RESUMEN
Alzheimer's disease (AD) is a common neurodegenerative disease with the main manifestations of progressive cognitive dysfunction,behavioral disorders,and gradual decline of living ability.The etiology of AD is complex,and the pathogenesis of this disease remains controversial.Calcium signaling plays an important role in regulating neuronal activities,including neurotransmitter release,synaptic plasticity,memory storage,and neuronal apoptosis.Increasing studies have shown that neuronal calcium dyshomeostasis is a major pathological factor in the occurrence and development of AD.This article reviews the role and research progress in intracellular calcium dyshomeostasis in AD,including the relationship between calcium homeostasis and amyloid ß,the role of calcium/calmodulin-dependent protein kinases in tau phosphorylation,calcium signaling pathways,the relationship between calcium homeostasis and mitochondrial function,autophagy,and neuroinflammation.
Asunto(s)
Enfermedad de Alzheimer , Calcio , Homeostasis , Enfermedad de Alzheimer/metabolismo , Humanos , Calcio/metabolismo , Péptidos beta-Amiloides/metabolismo , Señalización del Calcio/fisiología , Mitocondrias/metabolismo , Proteínas tau/metabolismo , Autofagia/fisiología , Animales , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Neuronas/metabolismo , FosforilaciónRESUMEN
Calcium (Ca2+) is a second messenger for many signal pathways, and changes in intracellular Ca2+ concentration ([Ca2+]i) are an important signaling mechanism in the oocyte maturation, activation, fertilization, function regulation of granulosa and cumulus cells and offspring development. Ca2+ oscillations occur during oocyte maturation and fertilization, which are maintained by Ca2+ stores and extracellular Ca2+ ([Ca2+]e). Abnormalities in Ca2+ signaling can affect the release of the first polar body, the first meiotic division, and chromosome and spindle morphology. Well-studied aspects of Ca2+ signaling in the oocyte are oocyte activation and fertilization. Oocyte activation, driven by sperm-specific phospholipase PLCζ, is initiated by concerted intracellular patterns of Ca2+ release, termed Ca2+ oscillations. Ca2+ oscillations persist for a long time during fertilization and are coordinately engaged by a variety of Ca2+ channels, pumps, regulatory proteins and their partners. Calcium signaling also regulates granulosa and cumulus cells' function, which further affects oocyte maturation and fertilization outcome. Clinically, there are several physical and chemical options for treating fertilization failure through oocyte activation. Additionally, various exogenous compounds or drugs can cause ovarian dysfunction and female infertility by inducing abnormal Ca2+ signaling or Ca2+ dyshomeostasis in oocytes and granulosa cells. Therefore, the reproductive health risks caused by adverse stresses should arouse our attention. This review will systematically summarize the latest research progress on the aforementioned aspects and propose further research directions on calcium signaling in female reproduction.
Asunto(s)
Señalización del Calcio , Oocitos , Oocitos/metabolismo , Oocitos/fisiología , Humanos , Señalización del Calcio/fisiología , Femenino , Animales , Calcio/metabolismo , Fertilización/fisiología , Células del Cúmulo/metabolismoRESUMEN
The clinical management of severe COVID-19 cases is not yet well resolved. Therefore, it is important to identify and characterize cell signaling pathways involved in virus pathogenesis that can be targeted therapeutically. Envelope (E) protein is a structural protein of the virus, which is known to be highly expressed in the infected host cell and is a key virulence factor; however, its role is poorly characterized. The E protein is a single-pass transmembrane protein that can assemble into a pentamer forming a viroporin, perturbing Ca2+ homeostasis. Because it is structurally similar to regulins such as, for example, phospholamban, that regulate the sarco/endoplasmic reticulum calcium ATPases (SERCA), we investigated whether the SARS-CoV-2 E protein affects the SERCA system as an exoregulin. Using FRET experiments we demonstrate that E protein can form oligomers with regulins, and thus can alter the monomer/multimer regulin ratio and consequently influence their interactions with SERCAs. We also confirm that a direct interaction between E protein and SERCA2b results in a decrease in SERCA-mediated ER Ca2+ reload. Structural modeling of the complexes indicates an overlapping interaction site for E protein and endogenous regulins. Our results reveal novel links in the host-virus interaction network that play an important role in viral pathogenesis and may provide a new therapeutic target for managing severe inflammatory responses induced by SARS-CoV-2.
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COVID-19 , Señalización del Calcio , Proteínas de la Envoltura de Coronavirus , SARS-CoV-2 , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Humanos , SARS-CoV-2/metabolismo , COVID-19/virología , COVID-19/metabolismo , Proteínas de la Envoltura de Coronavirus/metabolismo , Proteínas de Unión al Calcio/metabolismo , Calcio/metabolismo , Unión ProteicaRESUMEN
A long-held tenet in inositol-lipid signaling is that cleavage of membrane phosphoinositides by phospholipase Cß (PLCß) isozymes to increase cytosolic Ca2+ in living cells is exclusive to Gq- and Gi-sensitive G protein-coupled receptors (GPCRs). Here we extend this central tenet and show that Gs-GPCRs also partake in inositol-lipid signaling and thereby increase cytosolic Ca2+. By combining CRISPR/Cas9 genome editing to delete Gαs, the adenylyl cyclase isoforms 3 and 6, or the PLCß1-4 isozymes, with pharmacological and genetic inhibition of Gq and G11, we pin down Gs-derived Gßγ as driver of a PLCß2/3-mediated cytosolic Ca2+ release module. This module does not require but crosstalks with Gαs-dependent cAMP, demands Gαq to release PLCß3 autoinhibition, but becomes Gq-independent with mutational disruption of the PLCß3 autoinhibited state. Our findings uncover the key steps of a previously unappreciated mechanism utilized by mammalian cells to finetune their calcium signaling regulation through Gs-GPCRs.
Asunto(s)
Señalización del Calcio , Calcio , Fosfolipasa C beta , Receptores Acoplados a Proteínas G , Humanos , Fosfolipasa C beta/metabolismo , Fosfolipasa C beta/genética , Células HEK293 , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Calcio/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Sistemas CRISPR-Cas , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , AMP Cíclico/metabolismo , Animales , Edición Génica , Citosol/metabolismo , Subunidades beta de la Proteína de Unión al GTP/metabolismo , Subunidades beta de la Proteína de Unión al GTP/genética , Adenilil Ciclasas/metabolismo , Adenilil Ciclasas/genéticaRESUMEN
Activin A and hepatic stellate cells (HSCs) are involved in tissue repair and fibrosis in liver injury. This study investigated the impact of activin A on HSC activation and migration. A microfluidic D4-chip was used for examining the cell migration of mouse hepatic stellate cell line MHSteC. The analysis of differentially expressed genes revealed that activin ßA (Inhba), activin receptor type 1A (Acvr1a) and type 2A (Acvr2a) mRNAs were more significantly expressed in human HSCs than in the hepatocytes. Moreover, activin A promoted MHSteC proliferation and induced MHSteC migration. Furthermore, the MHSteCs treated with activin A exhibited increased levels of migration-related proteins, N-cadherin, Vimentin, α-SMA, MMP2 and MMP9, but a decreased level of E-cadherin. Additionally, activin A treatment significantly increased the p-Smad3 levels and p-Smad3/Smad3 ratio in the MHSteCs, and the Smad3 inhibitor SIS3 attenuated activin A-induced MHSteC proliferation and migration. Simultaneously, activin A increased the calcium levels in the MHSteCs, and the migratory effects of activin A on MHSteCs were weakened by the intracellular calcium ion-chelating agent BAPTA-AM. These data indicate that activin A can promote MHSteC activation and migration through the canonical Smad3 signaling and calcium signaling.
Asunto(s)
Activinas , Señalización del Calcio , Movimiento Celular , Proliferación Celular , Células Estrelladas Hepáticas , Proteína smad3 , Células Estrelladas Hepáticas/metabolismo , Movimiento Celular/efectos de los fármacos , Proteína smad3/metabolismo , Animales , Activinas/metabolismo , Ratones , Humanos , Línea CelularRESUMEN
The molecular mechanisms leading to saliva secretion are largely established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren's syndrome (SS) are not fully understood. A major conundrum is the lack of association between the severity of salivary gland immune cell infiltration and glandular hypofunction. SS-like disease was induced by treatment with DMXAA, a small molecule agonist of murine STING. We have previously shown that the extent of salivary secretion is correlated with the magnitude of intracellular Ca2+ signals (Takano et al., 2021). Contrary to our expectations, despite a significant reduction in fluid secretion, neural stimulation resulted in enhanced Ca2+ signals with altered spatiotemporal characteristics in vivo. Muscarinic stimulation resulted in reduced activation of the Ca2+-activated Cl- channel, TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca2+. Super-resolution microscopy revealed a disruption in the colocalization of Inositol 1,4,5-trisphosphate receptor Ca2+ release channels with TMEM16a, and channel activation was reduced when intracellular Ca2+ buffering was increased. These data indicate altered local peripheral coupling between the channels. Appropriate Ca2+ signaling is also pivotal for mitochondrial morphology and bioenergetics. Disrupted mitochondrial morphology and reduced oxygen consumption rate were observed in DMXAA-treated animals. In summary, early in SS disease, dysregulated Ca2+ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction.
Asunto(s)
Anoctamina-1 , Señalización del Calcio , Modelos Animales de Enfermedad , Mitocondrias , Síndrome de Sjögren , Animales , Síndrome de Sjögren/metabolismo , Ratones , Mitocondrias/metabolismo , Anoctamina-1/metabolismo , Calcio/metabolismo , Glándulas Salivales/metabolismo , Glándulas Salivales/patología , Femenino , Ratones Endogámicos C57BLRESUMEN
Upon stimulation of membrane receptors, nicotinic acid adenine dinucleotide phosphate (NAADP) is formed as second messenger within seconds and evokes Ca2+ signaling in many different cell types. Here, to directly stimulate NAADP signaling, MASTER-NAADP, a Membrane permeAble, STabilized, bio-rEversibly pRotected precursor of NAADP is synthesized and release of its active NAADP mimetic, benzoic acid C-nucleoside, 2'-phospho-3'F-adenosine-diphosphate, by esterase digestion is confirmed. In the presence of NAADP receptor HN1L/JPT2 (hematological and neurological expressed 1-like protein, HN1L, also known as Jupiter microtubule-associated homolog 2, JPT2), this active NAADP mimetic releases Ca2+ and increases the open probability of type 1 ryanodine receptor. When added to intact cells, MASTER-NAADP initially evokes single local Ca2+ signals of low amplitude. Subsequently, also global Ca2+ signaling is observed in T cells, natural killer cells, and Neuro2A cells. In contrast, control compound MASTER-NADP does not stimulate Ca2+ signaling. Likewise, in cells devoid of HN1L/JPT2, MASTER-NAADP does not affect Ca2+ signaling, confirming that the product released from MASTER-NAADP is a bona fide NAADP mimetic.
Asunto(s)
Señalización del Calcio , Calcio , NADP , NADP/análogos & derivados , NADP/metabolismo , Animales , Humanos , Calcio/metabolismo , Ratones , Sistemas de Mensajero Secundario , Permeabilidad de la Membrana Celular , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Células Asesinas Naturales/metabolismo , Linfocitos T/metabolismoRESUMEN
Atrial fibrillation (AF) is the most common sustained arrhythmia and carries an increased risk of stroke and heart failure. Here we investigated how the immune infiltrate of human epicardial adipose tissue (EAT), which directly overlies the myocardium, contributes to AF. Flow cytometry analysis revealed an enrichment of tissue-resident memory T (TRM) cells in patients with AF. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell T cell receptor (TCR) sequencing identified two transcriptionally distinct CD8+ TRM cells that are modulated in AF. Spatial transcriptomic analysis of EAT and atrial tissue identified the border region between the tissues to be a region of intense inflammatory and fibrotic activity, and the addition of TRM populations to atrial cardiomyocytes demonstrated their ability to differentially alter calcium flux as well as activate inflammatory and apoptotic signaling pathways. This study identified EAT as a reservoir of TRM cells that can directly modulate vulnerability to cardiac arrhythmia.
Asunto(s)
Tejido Adiposo , Fibrilación Atrial , Células T de Memoria , Pericardio , Fibrilación Atrial/inmunología , Fibrilación Atrial/genética , Fibrilación Atrial/patología , Fibrilación Atrial/metabolismo , Humanos , Pericardio/metabolismo , Pericardio/patología , Pericardio/inmunología , Tejido Adiposo/metabolismo , Tejido Adiposo/inmunología , Tejido Adiposo/patología , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Masculino , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Transcriptoma , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/inmunología , Femenino , Persona de Mediana Edad , Perfilación de la Expresión Génica , Anciano , Fenotipo , Señalización del Calcio , Apoptosis , Memoria Inmunológica , Transcripción Genética , Estudios de Casos y Controles , Atrios Cardíacos/patología , Atrios Cardíacos/inmunología , Atrios Cardíacos/metabolismo , Fibrosis/patología , Tejido Adiposo EpicárdicoRESUMEN
Ca2+ release from the sarcoplasmic reticulum (SR) plays a central role in excitation-contraction coupling (ECC) in skeletal muscles. However, the mechanism by which activation of the voltage-sensors/dihydropyridine receptors (DHPRs) in the membrane of the transverse tubular system leads to activation of the Ca2+-release channels/ryanodine receptors (RyRs) in the SR is not fully understood. Recent observations showing that a very small Ca2+ leak through RyR1s in mammalian skeletal muscle can markedly raise the background [Ca2+] in the junctional space (JS) above the Ca2+ level in the bulk of the cytosol indicate that there is a diffusional barrier between the JS and the cytosol at large. Here, I use a mathematical model to explore the hypothesis that a sudden rise in Ca2+ leak through DHPR-coupled RyR1s, caused by reduced inhibition at the RyR1 Ca2+/Mg2+ inhibitory I1-sites when the associated DHPRs are activated, is sufficient to enable synchronized responses that trigger a regenerative rise of Ca2+ release that remains under voltage control. In this way, the characteristic response to Ca2+ of RyR channels is key not only for the Ca2+ release mechanism in cardiac muscle and other tissues, but also for the DHPR-dependent Ca2+ release in skeletal muscle.
Asunto(s)
Canales de Calcio Tipo L , Calcio , Músculo Esquelético , Canal Liberador de Calcio Receptor de Rianodina , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Músculo Esquelético/metabolismo , Animales , Calcio/metabolismo , Canales de Calcio Tipo L/metabolismo , Retículo Sarcoplasmático/metabolismo , Señalización del Calcio/fisiología , Acoplamiento Excitación-Contracción , Modelos Biológicos , HumanosRESUMEN
Micro and nanoscale patterning of surface features and biochemical cues have emerged as tools to precisely direct neurite growth into close proximity with next generation neural prosthesis electrodes. Biophysical cues can exert greater influence on neurite pathfinding compared to the more well studied biochemical cues; yet the signaling events underlying the ability of growth cones to respond to these microfeatures remain obscure. Intracellular Ca2+ signaling plays a critical role in how a growth cone senses and grows in response to various cues (biophysical features, repulsive peptides, chemo-attractive gradients). Here, we investigate the role of inositol triphosphate (IP3) and ryanodine-sensitive receptor (RyR) signaling as sensory neurons (spiral ganglion neurons, SGNs, and dorsal root ganglion neurons, DRGNs) pathfind in response to micropatterned substrates of varied geometries. We find that IP3 and RyR signaling act in the growth cone as they navigate biophysical cues and enable proper guidance to biophysical, chemo-permissive, and chemo-repulsive micropatterns. In response to complex micropatterned geometries, RyR signaling appears to halt growth in response to both topographical features and chemo-repulsive cues. IP3 signaling appears to play a more complex role, as growth cones appear to sense the microfeatures in the presence of xestospongin C but are unable to coordinate turning in response to them. Overall, key Ca2+ signaling elements, IP3 and RyR, are found to be essential for SGNs to pathfind in response to engineered biophysical and biochemical cues. These findings inform efforts to precisely guide neurite regeneration for improved neural prosthesis function, including cochlear implants.
Asunto(s)
Neuritas , Canal Liberador de Calcio Receptor de Rianodina , Transducción de Señal , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Neuritas/metabolismo , Animales , Ganglios Espinales/metabolismo , Ganglios Espinales/citología , Conos de Crecimiento/metabolismo , Conos de Crecimiento/efectos de los fármacos , Señalización del Calcio , Ratas , Propiedades de Superficie , Células Cultivadas , Oxazoles , Compuestos MacrocíclicosRESUMEN
Sea urchin eggs are covered with layers of extracellular matrix, namely, the vitelline layer (VL) and jelly coat (JC). It has been shown that sea urchin eggs' JC components serve as chemoattractants or ligands for the receptor on the fertilizing sperm to promote the acrosome reaction. Moreover, the egg's VL provides receptors for conspecific sperm to bind, and, to date, at least two sperm receptors have been identified on the surface of sea urchin eggs. Interestingly, however, according to our previous work, denuded sea urchin eggs devoid of the JC and VL do not fail to become fertilized by sperm. Instead, they are bound and penetratedby multiple sperm, raising the possibility that an alternative pathway independent of the VL-residing sperm receptor may be at work. In this research, we studied the roles of the JC and VL using intact and denuded eggs and the synthetic polyamine BPA-C8. BPA-C8 is known to bind to the negatively charged macromolecular complexes in the cells, such as the JC, VL, and the plasma membrane of echinoderm eggs, as well as to the actin filaments in fibroblasts. Our results showed that, when added to seawater, BPA-C8 significantly repressed the Ca2+ wave in the intact P. lividus eggs at fertilization. In eggs deprived of the VL and JC, BPA-C8 binds to the plasma membrane and increases fibrous structures connecting microvilli, thereby allowing the denuded eggs to revert towards monospermy at fertilization. However, the reduced Ca2+ signal in denuded eggs was nullified compared to the intact eggs because removing the JC and VL already decreased the Ca2+ wave. BPA-C8 does not cross the VL and the cell membrane of unfertilized sea urchin eggs to diffuse into the cytoplasm at variance with the fibroblasts. Indeed, the jasplakinolide-induced polymerization of subplasmalemmal actin filaments was inhibited in the eggs microinjected with BPA-C8, but not in the ones bath-incubated with the same dose of BPA-C8.
Asunto(s)
Fertilización , Óvulo , Erizos de Mar , Animales , Fertilización/efectos de los fármacos , Erizos de Mar/efectos de los fármacos , Erizos de Mar/metabolismo , Óvulo/metabolismo , Óvulo/efectos de los fármacos , Masculino , Poliaminas/metabolismo , Poliaminas/farmacología , Femenino , Espermatozoides/metabolismo , Espermatozoides/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Interacciones Espermatozoide-Óvulo/efectos de los fármacos , Calcio/metabolismoRESUMEN
ATP and benzoylbenzoyl-ATP (BzATP) increase free cytosolic Ca2+ concentration ([Ca2+]i) in conjunctival goblet cells (CGCs) resulting in mucin secretion. The purpose of this study was to investigate the source of the Ca2+i mobilized by ATP and BzATP. First-passage cultured rat CGCs were incubated with Fura-2/AM, and [Ca2+]i was measured under several conditions with ATP and BzATP stimulation. The following conditions were used: 1) preincubation with the Ca2+ chelator EGTA, 2) preincubation with the SERCA inhibitor thapsigargin (10-6 M), which depletes ER Ca2+ stores, 3) preincubation with phospholipase C (PLC) or protein kinase A (PKA) inhibitor, or 4) preincubation with the voltage-gated calcium channel antagonist nifedipine (10-5 M) and the ryanodine receptor (RyR) antagonist dantrolene (10-5 M). Immunofluorescence microscopy (IF) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to investigate RyR presence in rat and human CGCs. ATP-stimulated peak [Ca2+]i was significantly lower after chelating Ca2+i with 2 mM EGTA in Ca2+-free buffer. The peak [Ca2+]i increase in CGCs preincubated with thapsigargin, the PKA inhibitor H89, nifedipine, and dantrolene, but not the PLC inhibitor, was reduced for ATP at 10-5 M and BzATP at 10-4 M. Incubating CGCs with dantrolene alone decreased [Ca2+]i and induced CGC cell death at a high concentration. RyR3 was detected in rat and human CGCs with IF and RT-qPCR. We conclude that ATP- and BzATP-induced Ca2+i increases originate from the ER and that RyR3 may be an essential regulator of CGC [Ca2+]i. This study contributes to the understanding of diseases arising from defective Ca2+ signaling in nonexcitable cells.NEW & NOTEWORTHY ATP and benzoylbenzoyl-ATP (BzATP) induce mucin secretion through an increase in free cytosolic calcium concentration ([Ca2+]i) in conjunctival goblet cells (CGCs). The mechanisms through which ATP and BzATP increase [Ca2+]i in CGCs are unclear. Ryanodine receptors (RyRs) are fundamental in [Ca2+]i regulation in excitable cells. Herein, we find that ATP and BzATP increase [Ca2+]i through the activation of protein kinase A, voltage-gated calcium channels, and RyRs, and that RyRs are crucial for nonexcitable CGCs' Ca2+i homeostasis.
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Adenosina Trifosfato , Calcio , Células Caliciformes , Canal Liberador de Calcio Receptor de Rianodina , Animales , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/genética , Calcio/metabolismo , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/análogos & derivados , Células Caliciformes/efectos de los fármacos , Células Caliciformes/metabolismo , Ratas , Células Cultivadas , Conjuntiva/metabolismo , Conjuntiva/efectos de los fármacos , Agonistas Purinérgicos/farmacología , Ratas Sprague-Dawley , Señalización del Calcio/efectos de los fármacos , Humanos , Masculino , Fosfolipasas de Tipo C/metabolismoRESUMEN
To facilitate our understanding of proteome dynamics during signaling events, robust workflows affording fast time resolution without confounding factors are essential. We present Surface-exposed protein Labeling using PeroxidaSe, H2O2, and Tyramide-derivative (SLAPSHOT) to label extracellularly exposed proteins in a rapid, specific, and sensitive manner. Simple and flexible SLAPSHOT utilizes recombinant soluble APEX2 protein applied to cells, thus circumventing the engineering of tools and cells, biological perturbations, and labeling biases. We applied SLAPSHOT and quantitative proteomics to examine the TMEM16F-dependent plasma membrane remodeling in WT and TMEM16F KO cells. Time-course data ranging from 1 to 30 min of calcium stimulation revealed co-regulation of known protein families, including the integrin and ICAM families, and identified proteins known to reside in intracellular organelles as occupants of the freshly deposited extracellularly exposed membrane. Our data provide the first accounts of the immediate consequences of calcium signaling on the extracellularly exposed proteome.
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Anoctaminas , Calcio , Membrana Celular , Proteoma , Proteoma/metabolismo , Membrana Celular/metabolismo , Calcio/metabolismo , Anoctaminas/metabolismo , Anoctaminas/genética , Animales , Proteómica/métodos , Humanos , Ratones , Fosfolípidos/metabolismo , Señalización del Calcio , Proteínas de Transferencia de Fosfolípidos/metabolismo , Proteínas de Transferencia de Fosfolípidos/genética , Peróxido de Hidrógeno/metabolismoRESUMEN
Activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.
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Señalización del Calcio , Proteínas de Unión al Calcio , Calcio , Proteínas de Transporte de Catión , Proteínas de Transporte de Membrana Mitocondrial , Miocitos Cardíacos , Animales , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Ratones , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , Humanos , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Miocitos Cardíacos/metabolismo , Señalización del Calcio/fisiología , Calcio/metabolismo , Mitocondrias Cardíacas/metabolismo , Canales de Calcio/metabolismo , Canales de Calcio/genética , Ratones Noqueados , Miocardio/metabolismo , MasculinoRESUMEN
One of the major breakthroughs of neurobiology was the identification of distinct ranges of oscillatory activity in the neuronal network that were found to be responsible for specific biological functions, both physiological and pathological in nature. Astrocytes, physically coupled by gap junctions and possessing the ability to simultaneously modulate the functions of a large number of surrounding synapses, are perfectly positioned to introduce synchronised oscillatory activity into the neural network. However, astrocytic somatic calcium signalling has not been investigated to date in the frequency ranges of common neuronal oscillations, since astrocytes are generally considered to be slow responders in terms of Ca2+ signalling. Using high-frequency two-photon imaging, we reveal fast Ca2+ oscillations in the soma of astrocytes in the delta (0.5-4 Hz) and theta (4-8 Hz) frequency bands in vivo in the rat cortex under ketamine-xylazine anaesthesia, which is known to induce permanent slow-wave sleep. The high-frequency astrocytic Ca2+ signals were not observed under fentanyl anaesthesia, excluding the possibility that the signals were introduced by motion artefacts. We also demonstrate that these fast astrocytic Ca2+ signals, previously considered to be exclusive to neurons, are present in a large number of astrocytes and are phase synchronised at the astrocytic network level. We foresee that the disclosure of these high-frequency astrocytic signals may help with understanding the appearance of synchronised oscillatory signals and may open up new avenues of treatment for neurological conditions characterised by altered neuronal oscillations.
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Astrocitos , Señalización del Calcio , Calcio , Astrocitos/metabolismo , Animales , Ratas , Calcio/metabolismo , Masculino , Ritmo Teta/fisiología , Ritmo Delta , Neuronas/metabolismo , Neuronas/fisiologíaRESUMEN
Intracellular communication and regulation in brain cells is controlled by the ubiquitous Ca2+ and by redox signalling. Both of these independent signalling systems regulate most of the processes in cells including the cell surviving mechanism or cell death. In physiology Ca2+ can regulate and trigger reactive oxygen species (ROS) production by various enzymes and in mitochondria but ROS could also transmit redox signal to calcium levels via modification of calcium channels or phospholipase activity. Changes in calcium or redox signalling could lead to severe pathology resulting in excitotoxicity or oxidative stress. Interaction of the calcium and ROS is essential to trigger opening of mitochondrial permeability transition pore - the initial step of apoptosis, Ca2+ and ROS-induced oxidative stress involved in necrosis and ferroptosis. Here we review the role of redox signalling and Ca2+ in cytosol and mitochondria in the physiology of brain cells - neurons and astrocytes and how this integration can lead to pathology, including ischaemia injury and neurodegeneration.
Asunto(s)
Encéfalo , Señalización del Calcio , Calcio , Mitocondrias , Neuronas , Estrés Oxidativo , Especies Reactivas de Oxígeno , Especies Reactivas de Oxígeno/metabolismo , Humanos , Mitocondrias/metabolismo , Encéfalo/metabolismo , Animales , Calcio/metabolismo , Neuronas/metabolismo , Astrocitos/metabolismo , Oxidación-Reducción , Apoptosis , Poro de Transición de la Permeabilidad Mitocondrial/metabolismoRESUMEN
Neurodegenerative diseases are complex disorders that significantly challenge human health, with their incidence increasing with age. A key pathological feature of these diseases is the accumulation of misfolded proteins. The underlying mechanisms involve an imbalance in calcium homeostasis and disturbances in autophagy, indicating a likely correlation between them. As the most important second messenger, Ca2+ plays a vital role in regulating various cell activities, including autophagy. Different organelles within cells serve as Ca2+ storage chambers and regulate Ca2+ levels under different conditions. Ca2+ in these compartments can affect autophagy via Ca2+ channels or other related signaling proteins. Researchers propose that Ca2+ regulates autophagy through distinct signal transduction mechanisms, under normal or stressful conditions, and thereby contributing to the occurrence and development of neurodegenerative diseases. This review provides a systematic examination of the regulatory mechanisms of Ca2+ in cell membranes and different organelles, as well as its downstream pathways that influence autophagy and its implications for neurodegenerative diseases. This comprehensive analysis may facilitate the development of new drugs and provide more precise treatments for neurodegenerative diseases.
Asunto(s)
Autofagia , Calcio , Enfermedades Neurodegenerativas , Humanos , Autofagia/fisiología , Enfermedades Neurodegenerativas/metabolismo , Calcio/metabolismo , Señalización del Calcio/fisiología , Transducción de SeñalRESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder with a complex and multifactorial pathogenesis. This chapter delves into the critical role of astrocytes in PD. Once viewed as supporting cells in the central nervous system, astrocytes have emerged as key players in both maintaining neuronal health and contributing to neurodegeneration in PD. Their functions play a dual role in the progression of PD, ranging from protective functions like secretion of neurotrophic factors and clearance of α-synuclein to detrimental functions like promotion of neuroinflammation. This chapter is structured into three primary sections: the morphological and functional organization of astrocytes, astrocytic calcium signaling, and the role of astrocyte heterogeneity in PD. We provide a detailed exploration of astrocytic organelles, bidirectional astrocyte-neuron interactions, and the impact of astrocytic secretions such as antioxidant molecules and neurotrophic factors. Furthermore, we discuss the influence of astrocytes on non-neuronal cells, including interactions with microglia and the blood-brain barrier (BBB). By examining the multifaceted roles of astrocytes, in this chapter, we aim to bridge basic astrocyte biology with the clinical complexities of PD, offering insights into novel therapeutic strategies. The inclusion of astrocyte biology in our broader research approach will aid in the development of more effective treatment strategies for PD.
Asunto(s)
Astrocitos , Enfermedad de Parkinson , Astrocitos/metabolismo , Astrocitos/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Humanos , Barrera Hematoencefálica/metabolismo , Microglía/metabolismo , Microglía/patología , Animales , Factores de Crecimiento Nervioso/metabolismo , alfa-Sinucleína/metabolismo , Señalización del Calcio/fisiología , Neuronas/metabolismo , Neuronas/patologíaRESUMEN
Calcium ions (Ca2+) play crucial roles in almost every cellular process, making the detection of changes in intracellular Ca2+ essential to understanding cell function. The fluorescence indicator method has garnered widespread application due to its exceptional sensitivity, rapid analysis, cost-effectiveness, and user-friendly nature. It has successfully delineated the spatial and temporal dynamics of Ca2+ signaling across diverse cell types. However, it is vital to understand that different indicators have varying levels of accuracy, sensitivity, and stability, making choosing the right inspection method crucial. As optical detection technologies advance, they continually broaden the horizons of scientific inquiry. This primer offers a systematic synthesis of the current fluorescence indicators and optical imaging modalities utilized for the detection of intracellular Ca2+. It elucidates their practical applications and inherent limitations, serving as an essential reference for researchers seeking to identify the most suitable detection methodologies for their calcium-centric investigations.