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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 -
Nature Nov 2023A fundamental and unresolved question in regenerative biology is how tissues return to homeostasis after injury. Answering this question is essential for understanding...
A fundamental and unresolved question in regenerative biology is how tissues return to homeostasis after injury. Answering this question is essential for understanding the aetiology of chronic disorders such as inflammatory bowel diseases and cancer. We used the Drosophila midgut to investigate this and discovered that during regeneration a subpopulation of cholinergic neurons triggers Ca currents among intestinal epithelial cells, the enterocytes, to promote return to homeostasis. We found that downregulation of the conserved cholinergic enzyme acetylcholinesterase in the gut epithelium enables acetylcholine from specific Egr (TNF in mammals)-sensing cholinergic neurons to activate nicotinic receptors in innervated enterocytes. This activation triggers high Ca, which spreads in the epithelium through Innexin2-Innexin7 gap junctions, promoting enterocyte maturation followed by reduction of proliferation and inflammation. Disrupting this process causes chronic injury consisting of ion imbalance, Yki (YAP in humans) activation, cell death and increase of inflammatory cytokines reminiscent of inflammatory bowel diseases. Altogether, the conserved cholinergic pathway facilitates epithelial Ca currents that heal the intestinal epithelium. Our findings demonstrate nerve- and bioelectric-dependent intestinal regeneration and advance our current understanding of how a tissue returns to homeostasis after injury.
Topics: Animals; Humans; Acetylcholine; Acetylcholinesterase; Calcium; Calcium Signaling; Cholinergic Neurons; Drosophila melanogaster; Enterocytes; Homeostasis; Inflammation; Inflammatory Bowel Diseases; Intestines; Receptors, Nicotinic; Disease Models, Animal
PubMed: 37722602
DOI: 10.1038/s41586-023-06627-y -
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 -
Journal of Experimental & Clinical... Aug 2023Bone metastasis is a principal cause of mortality in patients with prostate cancer (PCa). Increasing evidence indicates that high expression of stromal interaction...
BACKGROUND
Bone metastasis is a principal cause of mortality in patients with prostate cancer (PCa). Increasing evidence indicates that high expression of stromal interaction molecule 1 (STIM1)-mediated store-operated calcium entry (SOCE) significantly activates the calcium (Ca) signaling pathway and is involved in multiple steps of bone metastasis in PCa. However, the regulatory mechanism and target therapy of STIM1 is poorly defined.
METHODS
Liquid chromatography-mass spectrometry analysis was performed to identify tetraspanin 18 (TSPAN18) as a binding protein of STIM1. Co-IP assay was carried out to explore the mechanism by which TSPAN18 inhibits STIM1 degradation. The biological function of TSPAN18 in bone metastasis of PCa was further investigated in vitro and in vivo models.
RESULT
We identified that STIM1 directly interacted with TSPAN18, and TSPAN18 competitively inhibited E3 ligase tripartite motif containing 32 (TRIM32)-mediated STIM1 ubiquitination and degradation, leading to increasing STIM1 protein stability. Furthermore, TSPAN18 significantly stimulated Ca influx in an STIM1-dependent manner, and then markedly accelerated PCa cells migration and invasion in vitro and bone metastasis in vivo. Clinically, overexpression of TSPAN18 was positively associated with STIM1 protein expression, bone metastasis and poor prognosis in PCa.
CONCLUSION
Taken together, this work discovers a novel STIM1 regulative mechanism that TSPAN18 protects STIM1 from TRIM32-mediated ubiquitination, and enhances bone metastasis of PCa by activating the STIM1-Ca signaling axis, suggesting that TSPAN18 may be an attractive therapeutic target for blocking bone metastasis in PCa.
Topics: Male; Humans; Stromal Interaction Molecule 1; Calcium; Calcium Channels; Prostatic Neoplasms; Ubiquitination; Calcium Signaling; ORAI1 Protein; Neoplasm Proteins; Tripartite Motif Proteins; Transcription Factors; Ubiquitin-Protein Ligases; Tetraspanins
PubMed: 37542345
DOI: 10.1186/s13046-023-02764-4 -
Nature Jul 2023Whereas progress has been made in the identification of neural signals related to rapid, cued decisions, less is known about how brains guide and terminate more...
Whereas progress has been made in the identification of neural signals related to rapid, cued decisions, less is known about how brains guide and terminate more ethologically relevant decisions in which an animal's own behaviour governs the options experienced over minutes. Drosophila search for many seconds to minutes for egg-laying sites with high relative value and have neurons, called oviDNs, whose activity fulfills necessity and sufficiency criteria for initiating the egg-deposition motor programme. Here we show that oviDNs express a calcium signal that (1) dips when an egg is internally prepared (ovulated), (2) drifts up and down over seconds to minutes-in a manner influenced by the relative value of substrates-as a fly determines whether to lay an egg and (3) reaches a consistent peak level just before the abdomen bend for egg deposition. This signal is apparent in the cell bodies of oviDNs in the brain and it probably reflects a behaviourally relevant rise-to-threshold process in the ventral nerve cord, where the synaptic terminals of oviDNs are located and where their output can influence behaviour. We provide perturbational evidence that the egg-deposition motor programme is initiated once this process hits a threshold and that subthreshold variation in this process regulates the time spent considering options and, ultimately, the choice taken. Finally, we identify a small recurrent circuit that feeds into oviDNs and show that activity in each of its constituent cell types is required for laying an egg. These results argue that a rise-to-threshold process regulates a relative-value, self-paced decision and provide initial insight into the underlying circuit mechanism for building this process.
Topics: Animals; Female; Calcium Signaling; Decision Making; Drosophila melanogaster; Neural Pathways; Neurons; Oviposition; Presynaptic Terminals; Psychomotor Performance
PubMed: 37407812
DOI: 10.1038/s41586-023-06271-6 -
International Journal of Molecular... Sep 2023Dopamine is synthesized in the nervous system where it acts as a neurotransmitter. Dopamine is also synthesized in a number of peripheral organs as well as in several... (Review)
Review
Dopamine is synthesized in the nervous system where it acts as a neurotransmitter. Dopamine is also synthesized in a number of peripheral organs as well as in several types of cells and has organ-specific functions and, as demonstrated more recently, is involved in the regulation of the immune response and inflammatory reaction. In particular, the renal dopaminergic system is very important in the regulation of sodium transport and blood pressure and is particularly sensitive to stimuli that cause oxidative stress and inflammation. This review is focused on how dopamine is synthesized in organs and tissues and the mechanisms by which dopamine and its receptors exert their effects on the inflammatory response.
Topics: Humans; Dopamine; Blood Pressure; Inflammation; Ion Transport; Radiopharmaceuticals; Anti-Inflammatory Agents
PubMed: 37762126
DOI: 10.3390/ijms241813816