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1.
Sci Signal ; 14(675)2021 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-33758061

RESUMEN

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca2+ from acidic organelles through the activation of two-pore channels (TPCs) to regulate endolysosomal trafficking events. NAADP action is mediated by NAADP-binding protein(s) of unknown identity that confer NAADP sensitivity to TPCs. Here, we used a "clickable" NAADP-based photoprobe to isolate human NAADP-binding proteins and identified Jupiter microtubule-associated homolog 2 (JPT2) as a TPC accessory protein required for endogenous NAADP-evoked Ca2+ signaling. JPT2 was also required for the translocation of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus through the endolysosomal system. Thus, JPT2 is a component of the NAADP receptor complex that is essential for TPC-dependent Ca2+ signaling and control of coronaviral entry.


Asunto(s)
/metabolismo , Señalización del Calcio/fisiología , Proteínas Asociadas a Microtúbulos/metabolismo , NADP/análogos & derivados , /fisiología , Marcadores de Afinidad , Animales , Canales de Calcio/metabolismo , Proteínas Portadoras/metabolismo , Química Clic/métodos , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/genética , NADP/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sistemas de Mensajero Secundario/fisiología , Transcriptoma , Internalización del Virus
2.
Int J Nanomedicine ; 16: 1423-1434, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33654394

RESUMEN

Background: Interleukin-1ß (IL-1)-treated mesenchymal stem cells (MSCs) and IL-1-MSCs-conditioned medium (CM) exert anti-inflammatory roles. Astrocytes are essential for the modulation of synaptic activity and neuronal homeostasis in the brain. Exosomes are the critical mediators in intercellular communication. However, the mechanism underlying the anti-inflammatory effect of IL-1-treated MSCs remains unknown. Methods: In this study, exosomes (IL-1-Exo) were isolated from IL-1-treated MSCs. In addition, lipopolysaccharide (LPS)-treated hippocampal astrocytes and status epilepticus (SE) mice were treated with IL-1-Exo. Inflammatory activity, astrogliosis, and cognitive performance were measured to determine the effect of IL-1-Exo on inflammation. Results: The results revealed that IL-1-Exo significantly inhibited LPS-induced astrogliosis and inflammatory responses of astrocytes. Also, IL-1-Exo reversed the LPS-induced effect on calcium signaling. The Nrf2 signaling pathway was associated with the effect of IL-1-Exo in LPS-treated astrocytes. Furthermore, IL-1-Exo reduced the inflammatory response and improved the cognitive performance of SE mice. Conclusion: The results suggest that IL-1-Exo inhibited LPS-induced inflammatory responses in astrocytes and SE mice and that the effect of IL-1-Exo was primarily mediated through the Nrf-2 signaling pathway. This study provides a new understanding of the molecular mechanism of inflammation-associated brain diseases and an avenue to develop nanotherapeutic agents for the treatment of inflammatory conditions in the brain.


Asunto(s)
Astrocitos/patología , Exosomas/metabolismo , Hipocampo/patología , Inflamación/terapia , Interleucina-1beta/farmacología , Células Madre Mesenquimatosas/citología , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Animales , Animales Recién Nacidos , Antiinflamatorios/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Conducta Animal/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Exosomas/efectos de los fármacos , Exosomas/ultraestructura , Humanos , Inflamación/patología , Lipopolisacáridos , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Transducción de Señal/efectos de los fármacos , Estado Epiléptico/patología
3.
Int J Mol Sci ; 22(4)2021 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-33669995

RESUMEN

Oxidative stress and increased cytoplasmic calcium are key mediators of the detrimental effects on neuronal function and survival in Alzheimer's disease (AD). Pathways whereby these perturbations arise, and then prevent dendritic spine formation, promote tau hyperphosphorylation, further amplify amyloid ß generation, and induce neuronal apoptosis, are described. A comprehensive program of nutraceutical supplementation, comprised of the NADPH oxidase inhibitor phycocyanobilin, phase two inducers, the mitochondrial antioxidant astaxanthin, and the glutathione precursor N-acetylcysteine, may have important potential for antagonizing the toxic effects of amyloid ß on neurons and thereby aiding prevention of AD. Moreover, nutraceutical antioxidant strategies may oppose the adverse impact of amyloid ß oligomers on astrocyte clearance of glutamate, and on the ability of brain capillaries to export amyloid ß monomers/oligomers from the brain. Antioxidants, docosahexaenoic acid (DHA), and vitamin D, have potential for suppressing microglial production of interleukin-1ß, which potentiates the neurotoxicity of amyloid ß. Epidemiology suggests that a health-promoting lifestyle, incorporating a prudent diet, regular vigorous exercise, and other feasible measures, can cut the high risk for AD among the elderly by up to 60%. Conceivably, complementing such lifestyle measures with long-term adherence to the sort of nutraceutical regimen outlined here may drive down risk for AD even further.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/prevención & control , Antioxidantes/uso terapéutico , Señalización del Calcio , Oxidantes/toxicidad , Péptidos beta-Amiloides/toxicidad , Animales , Señalización del Calcio/efectos de los fármacos , Suplementos Dietéticos , Humanos
4.
Adv Exp Med Biol ; 1303: 319-331, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33788200

RESUMEN

Asthma is a chronic disease characterized by airway hyperresponsiveness, which can be caused by exposure to an allergen, spasmogen, or be induced by exercise. Despite its prevalence, the exact mechanisms by which the airway becomes hyperresponsive in asthma are not fully understood. There is evidence that myosin light-chain kinase is overexpressed, with a concomitant downregulation of myosin light-chain phosphatase in the airway smooth muscle, leading to sustained contraction. Additionally, the sarco/endoplasmic reticulum ATPase may be affected by inflammatory cytokines, such as IL-4, IL-5, IL-13, and TNF-α, which are all associated with asthmatic airway inflammation. IL-13 and TNF-α seem to promote sodium/calcium exchanger 1 overexpression as well. Anyhow, the exact mechanisms beyond these dysregulations need to be clarified. Of note, multiple studies show an association between asthma and the ORMLD3 gene, opening new perspectives to future potential gene therapies. Currently, several treatments are available for asthma, although many of them have systemic side effects, or are not effective in patients with severe asthma. Furthering our knowledge on the molecular and pathophysiological mechanisms of asthma plays a pivotal role for the development of new and more targeted treatments for patients who cannot totally benefit from the current therapies.


Asunto(s)
Asma , Hipersensibilidad Respiratoria , Asma/genética , Asma/metabolismo , Calcio/metabolismo , Señalización del Calcio , Humanos , Músculo Liso , Sistema Respiratorio/metabolismo
5.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540826

RESUMEN

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N-palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells; (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines; (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas; (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI); (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.


Asunto(s)
Analgésicos/uso terapéutico , Antiinflamatorios/uso terapéutico , Glucolípidos/uso terapéutico , Hiperalgesia/prevención & control , Queratitis/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Receptor Toll-Like 4/antagonistas & inhibidores , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Señalización del Calcio/efectos de los fármacos , Citocinas/metabolismo , Evaluación Preclínica de Medicamentos , Glucolípidos/farmacología , Células HEK293 , Humanos , Hiperalgesia/etiología , Queratitis/inducido químicamente , Queratitis/patología , Lipopolisacáridos/toxicidad , Antígeno 96 de los Linfocitos/metabolismo , Masculino , Ratones , MicroARNs/genética , Modelos Moleculares , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Conformación Proteica , Células RAW 264.7 , Distribución Aleatoria , Nervio Ciático/lesiones , Canal Catiónico TRPA1/metabolismo
6.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540894

RESUMEN

Heart failure remains the most common cause of death in the industrialized world. In spite of new therapeutic interventions that are constantly being developed, it is still not possible to completely protect against heart failure development and progression. This shows how much more research is necessary to understand the underlying mechanisms of this process. In this review, we give a detailed overview of the contribution of impaired mitochondrial dynamics and energy homeostasis during heart failure progression. In particular, we focus on the regulation of fatty acid metabolism and the effects of fatty acid accumulation on mitochondrial structural and functional homeostasis.


Asunto(s)
Ácidos Grasos/metabolismo , Insuficiencia Cardíaca/metabolismo , Mitocondrias Cardíacas/metabolismo , Dinámicas Mitocondriales , Tejido Adiposo/metabolismo , Señalización del Calcio , Cardiomiopatías/metabolismo , Ceramidas/biosíntesis , Ciclo del Ácido Cítrico , Progresión de la Enfermedad , Ácidos Grasos/efectos adversos , Homeostasis , Humanos , Cuerpos Cetónicos/metabolismo , Enfermedades Mitocondriales/metabolismo , Mitofagia , NAD/metabolismo , Pericardio/metabolismo , Receptores Activados del Proliferador del Peroxisoma/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Especies Reactivas de Oxígeno/metabolismo
7.
BMC Infect Dis ; 21(1): 228, 2021 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-33639860

RESUMEN

BACKGROUND: Family with sequence similarity 26, member F (FAM26F) is an important innate immunity modulator playing a significant role in diverse immune responses, however, the association of FAM26F expression with HBV infection is not yet known. Thus, the current study aims to explore the differential expression of FAM26F in vitro in HepAD38 and HepG2 cell lines upon HBV infection, and in vivo in HBV infected individuals. The effects of antioxidant and calcium inhibitors on the regulation of FAM26F expression were also evaluated. The expression of FAM26F was simultaneously determined with well-established HBV infection markers: IRF3, and IFN-ß. METHODS: The expression of FAM26F and marker genes was analyzed through Real-time qPCR and western blot. RESULTS: Our results indicate that the differential expression of FAM26F followed the same trend as that of IRF3 and IFN-ß. The in vitro study revealed that, in both HBV infected cell lines, FAM26F expression was significantly down-regulated as compared to uninfected control cells. Treatment of cells with N-acetyl-L-cysteine (NAC), EGTA-AM, BAPTA-AM, and Ru360 significantly upregulated the expression of FAM26F in both the cell lines. Moreover, in in vivo study, FAM26F expression was significantly downregulated in all HBV infected groups as compared to controls (p = 0.0007). The expression was higher in the HBV recovered cases, probably due to the decrease in infection and increase in the immunity of these individuals. CONCLUSION: Our study is the first to show the association of FAM26F with HBV infection. It is proposed that FAM26F expression could be an early predictive marker for HBV infection, and thus is worthy of further investigation.


Asunto(s)
Calcio/farmacología , Hepatitis B/genética , Glicoproteínas de Membrana/genética , Estrés Oxidativo/fisiología , Adolescente , Adulto , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/genética , Estudios de Casos y Controles , Línea Celular , Niño , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Hepatitis B/inmunología , Hepatitis B/metabolismo , Hepatitis B/patología , Virus de la Hepatitis B/fisiología , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Adulto Joven
8.
Nature ; 590(7844): 57-66, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33536648

RESUMEN

Mitochondria form dynamic networks in the cell that are balanced by the flux of iterative fusion and fission events of the organelles. It is now appreciated that mitochondrial fission also represents an end-point event in a signalling axis that allows cells to sense and respond to external cues. The fission process is orchestrated by membrane-associated adaptors, influenced by organellar and cytoskeletal interactions and ultimately executed by the dynamin-like GTPase DRP1. Here we invoke the framework of the 'mitochondrial divisome', which is conceptually and operationally similar to the bacterial cell-division machinery. We review the functional and regulatory aspects of the mitochondrial divisome and, within this framework, parse the core from the accessory machinery. In so doing, we transition from a phenomenological to a mechanistic understanding of the fission process.


Asunto(s)
Mitocondrias/química , Mitocondrias/metabolismo , Dinámicas Mitocondriales/fisiología , Animales , Evolución Biológica , Señalización del Calcio , Muerte Celular , Enfermedad , Dinaminas/química , Dinaminas/genética , Dinaminas/metabolismo , Salud , Humanos , Mitocondrias/patología
9.
Science ; 371(6536)2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33632896

RESUMEN

Cell-cell communication relies on the assembly of receptor-ligand complexes at the plasma membrane. The spatiotemporal receptor organization has a pivotal role in evoking cellular responses. We studied the clustering of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) and established a photoinstructive matrix with ultrasmall lock-and-key interaction pairs to control lateral membrane organization of hormone neuropeptide Y2 receptors in living cells by light. Within seconds, receptor clustering was modulated in size, location, and density. After in situ confinement, changes in cellular morphology, motility, and calcium signaling revealed ligand-independent receptor activation. This approach may enhance the exploration of mechanisms in cell signaling and mechanotransduction.


Asunto(s)
Membrana Celular/metabolismo , Receptores de Neuropéptido Y/metabolismo , Transducción de Señal , Calcio/metabolismo , Señalización del Calcio , Línea Celular , Movimiento Celular , Citosol/metabolismo , Difusión , Humanos , Rayos Láser , Ligandos , Lípidos/análisis , Modelos Biológicos , Neuropéptido Y/farmacología , Agregación de Receptores , Receptores de Neuropéptido Y/agonistas , Receptores de Neuropéptido Y/antagonistas & inhibidores
10.
Nat Commun ; 12(1): 869, 2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33558521

RESUMEN

The beating heart possesses the intrinsic ability to adapt cardiac output to changes in mechanical load. The century-old Frank-Starling law and Anrep effect have documented that stretching the heart during diastolic filling increases its contractile force. However, the molecular mechanotransduction mechanism and its impact on cardiac health and disease remain elusive. Here we show that the mechanically activated Piezo1 channel converts mechanical stretch of cardiomyocytes into Ca2+ and reactive oxygen species (ROS) signaling, which critically determines the mechanical activity of the heart. Either cardiac-specific knockout or overexpression of Piezo1 in mice results in defective Ca2+ and ROS signaling and the development of cardiomyopathy, demonstrating a homeostatic role of Piezo1. Piezo1 is pathologically upregulated in both mouse and human diseased hearts via an autonomic response of cardiomyocytes. Thus, Piezo1 serves as a key cardiac mechanotransducer for initiating mechano-chemo transduction and consequently maintaining normal heart function, and might represent a novel therapeutic target for treating human heart diseases.


Asunto(s)
Canales Iónicos/metabolismo , Mecanotransducción Celular , Miocardio/metabolismo , Animales , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatología , Calcio/metabolismo , Señalización del Calcio , Cardiomiopatías/metabolismo , Cardiomiopatías/fisiopatología , Eliminación de Gen , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Pruebas de Función Cardíaca , Homeostasis , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Especificidad de Órganos , Pirazinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Tiadiazoles/metabolismo , Regulación hacia Arriba
11.
Cell Calcium ; 94: 102340, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33601151

RESUMEN

The recent paper by Pfeil et al., "Heterotrimeric G Protein Subunit Gαq Is a Master Switch for Gßγ-Mediated Calcium Mobilization by Gi-Coupled GPCRs", opens another path from biochemical in vitro reconstitution to understanding the complex regulation of calcium signaling inside the cell.


Asunto(s)
Calcio , Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Calcio/metabolismo , Señalización del Calcio , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Fosfolipasa C beta/metabolismo
12.
Ecotoxicol Environ Saf ; 213: 112025, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33578098

RESUMEN

The detailed molecular mechanism of wilforine, a novel botanical insecticidal component, remains unclear, except for the knowledge that it affects the calcium signaling pathway. The aim of the current study was to examine the underlying molecular mechanism of wilforine in Mythimna separata (Walker) by transcriptome and RNA interference (RNAi), with chlorantraniliprole as control. RNA sequencing showed that the relative expression of genes related to the calcium signaling pathway and muscle contraction in M. separata treated with wilforine significantly changed and was further validated by qRT-PCR. Interestingly, the expression level of the ryanodine receptor (MsRyR) gene was downregulated by wilforine at relatively high concentrations and long treatment time, contrary to that observed using chlorantraniliprole. Furthermore, a putative MsRyR was cloned using a 16,258-bp contiguous sequence containing a 308-bp 5'-untranslated region and 578-bp 3'-untranslated region by RT-PCR and RACE. The results of the RNAi experiment showed that injection of dsMsRyR significantly reduced MsRyR mRNA levels, and growth and development were inhibited. Importantly, silencing of the MsRyR gene resulted in decreased susceptibility to both wilforine and chlorantraniliprole. Together with the results of our previous studies on toxic symptoms and muscle tissue lesions between wilforine and chlorantraniliprole, we propose that RyR Ca2+ release channel dysfunction is closely related with significant lethal mechanisms of wilforine.


Asunto(s)
Insecticidas/toxicidad , Lactonas/toxicidad , Mariposas Nocturnas/fisiología , Piridinas/toxicidad , Animales , Señalización del Calcio/efectos de los fármacos , Larva/metabolismo , Mariposas Nocturnas/metabolismo , ARN Mensajero/metabolismo , Rianodina , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Transcriptoma/efectos de los fármacos , ortoaminobenzoatos
13.
Nat Commun ; 12(1): 907, 2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33568645

RESUMEN

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are two distinct autoimmune diseases that manifest with chronic synovial inflammation. Here, we show that CD4+ T cells from patients with RA and PsA have increased expression of the pore-forming calcium channel component ORAI3, thereby increasing the activity of the arachidonic acid-regulated calcium-selective (ARC) channel and making T cells sensitive to arachidonic acid. A similar increase does not occur in T cells from patients with systemic lupus erythematosus. Increased ORAI3 transcription in RA and PsA T cells is caused by reduced IKAROS expression, a transcriptional repressor of the ORAI3 promoter. Stimulation of the ARC channel with arachidonic acid induces not only a calcium influx, but also the phosphorylation of components of the T cell receptor signaling cascade. In a human synovium chimeric mouse model, silencing ORAI3 expression in adoptively transferred T cells from patients with RA attenuates tissue inflammation, while adoptive transfer of T cells from healthy individuals with reduced expression of IKAROS induces synovitis. We propose that increased ARC activity due to reduced IKAROS expression makes T cells more responsive and contributes to chronic inflammation in RA and PsA.


Asunto(s)
Ácido Araquidónico/inmunología , Artritis Reumatoide/inmunología , Linfocitos T CD4-Positivos/inmunología , Membrana Sinovial/inmunología , Anciano , Artritis Psoriásica/genética , Artritis Psoriásica/inmunología , Artritis Reumatoide/genética , Calcio/inmunología , Canales de Calcio/genética , Canales de Calcio/inmunología , Señalización del Calcio , Femenino , Humanos , Masculino , Persona de Mediana Edad
14.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33498392

RESUMEN

Four drugs are currently approved for the treatment of Alzheimer's disease (AD) by the FDA. Three of these drugs-donepezil, rivastigmine, and galantamine-belong to the class of acetylcholine esterase inhibitors. Memantine, a NMDA receptor antagonist, represents the fourth and a combination of donepezil and memantine the fifth treatment option. Recently, the gut and its habitants, its microbiome, came into focus of AD research and added another important factor to therapeutic considerations. While the first data provide evidence that AD patients might carry an altered microbiome, the influence of administered drugs on gut properties and commensals have been largely ignored so far. However, the occurrence of digestive side effects with these drugs and the knowledge that cholinergic transmission is crucial for several gut functions enforces the question if, and how, this medication influences the gastrointestinal system and its microbial stocking. Here, we investigated aspects such as microbial viability, colonic propulsion, and properties of enteric neurons, affected by assumed intestinal concentration of the four drugs using the mouse as a model organism. All ex vivo administered drugs revealed no direct effect on fecal bacteria viability and only a high dosage of memantine resulted in reduced biofilm formation of E. coli. Memantine was additionally the only compound that elevated calcium influx in enteric neurons, while all acetylcholine esterase inhibitors significantly reduced esterase activity in colonic tissue specimen and prolonged propulsion time. Both, acetylcholine esterase inhibitors and memantine, had no effect on general viability and neurite outgrowth of enteric neurons. In sum, our findings indicate that all AD symptomatic drugs have the potential to affect distinct intestinal functions and with this-directly or indirectly-microbial commensals.


Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Memantina/farmacología , Fármacos Neuroprotectores/farmacología , Animales , Señalización del Calcio , Células Cultivadas , Colon/efectos de los fármacos , Colon/metabolismo , Colon/microbiología , Colon/fisiología , Sistema Nervioso Entérico/efectos de los fármacos , Sistema Nervioso Entérico/metabolismo , Sistema Nervioso Entérico/fisiología , Ratones , Ratones Endogámicos C57BL , Proyección Neuronal
15.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33466510

RESUMEN

Ca2+ signaling has been involved in controling critical cellular functions such as activation of proteases, cell death, and cell cycle control. The endoplasmatic reticulum plays a significant role in Ca2+ storage inside the cell, but mitochondria have long been recognized as a fundamental Ca2+ pool. Protozoan parasites such as Plasmodium falciparum, Toxoplasma gondii, and Trypanosoma cruzi display a Ca2+ signaling toolkit with similarities to higher eukaryotes, including the participation of mitochondria in Ca2+-dependent signaling events. This review summarizes the most recent knowledge in mitochondrial Ca2+ signaling in protozoan parasites, focusing on the mechanism involved in mitochondrial Ca2+ uptake by pathogenic protists.


Asunto(s)
Señalización del Calcio/fisiología , Calcio/metabolismo , Mitocondrias/metabolismo , Parásitos/metabolismo , Animales , Eucariontes/metabolismo , Humanos , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/metabolismo , Toxoplasma/metabolismo , Trypanosoma cruzi/metabolismo
16.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-33466866

RESUMEN

The Ca2+ selective channel ORAI1 and endoplasmic reticulum (ER)-resident STIM proteins form the core of the channel complex mediating store operated Ca2+ entry (SOCE). Using liquid phase electron microscopy (LPEM), the distribution of ORAI1 proteins was examined at rest and after SOCE-activation at nanoscale resolution. The analysis of over seven hundred thousand ORAI1 positions revealed a number of ORAI1 channels had formed STIM-independent distinct supra-molecular clusters. Upon SOCE activation and in the presence of STIM proteins, a fraction of ORAI1 assembled in micron-sized two-dimensional structures, such as the known puncta at the ER plasma membrane contact zones, but also in divergent structures such as strands, and ring-like shapes. Our results thus question the hypothesis that stochastically migrating single ORAI1 channels are trapped at regions containing activated STIM, and we propose instead that supra-molecular ORAI1 clusters fulfill an amplifying function for creating dense ORAI1 accumulations upon SOCE-activation.


Asunto(s)
Señalización del Calcio , Calcio/metabolismo , Membrana Celular/metabolismo , Retículo Endoplásmico/metabolismo , Proteína ORAI1/metabolismo , Membrana Celular/ultraestructura , Retículo Endoplásmico/ultraestructura , Células HEK293 , Humanos , Microscopía Electrónica , Microscopía Fluorescente , Tamaño de la Partícula , Transporte de Proteínas , Molécula de Interacción Estromal 1/metabolismo
17.
Mol Cell ; 81(4): 675-690.e8, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33453167

RESUMEN

Neural network computations are usually assumed to emerge from patterns of fast electrical activity. Challenging this view, we show that a male fly's decision to persist in mating hinges on a biochemical computation that enables processing over minutes to hours. Each neuron in a recurrent network contains slightly different internal molecular estimates of mating progress. Protein kinase A (PKA) activity contrasts this internal measurement with input from the other neurons to represent accumulated evidence that the goal of the network has been achieved. When consensus is reached, PKA pushes the network toward a large-scale and synchronized burst of calcium influx that we call an eruption. Eruptions transform continuous deliberation within the network into an all-or-nothing output, after which the male will no longer sacrifice his life to continue mating. Here, biochemical activity, invisible to most large-scale recording techniques, is the key computational currency directing behavior and motivational state.


Asunto(s)
Señalización del Calcio , Calcio/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas de Drosophila/metabolismo , Red Nerviosa/metabolismo , Neuronas/metabolismo , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas de Drosophila/genética , Drosophila melanogaster
18.
Int J Mol Sci ; 22(2)2021 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-33430308

RESUMEN

Cell survival and normal cell function require a highly coordinated and precise regulation of basal cytosolic Ca2+ concentrations. The primary source of Ca2+ entry into the cell is mediated by the Ca2+ release-activated Ca2+ (CRAC) channel. Its action is stimulated in response to internal Ca2+ store depletion. The fundamental constituents of CRAC channels are the Ca2+ sensor, stromal interaction molecule 1 (STIM1) anchored in the endoplasmic reticulum, and a highly Ca2+-selective pore-forming subunit Orai1 in the plasma membrane. The precise nature of the Orai1 pore opening is currently a topic of intensive research. This review describes how Orai1 gating checkpoints in the middle and cytosolic extended transmembrane regions act together in a concerted manner to ensure an opening-permissive Orai1 channel conformation. In this context, we highlight the effects of the currently known multitude of Orai1 mutations, which led to the identification of a series of gating checkpoints and the determination of their role in diverse steps of the Orai1 activation cascade. The synergistic action of these gating checkpoints maintains an intact pore geometry, settles STIM1 coupling, and governs pore opening. We describe the current knowledge on Orai1 channel gating mechanisms and summarize still open questions of the STIM1-Orai1 machinery.


Asunto(s)
Señalización del Calcio/genética , Calcio/metabolismo , Proteína ORAI1/genética , Molécula de Interacción Estromal 1/genética , Canales de Calcio Activados por la Liberación de Calcio/metabolismo , Supervivencia Celular/genética , Citosol/metabolismo , Retículo Endoplásmico/genética , Humanos
19.
Int J Mol Sci ; 22(2)2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33477936

RESUMEN

Already in the early 1960s, researchers noted the potential of mitochondria to take up large amounts of Ca2+. However, the physiological role and the molecular identity of the mitochondrial Ca2+ uptake mechanisms remained elusive for a long time. The identification of the individual components of the mitochondrial calcium uniporter complex (MCUC) in the inner mitochondrial membrane in 2011 started a new era of research on mitochondrial Ca2+ uptake. Today, many studies investigate mitochondrial Ca2+ uptake with a strong focus on function, regulation, and localization of the MCUC. However, on its way into mitochondria Ca2+ has to pass two membranes, and the first barrier before even reaching the MCUC is the outer mitochondrial membrane (OMM). The common opinion is that the OMM is freely permeable to Ca2+. This idea is supported by the presence of a high density of voltage-dependent anion channels (VDACs) in the OMM, forming large Ca2+ permeable pores. However, several reports challenge this idea and describe VDAC as a regulated Ca2+ channel. In line with this idea is the notion that its Ca2+ selectivity depends on the open state of the channel, and its gating behavior can be modified by interaction with partner proteins, metabolites, or small synthetic molecules. Furthermore, mitochondrial Ca2+ uptake is controlled by the localization of VDAC through scaffolding proteins, which anchor VDAC to ER/SR calcium release channels. This review will discuss the possibility that VDAC serves as a physiological regulator of mitochondrial Ca2+ uptake in the OMM.


Asunto(s)
Calcio/metabolismo , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Canales Aniónicos Dependientes del Voltaje/genética , Apoptosis/genética , Transporte Biológico/genética , Canales de Calcio , Señalización del Calcio/genética , Humanos , Transporte Iónico/genética , Mitocondrias/genética , Canales Aniónicos Dependientes del Voltaje/metabolismo
20.
Nat Commun ; 12(1): 480, 2021 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-33473127

RESUMEN

The cytoplasm in mammalian cells is considered homogeneous. In this study, we report that the cytoplasmic fluidity is regulated in the blebbing cells; the cytoplasm of rapidly expanding membrane blebs is more disordered than the cytoplasm of retracting blebs. The increase of cytoplasmic fluidity in the expanding bleb is caused by a sharp rise in the calcium concentration. The STIM-Orai1 pathway regulates this rapid and restricted increase of calcium in the expanding blebs. Conversely, activated ERM protein binds to Orai1 to inhibit the store-operated calcium entry in retracting blebs, which results in decreased in cytoplasmic calcium, rapid reassembly of the actin cortex.


Asunto(s)
Calcio/metabolismo , Membrana Celular/metabolismo , Citoplasma/metabolismo , Proteína ORAI1/metabolismo , Molécula de Interacción Estromal 1/metabolismo , Citoesqueleto de Actina , Actinas/metabolismo , Animales , Señalización del Calcio/fisiología , Línea Celular , Línea Celular Tumoral , Proteínas del Citoesqueleto/antagonistas & inhibidores , Células HEK293 , Humanos , Proteínas de la Membrana/fisiología
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