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Channels (Austin, Tex.) Dec 2024Voltage-gated calcium (Ca) channels mediate Ca influx in response to membrane depolarization, playing critical roles in diverse physiological processes. Dysfunction or... (Review)
Review
Voltage-gated calcium (Ca) channels mediate Ca influx in response to membrane depolarization, playing critical roles in diverse physiological processes. Dysfunction or aberrant regulation of Ca channels can lead to life-threatening consequences. Ca-targeting drugs have been clinically used to treat cardiovascular and neuronal disorders for several decades. This review aims to provide an account of recent developments in the structural dissection of Ca channels. High-resolution structures have significantly advanced our understanding of the working and disease mechanisms of Ca channels, shed light on the molecular basis for their modulation, and elucidated the modes of actions (MOAs) of representative drugs and toxins. The progress in structural studies of Ca channels lays the foundation for future drug discovery efforts targeting Ca channelopathies.
Topics: Humans; Calcium Channels; Calcium Signaling; Calcium; Channelopathies; Biology
PubMed: 38062897
DOI: 10.1080/19336950.2023.2290807 -
EMBO Reports Jul 2023Members of the polycystin family (PKD2 and PKD2L1) of transient receptor potential (TRP) channels conduct Ca and depolarizing monovalent cations. Variants in PKD2 cause...
Members of the polycystin family (PKD2 and PKD2L1) of transient receptor potential (TRP) channels conduct Ca and depolarizing monovalent cations. Variants in PKD2 cause autosomal dominant polycystic kidney disease (ADPKD) in humans, whereas loss of PKD2L1 expression causes seizure susceptibility in mice. Understanding structural and functional regulation of these channels will provide the basis for interpreting their molecular dysregulation in disease states. However, the complete structures of polycystins are unresolved, as are the conformational changes regulating their conductive states. To provide a holistic understanding of the polycystin gating cycle, we use computational prediction tools to model missing PKD2L1 structural motifs and evaluate more than 150 mutations in an unbiased mutagenic functional screen of the entire pore module. Our results provide an energetic landscape of the polycystin pore, which enumerates gating sensitive sites and interactions required for opening, inactivation, and subsequent desensitization. These findings identify the external pore helices and specific cross-domain interactions as critical structural regulators controlling the polycystin ion channel conductive and nonconductive states.
Topics: Humans; Mice; Animals; TRPP Cation Channels; Signal Transduction; Ion Transport; Transient Receptor Potential Channels; Mutation; Receptors, Cell Surface; Calcium Channels
PubMed: 37158562
DOI: 10.15252/embr.202356783 -
Science Advances Feb 2024Lysosomal calcium (Ca) release is critical to cell signaling and is mediated by well-known lysosomal Ca channels. Yet, how lysosomes refill their Ca remains hitherto...
Lysosomal calcium (Ca) release is critical to cell signaling and is mediated by well-known lysosomal Ca channels. Yet, how lysosomes refill their Ca remains hitherto undescribed. Here, from an RNA interference screen in , we identify an evolutionarily conserved gene, , that facilitates lysosomal Ca entry in and mammalian cells. We found that its human homolog TMEM165, previously designated as a Ca/H exchanger, imports Ca pH dependently into lysosomes. Using two-ion mapping and electrophysiology, we show that TMEM165, hereafter referred to as human LCI, acts as a proton-activated, lysosomal Ca importer. Defects in lysosomal Ca channels cause several neurodegenerative diseases, and knowledge of lysosomal Ca importers may provide previously unidentified avenues to explore the physiology of Ca channels.
Topics: Animals; Humans; Calcium; Caenorhabditis elegans; Calcium Channels; Signal Transduction; Lysosomes; Calcium Signaling; Mammals; Antiporters; Cation Transport Proteins
PubMed: 38354239
DOI: 10.1126/sciadv.adk2317 -
Nature May 2024Astrocytes, the most abundant non-neuronal cell type in the mammalian brain, are crucial circuit components that respond to and modulate neuronal activity through...
Astrocytes, the most abundant non-neuronal cell type in the mammalian brain, are crucial circuit components that respond to and modulate neuronal activity through calcium (Ca) signalling. Astrocyte Ca activity is highly heterogeneous and occurs across multiple spatiotemporal scales-from fast, subcellular activity to slow, synchronized activity across connected astrocyte networks-to influence many processes. However, the inputs that drive astrocyte network dynamics remain unclear. Here we used ex vivo and in vivo two-photon astrocyte imaging while mimicking neuronal neurotransmitter inputs at multiple spatiotemporal scales. We find that brief, subcellular inputs of GABA and glutamate lead to widespread, long-lasting astrocyte Ca responses beyond an individual stimulated cell. Further, we find that a key subset of Ca activity-propagative activity-differentiates astrocyte network responses to these two main neurotransmitters, and may influence responses to future inputs. Together, our results demonstrate that local, transient neurotransmitter inputs are encoded by broad cortical astrocyte networks over a minutes-long time course, contributing to accumulating evidence that substantial astrocyte-neuron communication occurs across slow, network-level spatiotemporal scales. These findings will enable future studies to investigate the link between specific astrocyte Ca activity and specific functional outputs, which could build a consistent framework for astrocytic modulation of neuronal activity.
Topics: Animals; Female; Male; Mice; Astrocytes; Calcium; Calcium Signaling; Cell Communication; Cerebral Cortex; gamma-Aminobutyric Acid; Glutamic Acid; Mice, Inbred C57BL; Nerve Net; Neurons; Neurotransmitter Agents; Time Factors
PubMed: 38632406
DOI: 10.1038/s41586-024-07311-5 -
Nature Communications Oct 2023Calcium in interstitial fluids is central to systemic physiology and a crucial ion pool for entry into cells through numerous plasma membrane channels. Its study has...
Calcium in interstitial fluids is central to systemic physiology and a crucial ion pool for entry into cells through numerous plasma membrane channels. Its study has been limited by the scarcity of methods that allow monitoring in tight inter-cell spaces of living tissues. Here we present high performance ultra-low affinity genetically encoded calcium biosensors named GreenT-ECs. GreenT-ECs combine large fluorescence changes upon calcium binding and binding affinities (Kds) ranging from 0.8 mM to 2.9 mM, making them tuned to calcium concentrations in extracellular organismal fluids. We validated GreenT-ECs in rodent hippocampal neurons and transgenic zebrafish in vivo, where the sensors enabled monitoring homeostatic regulation of tissue interstitial calcium. GreenT-ECs may become useful for recording very large calcium transients and for imaging calcium homeostasis in inter-cell structures in live tissues and organisms.
Topics: Animals; Calcium; Zebrafish; Fluorescence; Calcium Signaling; Diagnostic Imaging; Coloring Agents
PubMed: 37798285
DOI: 10.1038/s41467-023-41928-w -
The Journal of Physical Chemistry. C,... Sep 2023In the face of the current climate emergency and the performance, safety, and cost limitations current state-of-art Li-ion batteries present, solid-state batteries are... (Review)
Review
In the face of the current climate emergency and the performance, safety, and cost limitations current state-of-art Li-ion batteries present, solid-state batteries are widely anticipated to revolutionize energy storage. The heart of this technology lies in the substitution of liquid electrolytes with solid counterparts, resulting in potential critical advantages, such as higher energy density and safety profiles. In recent years, antiperovskites have become one of the most studied solid electrolyte families for solid-state battery applications as a result of their salient advantages, which include high ionic conductivity, structural versatility, low cost, and stability against metal anodes. This Review highlights the latest progress in the computational design of Li- and Na-based antiperovskite solid electrolytes, focusing on critical topics for their development, including high-throughput screening for novel compositions, synthesizability, doping, ion transport mechanisms, grain boundaries, and electrolyte-electrode interfaces. Moreover, we discuss the remaining challenges facing these materials and provide our perspective on their possible future advances and applications.
PubMed: 37752904
DOI: 10.1021/acs.jpcc.3c04953 -
Frontiers in Immunology 2023
Topics: Humans; Calcium Signaling; Neoplasms; Myeloid Cells
PubMed: 38022525
DOI: 10.3389/fimmu.2023.1315490 -
Frontiers in Bioscience (Landmark... Oct 2023Calcium (Ca2+) plays a critical role in podocyte function. The Ca2+-sensitive receptors on the cell surface can sense changes in Ca2+ concentration, and Ca2+ flow into... (Review)
Review
Calcium (Ca2+) plays a critical role in podocyte function. The Ca2+-sensitive receptors on the cell surface can sense changes in Ca2+ concentration, and Ca2+ flow into podocytes, after activation of Ca2+ channels (such as transient receptor potential canonical (TRPC) channels and N-type calcium channels) by different stimuli. In addition, the type 2 ryanodine receptor (RyR2) and the voltage-dependent anion channel 1 (VDAC1) on mitochondrial store-operated calcium channels (SOCs) on the endoplasmic reticulum maintain the Ca2+ homeostasis of the organelle. Ca2+ signaling is transmitted through multiple downstream signaling pathways and participates in the morphogenesis, structural maintenance, and survival of podocytes. When Ca2+ is dysregulated, it leads to the occurrence and progression of various diseases, such as focal segmental glomerulosclerosis, diabetic kidney disease, lupus nephritis, transplant glomerulopathy, and hypertensive renal injury. Ca2+ signaling is a promising therapeutic target for podocyte-related diseases. This review first summarizes the role of Ca2+ sensing, Ca2+ channels, and different Ca2+-signaling pathways in the biological functions of podocytes, then, explores the status of Ca2+ signaling in different podocyte-related diseases and its advances as a therapeutic target.
Topics: Humans; Podocytes; Calcium Signaling; TRPC6 Cation Channel; Calcium; Diabetic Nephropathies
PubMed: 37919067
DOI: 10.31083/j.fbl2810240