized in 1992, coinciding with the discovery that these cells display a form of intracellular Ca signaling sensitive to neuroactive molecules. This finding fostered conceptual leaps crystalized around the idea that astrocytes, once thought to be passive, participate actively in brain signaling and outputs. A multitude of disparate roles of astrocytes has since emerged, but their meaningful integration has been muddied by the lack of consensus and models of how we conceive the functional position of these cells in brain circuitry. In this Perspective, we propose an intuitive, data-driven and transferable conceptual framework we coin 'contextual guidance'. It describes astrocytes as 'contextual gates' that shape neural circuitry in an adaptive, state-dependent fashion. This paradigm provides fresh perspectives on principles of astrocyte signaling and its relevance to brain function, which could spur new experimental avenues, including in computational space.
Topics: Astrocytes; Signal Transduction; Neurons; Synapses; Brain; Calcium Signaling
PubMed: 37857773
DOI: 10.1038/s41593-023-01448-8 -
The Journal of Physiological Sciences :... Nov 2023Physiological roles of Cl, a major anion in the body, are not well known compared with those of cations. This review article introduces: (1) roles of Cl in bodily and... (Review)
Review
Physiological roles of Cl, a major anion in the body, are not well known compared with those of cations. This review article introduces: (1) roles of Cl in bodily and cellular functions; (2) the range of cytosolic Cl concentration ([Cl]); (3) whether [Cl] could change with cell volume change under an isosmotic condition; (4) whether [Cl] could change under conditions where multiple Cl transporters and channels contribute to Cl influx and efflux in an isosmotic state; (5) whether the change in [Cl] could be large enough to act as signals; (6) effects of Cl on cytoskeletal tubulin polymerization through inhibition of GTPase activity and tubulin polymerization-dependent biological activity; (7) roles of cytosolic Cl in cell proliferation; (8) Cl-regulatory mechanisms of ciliary motility; (9) roles of Cl in sweet/umami taste receptors; (10) Cl-regulatory mechanisms of with-no-lysine kinase (WNK); (11) roles of Cl in regulation of epithelial Na transport; (12) relationship between roles of Cl and H in body functions.
Topics: Chlorides; Tubulin; Ion Transport; Biological Transport; Sodium; Chloride Channels
PubMed: 37968609
DOI: 10.1186/s12576-023-00889-x -
Physiological Reviews Jul 2023The pulmonary circulation is a low-resistance, low-pressure, and high-compliance system that allows the lungs to receive the entire cardiac output. Pulmonary arterial... (Review)
Review
The pulmonary circulation is a low-resistance, low-pressure, and high-compliance system that allows the lungs to receive the entire cardiac output. Pulmonary arterial pressure is a function of cardiac output and pulmonary vascular resistance, and pulmonary vascular resistance is inversely proportional to the fourth power of the intraluminal radius of the pulmonary artery. Therefore, a very small decrease of the pulmonary vascular lumen diameter results in a significant increase in pulmonary vascular resistance and pulmonary arterial pressure. Pulmonary arterial hypertension is a fatal and progressive disease with poor prognosis. Regardless of the initial pathogenic triggers, sustained pulmonary vasoconstriction, concentric vascular remodeling, occlusive intimal lesions, in situ thrombosis, and vascular wall stiffening are the major and direct causes for elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension and other forms of precapillary pulmonary hypertension. In this review, we aim to discuss the basic principles and physiological mechanisms involved in the regulation of lung vascular hemodynamics and pulmonary vascular function, the changes in the pulmonary vasculature that contribute to the increased vascular resistance and arterial pressure, and the pathogenic mechanisms involved in the development and progression of pulmonary hypertension. We focus on reviewing the pathogenic roles of membrane receptors, ion channels, and intracellular Ca signaling in pulmonary vascular smooth muscle cells in the development and progression of pulmonary hypertension.
Topics: Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Ion Channels; Lung; Vasoconstriction; Calcium Signaling; Myocytes, Smooth Muscle
PubMed: 36422993
DOI: 10.1152/physrev.00030.2021 -
Free Radical Biology & Medicine Aug 2023Endoplasmic reticulum (ER) and mitochondria are the main sites for the storage and regulation of Ca homeostasis. An imbalance of Ca homeostasis can cause ER stress and...
Endoplasmic reticulum (ER) and mitochondria are the main sites for the storage and regulation of Ca homeostasis. An imbalance of Ca homeostasis can cause ER stress and mitochondrial dysfunction, thereby inducing apoptosis. The store-operated calcium entry (SOCE) is the main channel for extracellular calcium influx. Mitochondria-associated endoplasmic reticulum (MAM) is an important agent for Ca transfer from the ER to the mitochondria. Therefore, regulation of SOCE and MAMs has potential therapeutic value for disease prevention and treatment. In this study, bovine mammary epithelial cells (BMECs) and mice were used as models to explore the mechanisms of β-carotene to relieve ER stress and mitochondrial dysfunction. BAPTA-AM, EGTA (Ca inhibitor), and BTP2 (SOCE channel inhibitor) alleviated ER stress and mitochondrial oxidative damage induced by increased intracellular Ca levels after lipopolysaccharide (LPS) stimulation. Furthermore, inhibition of ER stress by 4-PBA (ER stress inhibitor), 2-APB (IP3R inhibitor), and ruthenium red (mitochondrial calcium uniporter (MCU) inhibitor) restored mitochondrial function by reducing mitochondrial ROS. Our data also confirm that β-carotene targeted STIM1 and IP3R channels to repair LPS-induced ER stress and mitochondrial disorders. Consistent with the in vitro study, in vito experiments in mice further showed that β-carotene attenuated LPS-induced ER stress and mitochondrial oxidative damage by inhibiting the expression of STIM1 and ORAI1, and reducing the level of Ca in mouse mammary glands. Therefore, ER stress-mitochondrial oxidative damage mediated by the STIM1-ER-IP3R/GRP75/VDAC1-MCU axis plays an vital role in the development of mastitis. Our results provided novel ideas and therapeutic targets for the prevention and treatment of mastitis.
Topics: Animals; Mice; Cattle; Lipopolysaccharides; beta Carotene; Calcium; Mitochondria; Calcium Signaling; Oxidative Stress
PubMed: 37270031
DOI: 10.1016/j.freeradbiomed.2023.05.021 -
Science (New York, N.Y.) Mar 2024Endocannabinoid (eCB)-mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the...
Endocannabinoid (eCB)-mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the difficulty in tracking eCB dynamics and synaptic plasticity during behavior. In mice navigating a linear track, we observed location-specific eCB signaling in hippocampal CA1 place cells, and this was detected both in the postsynaptic membrane and the presynaptic inhibitory axons. All-optical in vivo investigation of synaptic responses revealed that postsynaptic depolarization was followed by a suppression of inhibitory synaptic potentials. Furthermore, interneuron-specific cannabinoid receptor deletion altered place cell tuning. Therefore, rapid, postsynaptic, activity-dependent eCB signaling modulates inhibitory synapses on a timescale of seconds during behavior.
Topics: Animals; Mice; Endocannabinoids; Neuronal Plasticity; Synapses; Synaptic Transmission; Calcium Signaling; CA1 Region, Hippocampal; Inhibitory Postsynaptic Potentials; Receptor, Cannabinoid, CB1; Male; Female; Mice, Knockout
PubMed: 38422134
DOI: 10.1126/science.adk3863 -
Biomolecules Feb 2024The dysregulation of intracellular calcium levels is a critical factor in neurodegeneration, leading to the aberrant activation of calcium-dependent processes and,... (Review)
Review
The dysregulation of intracellular calcium levels is a critical factor in neurodegeneration, leading to the aberrant activation of calcium-dependent processes and, ultimately, cell death. Ca signals vary in magnitude, duration, and the type of neuron affected. A moderate Ca concentration can initiate certain cellular repair pathways and promote neuroregeneration. While the peripheral nervous system exhibits an intrinsic regenerative capability, the central nervous system has limited self-repair potential. There is evidence that significant variations exist in evoked calcium responses and axonal regeneration among neurons, and individual differences in regenerative capacity are apparent even within the same type of neurons. Furthermore, some studies have shown that neuronal activity could serve as a potent regulator of this process. The spatio-temporal patterns of calcium dynamics are intricately controlled by a variety of proteins, including channels, ion pumps, enzymes, and various calcium-binding proteins, each of which can exert either positive or negative effects on neural repair, depending on the cellular context. In this concise review, we focus on several calcium-associated proteins such as CaM kinase II, GAP-43, oncomodulin, caldendrin, calneuron, and NCS-1 in order to elaborate on their roles in the intrinsic mechanisms governing neuronal regeneration following traumatic damage processes.
Topics: Calcium; Neurons; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Nerve Regeneration
PubMed: 38397420
DOI: 10.3390/biom14020183 -
Proceedings of the National Academy of... Jul 2023Osteoarthritis is a chronic disease that can be initiated by altered joint loading or injury of the cartilage. The mechanically sensitive PIEZO ion channels have been...
Osteoarthritis is a chronic disease that can be initiated by altered joint loading or injury of the cartilage. The mechanically sensitive PIEZO ion channels have been shown to transduce injurious levels of biomechanical strain in articular chondrocytes and mediate cell death. However, the mechanisms of channel gating in response to high cellular deformation and the strain thresholds for activating PIEZO channels remain unclear. We coupled studies of single-cell compression using atomic force microscopy (AFM) with finite element modeling (FEM) to identify the biophysical mechanisms of PIEZO-mediated calcium (Ca) signaling in chondrocytes. We showed that PIEZO1 and PIEZO2 are needed for initiating Ca signaling at moderately high levels of cellular deformation, but at the highest strains, PIEZO1 functions independently of PIEZO2. Biophysical factors that increase apparent chondrocyte membrane tension, including hypoosmotic prestrain, high compression magnitudes, and low deformation rates, also increased PIEZO1-driven Ca signaling. Combined AFM/FEM studies showed that 50% of chondrocytes exhibit Ca signaling at 80 to 85% nominal cell compression, corresponding to a threshold of apparent membrane finite principal strain of E = 1.31, which represents a membrane stretch ratio (λ) of 1.9. Both intracellular and extracellular Ca are necessary for the PIEZO1-mediated Ca signaling response to compression. Our results suggest that PIEZO1-induced signaling drives chondrocyte mechanical injury due to high membrane tension, and this threshold can be altered by factors that influence membrane prestress, such as cartilage hypoosmolarity, secondary to proteoglycan loss. These findings suggest that modulating PIEZO1 activation or downstream signaling may offer avenues for the prevention or treatment of osteoarthritis.
Topics: Humans; Chondrocytes; Ion Channels; Joints; Osteoarthritis; Mechanotransduction, Cellular; Calcium Signaling
PubMed: 37459546
DOI: 10.1073/pnas.2221958120 -
Circulation Research Jul 2023
Topics: Ryanodine Receptor Calcium Release Channel; Myocytes, Cardiac; Calcium Signaling; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Sarcoplasmic Reticulum
PubMed: 37410856
DOI: 10.1161/CIRCRESAHA.123.323144 -
Cell Calcium Jul 2023Alterations in calcium (Ca) signaling is a major mechanism in the development of chemotherapy-induced peripheral neuropathy (CIPN), a side effect caused by multiple...
Alterations in calcium (Ca) signaling is a major mechanism in the development of chemotherapy-induced peripheral neuropathy (CIPN), a side effect caused by multiple chemotherapy regimens. CIPN is associated with numbness and incessant tingling in hands and feet which diminishes quality of life during treatment. In up to 50% of survivors, CIPN is essentially irreversible. There are no approved, disease-modifying treatments for CIPN. The only recourse for oncologists is to modify the chemotherapy dose, a situation that can compromise optimal chemotherapy and impact patient outcomes. Here we focus on taxanes and other chemotherapeutic agents that work by altering microtubule assemblies to kill cancer cells, but also have off-target toxicities. There have been many molecular mechanisms proposed to explain the effects of microtubule-disrupting drugs. In neurons, an initiating step in the off-target effects of treatment by taxane is binding to neuronal calcium sensor 1 (NCS1), a sensitive Ca sensor protein that maintains the resting Ca concentration and dynamically enhances responses to cellular stimuli. The taxane/NCS1 interaction causes a Ca surge that starts a pathophysiological cascade of consequences. This same mechanism contributes to other conditions including chemotherapy-induced cognitive impairment. Strategies to prevent the Ca surge are the foundation of current work.
Topics: Humans; Antineoplastic Agents; Quality of Life; Calcium Signaling; Peripheral Nervous System Diseases
PubMed: 37244172
DOI: 10.1016/j.ceca.2023.102762