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Voltage-gated calcium channel nanodomains: molecular composition and function.
Gandini, MA, Zamponi, GW
The FEBS journal. 2022;(3):614-633
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Abstract
Voltage-gated calcium (CaV ) channels and their regulation by proteins at the synaptic cleft play a critical role in neurotransmission. These interactions fine-tune the synaptic response through the regulation of Ca2+ entry into the presynaptic terminal and trigger the fusion of vesicles filled with neurotransmitters and peptides. Regulation of CaV channel intrinsic properties and their numbers at the active zones shape the timing and strength of synaptic function. Here, we provide an overview of a number of proteins reported to be part of CaV channel nanodomains at the synaptic cleft and the repercussions of these interactions for CaV channel trafficking, tethering at the active zone, and regulation of their biophysical properties. We summarize the current state of knowledge by which CaV channels are regulated at presynaptic sites.
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A comprehensive overview of the complex world of the endo- and sarcoplasmic reticulum Ca2+-leak channels.
Lemos, FO, Bultynck, G, Parys, JB
Biochimica et biophysica acta. Molecular cell research. 2021;(7):119020
Abstract
Inside cells, the endoplasmic reticulum (ER) forms the largest Ca2+ store. Ca2+ is actively pumped by the SERCA pumps in the ER, where intraluminal Ca2+-binding proteins enable the accumulation of large amount of Ca2+. IP3 receptors and the ryanodine receptors mediate the release of Ca2+ in a controlled way, thereby evoking complex spatio-temporal signals in the cell. The steady state Ca2+ concentration in the ER of about 500 μM results from the balance between SERCA-mediated Ca2+ uptake and the passive leakage of Ca2+. The passive Ca2+ leak from the ER is often ignored, but can play an important physiological role, depending on the cellular context. Moreover, excessive Ca2+ leakage significantly lowers the amount of Ca2+ stored in the ER compared to normal conditions, thereby limiting the possibility to evoke Ca2+ signals and/or causing ER stress, leading to pathological consequences. The so-called Ca2+-leak channels responsible for Ca2+ leakage from the ER are however still not well understood, despite over 20 different proteins have been proposed to contribute to it. This review has the aim to critically evaluate the available evidence about the various channels potentially involved and to draw conclusions about their relative importance.
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Mitochondrial calcium handling and heart disease in diabetes mellitus.
Diaz-Juarez, J, Suarez, JA, Dillmann, WH, Suarez, J
Biochimica et biophysica acta. Molecular basis of disease. 2021;(1):165984
Abstract
Diabetes mellitus-induced heart disease, including diabetic cardiomyopathy, is an important medical problem and is difficult to treat. Diabetes mellitus increases the risk for heart failure and decreases cardiac myocyte function, which are linked to changes in cardiac mitochondrial energy metabolism. The free mitochondrial calcium concentration ([Ca2+]m) is fundamental in activating the mitochondrial respiratory chain complexes and ATP production and is also known to regulate the activity of key mitochondrial dehydrogenases. The mitochondrial calcium uniporter complex (MCUC) plays a major role in mediating mitochondrial Ca2+ import, and its expression and function therefore may have a marked impact on cardiac myocyte metabolism and function. Here, we summarize the pathophysiological role of [Ca2+]m handling and MCUC in the diabetic heart. In addition, we evaluate potential therapeutic targets, directed to the machinery that regulates mitochondrial calcium handling, to alleviate diabetes-related cardiac disease.
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The Discovery of Naringenin as Endolysosomal Two-Pore Channel Inhibitor and Its Emerging Role in SARS-CoV-2 Infection.
D'Amore, A, Gradogna, A, Palombi, F, Minicozzi, V, Ceccarelli, M, Carpaneto, A, Filippini, A
Cells. 2021;(5)
Abstract
The flavonoid naringenin (Nar), present in citrus fruits and tomatoes, has been identified as a blocker of an emerging class of human intracellular channels, namely the two-pore channel (TPC) family, whose role has been established in several diseases. Indeed, Nar was shown to be effective against neoangiogenesis, a process essential for solid tumor progression, by specifically impairing TPC activity. The goal of the present review is to illustrate the rationale that links TPC channels to the mechanism of coronavirus infection, and how their inhibition by Nar could be an efficient pharmacological strategy to fight the current pandemic plague COVID-19.
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Store-operated calcium entry: Pivotal roles in renal physiology and pathophysiology.
Chaudhari, S, Mallet, RT, Shotorbani, PY, Tao, Y, Ma, R
Experimental biology and medicine (Maywood, N.J.). 2021;(3):305-316
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Abstract
Research conducted over the last two decades has dramatically advanced the understanding of store-operated calcium channels (SOCC) and their impact on renal function. Kidneys contain many types of cells, including those specialized for glomerular filtration (fenestrated capillary endothelium, podocytes), water and solute transport (tubular epithelium), and regulation of glomerular filtration and renal blood flow (vascular smooth muscle cells, mesangial cells). The highly integrated function of these myriad cells effects renal control of blood pressure, extracellular fluid volume and osmolality, electrolyte balance, and acid-base homeostasis. Many of these cells are regulated by Ca2+ signaling. Recent evidence demonstrates that SOCCs are major Ca2+ entry portals in several renal cell types. SOCC is activated by depletion of Ca2+ stores in the sarco/endoplasmic reticulum, which communicates with plasma membrane SOCC via the Ca2+ sensor Stromal Interaction Molecule 1 (STIM1). Orai1 is recognized as the main pore-forming subunit of SOCC in the plasma membrane. Orai proteins alone can form highly Ca2+ selective SOCC channels. Also, members of the Transient Receptor Potential Canonical (TRPC) channel family are proposed to form heteromeric complexes with Orai1 subunits, forming SOCC with low Ca2+ selectivity. Recently, Ca2+ entry through SOCC, known as store-operated Ca2+ entry (SOCE), was identified in glomerular mesangial cells, tubular epithelium, and renovascular smooth muscle cells. The physiological and pathological relevance and the characterization of SOCC complexes in those cells are still unclear. In this review, we summarize the current knowledge of SOCC and their roles in renal glomerular, tubular and vascular cells, including studies from our laboratory, emphasizing SOCE regulation of fibrotic protein deposition. Understanding the diverse roles of SOCE in different renal cell types is essential, as SOCC and its signaling pathways are emerging targets for treatment of SOCE-related diseases.
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Pathophysiological role of calcium channels and transporters in the multiple myeloma.
Li, T, Chen, J, Zeng, Z
Cell communication and signaling : CCS. 2021;(1):99
Abstract
Multiple myeloma (MM) is a common malignant tumor of plasma cells. Despite several treatment approaches in the past two decades, MM remains an aggressive and incurable disease in dire need of new treatment strategies. Approximately 70-80% of patients with MM have myeloma bone disease (MBD), often accompanied by pathological fractures and hypercalcemia, which seriously affect the prognosis of the patients. Calcium channels and transporters can mediate Ca2+ balance inside and outside of the membrane, indicating that they may be closely related to the prognosis of MM. Therefore, this review focuses on the roles of some critical calcium channels and transporters in MM prognosis, which located in the plasma membrane, endoplasmic reticulum and mitochondria. The goal of this review is to facilitate the identification of new targets for the treatment and prognosis of MM. Video Abstract.
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Two distinct phenotypes, hemiplegic migraine and episodic Ataxia type 2, caused by a novel common CACNA1A variant.
Nardello, R, Plicato, G, Mangano, GD, Gennaro, E, Mangano, S, Brighina, F, Raieli, V, Fontana, A
BMC neurology. 2020;(1):155
Abstract
BACKGROUND To investigate the genetic and environmental factors responsible for phenotype variability in a family carrying a novel CACNA1A missense mutation. Mutations in the CACNA1A gene were identified as responsible for at least three autosomal dominant disorders: FHM1 (Familial Hemiplegic Migraine), EA2 (Episodic Ataxia type 2), and SCA6 (Spinocerebellar Ataxia type 6). Overlapping clinical features within individuals of some families sharing the same CACNA1A mutation are not infrequent. Conversely, reports with distinct phenotypes within the same family associated with a common CACNA1A mutation are very rare. CASE PRESENTATION A clinical, molecular, neuroradiological, neuropsychological, and neurophysiological study was carried out in proband and his carrier mother. The new heterozygous missense variant c.4262G > A (p.Arg1421Gln) in the CACNA1A gene was detected in the two affected family members. The proband showed a complex clinical presentation characterized by developmental delay, poor motor coordination, hemiplegic migraine attacks, behavioral dysregulation, and EEG abnormalities. The mother showed typical episodic ataxia attacks during infancy with no other comorbidities and mild cerebellar signs at present neurological evaluation. CONCLUSIONS The proband and his mother exhibit two distinct clinical phenotypes. It can be hypothesized that other unknown modifying genes and/or environmental factors may cooperate to generate the wide intrafamilial variability.
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Regulation of Dietary Amino Acids and Voltage-Gated Calcium Channels in Autism Spectrum Disorder.
Singh, S, Sangam, SR, Senthilkumar, R
Advances in neurobiology. 2020;:647-660
Abstract
Autism, or autism spectrum disorders (ASD), is one of the complex genetic diseases and its etiology is unknown for majority of the patients. It is characterized by deterioration in social interaction, communication, interests, imagination, and activities. As autism is a highly heterogeneous disorder, the symptoms can vary greatly in each affected individual. Oxidative stress implicates major pathogenesis of neurological disorders like ASD. Nutrients and dietary supplements play an important role in the health of an individual and there are several lines of evidence suggesting the role of dietary factors in the development or pathogenesis of ASD. The amino acids supplement has been found to reduce symptoms as they act as the precursors of neurotransmitters which in turn may extenuate mental disorders. The biosynthesis of amino acids in the brain is regulated by the concentration of amino acids in plasma. Amino acids are also considerable entities as they themselves, or peptides consisting of them, have profound antioxidant activities. Dietary constituents have an effect on the transport of amino acids across the blood-brain barrier (BBB) thus indirectly modulating the therapeutic value of amino acids. Among the other factors, voltage-gated calcium channels are directly linked to ASD as per results of genetic studies. Malfunctioning of these calcium channels causes ASD. The intricate biochemical and molecular machinery contributing to neurological disorders is still unknown. Here we discuss the preventive role of dietary amino acids against and regulation of voltage-gated calcium channels on ASD.
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Charge Inversion and Calcium Gating in Mixtures of Ions in Nanopores.
Lin, K, Lin, CY, Polster, JW, Chen, Y, Siwy, ZS
Journal of the American Chemical Society. 2020;(6):2925-2934
Abstract
Calcium ions play important roles in many physiological processes, yet their concentration is much lower than the concentrations of potassium and sodium ions. The selectivity of calcium channels is often probed in mixtures of calcium and a monovalent salt, e.g., KCl or NaCl, prepared such that the concentration of cations is kept constant with the mole fraction of calcium varying from 0 and 1. In biological channels, even sub-mM concentration of calcium can modulate the channels' transport characteristics; this effect is often explained via the existence of high affinity Ca2+ binding sites on the channel walls. Inspired by properties of biological calcium-selective channels, we prepared a set of nanopores with tunable opening diameters that exhibited a similar response to the presence of calcium ions as biochannels. Nanopores in 15 nm thick silicon nitride films were drilled using focused ion beam and e-beam in a transmission electron microscope and subsequently rendered negatively charged through silanization. We found that nanopores with diameters smaller than 20 nm were blocked by calcium ions such that the ion currents in mixtures of KCl and CaCl2 and in CaCl2 were even ten times smaller than the ion currents in KCl solution. The ion current blockage was explained by the effect of local charge inversion where accumulated calcium ions switch the effective surface charge from negative to positive. The modulation of surface charge with calcium leads to concentration and voltage dependent local charge density and ion current. The combined experimental and modeling results provide a link between calcium ion-induced changes in surface charge properties and resulting ionic transport.
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10.
Genetic associations between voltage-gated calcium channels and autism spectrum disorder: a systematic review.
Liao, X, Li, Y
Molecular brain. 2020;(1):96
Abstract
OBJECTIVES The present review systematically summarized existing publications regarding the genetic associations between voltage-gated calcium channels (VGCCs) and autism spectrum disorder (ASD). METHODS A comprehensive literature search was conducted to gather pertinent studies in three online databases. Two authors independently screened the included records based on the selection criteria. Discrepancies in each step were settled through discussions. RESULTS From 1163 resulting searched articles, 28 were identified for inclusion. The most prominent among the VGCCs variants found in ASD were those falling within loci encoding the α subunits, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, and CACNA1I as well as those of their accessory subunits CACNB2, CACNA2D3, and CACNA2D4. Two signaling pathways, the IP3-Ca2+ pathway and the MAPK pathway, were identified as scaffolds that united genetic lesions into a consensus etiology of ASD. CONCLUSIONS Evidence generated from this review supports the role of VGCC genetic variants in the pathogenesis of ASD, making it a promising therapeutic target. Future research should focus on the specific mechanism that connects VGCC genetic variants to the complex ASD phenotype.