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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 -
Handbook of Experimental Pharmacology 2024Solute carrier family 26 (SLC26) is a family of functionally diverse anion transporters found in all kingdoms of life. Anions transported by SLC26 proteins include... (Review)
Review
Solute carrier family 26 (SLC26) is a family of functionally diverse anion transporters found in all kingdoms of life. Anions transported by SLC26 proteins include chloride, bicarbonate, and sulfate, but also small organic dicarboxylates such as fumarate and oxalate. The human genome encodes ten functional homologs, several of which are causally associated with severe human diseases, highlighting their physiological importance. Here, we review novel insights into the structure and function of SLC26 proteins and summarize the physiological relevance of human members.
Topics: Humans; Sulfate Transporters; Anion Transport Proteins; Anions; Biological Transport
PubMed: 37947907
DOI: 10.1007/164_2023_698 -
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 -
Trends in Biochemical Sciences Dec 2023In T cells, stromal interaction molecule (STIM) and Orai are dispensable for conventional T cell development, but critical for activation and differentiation. This... (Review)
Review
In T cells, stromal interaction molecule (STIM) and Orai are dispensable for conventional T cell development, but critical for activation and differentiation. This review focuses on novel STIM-dependent mechanisms for control of Ca signals during T cell activation and its impact on mitochondrial function and transcriptional activation for control of T cell differentiation and function. We highlight areas that require further work including the roles of plasma membrane Ca ATPase (PMCA) and partner of STIM1 (POST) in controlling Orai function. A major knowledge gap also exists regarding the independence of T cell development from STIM and Orai, despite compelling evidence that it requires Ca signals. Resolving these and other outstanding questions ensures that the field will remain active for many years to come.
Topics: ORAI1 Protein; Stromal Interaction Molecule 1; Cell Membrane; Cell Differentiation; Calcium; Calcium Signaling
PubMed: 37696713
DOI: 10.1016/j.tibs.2023.08.006 -
Chemical Society Reviews Sep 2023Bio-markers, such as ions, small molecules, nucleic acids, peptides, proteins and cells, participate in the construction of living organisms and play important roles in... (Review)
Review
Bio-markers, such as ions, small molecules, nucleic acids, peptides, proteins and cells, participate in the construction of living organisms and play important roles in biological processes. It is of great significance to accurately detect these bio-markers for studying their basic functions, the development of molecular diagnosis and to better understand life processes. Solid-state nanochannel-based sensing systems have been demonstrated for the detection of bio-markers, due to their rapid, label-free and high-throughput screening, with high sensitivity and specificity. Generally, studies on solid-state nanochannels have focused on probes on the inner-wall (PIW), ignoring probes on the outer-surface (POS). As a result, the direct detection of cells is difficult to realize by these inner-wall focused nanochannels. Moreover, the sensitivity for detecting ions, small molecules, nucleic acids, peptides and proteins requires further improvement. Recent research has focused on artificial solid-state nanochannels with POS, which have demonstrated the ability to independently regulate ion transport. This design not only contributes to the detection of large analytes, such as cells, but also provides promising opportunities for ultra-high sensitivity detection with a clear mechanism. In this tutorial review, we present an overview of the detection principle used for solid-state nanochannels, inner-wall focused nanochannels and outer-surface focused nanochannels. Furthermore, we discuss the remaining challenges faced by current nanochannel technologies and provide insights into their prospects.
Topics: Nanostructures; Ion Transport; Nucleic Acids; Peptides; Ions
PubMed: 37581902
DOI: 10.1039/d2cs00865c -
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 -
Biochemistry. Biokhimiia Oct 2023Channelrhodopsins stand out among other retinal proteins because of their capacity to generate passive ionic currents following photoactivation. Owing to that,... (Review)
Review
Channelrhodopsins stand out among other retinal proteins because of their capacity to generate passive ionic currents following photoactivation. Owing to that, channelrhodopsins are widely used in neuroscience and cardiology as instruments for optogenetic manipulation of the activity of excitable cells. Photocurrents generated by channelrhodopsins were first discovered in the cells of green algae in the 1970s. In this review we describe this discovery and discuss the current state of research in the field.
Topics: Channelrhodopsins; Optogenetics; Phototaxis; Light; Ion Transport
PubMed: 38105024
DOI: 10.1134/S0006297923100115