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1.
Adv Exp Med Biol ; 1131: 547-604, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646526

RESUMO

Ca2+ release activated Ca2+ (CRAC) channels represent a primary pathway for Ca2+ to enter non-excitable cells. The two key players in this process are the stromal interaction molecule (STIM), a Ca2+ sensor embedded in the membrane of the endoplasmic reticulum, and Orai, a highly Ca2+ selective ion channel located in the plasma membrane. Upon depletion of the internal Ca2+ stores, STIM is activated, oligomerizes, couples to and activates Orai. This review provides an overview of novel findings about the CRAC channel activation mechanisms, structure and gating. In addition, it highlights, among diverse STIM and Orai mutants, also the disease-related mutants and their implications.


Assuntos
Canais de Cálcio Ativados pela Liberação de Cálcio , Membrana Celular , Animais , Cálcio/metabolismo , Canais de Cálcio Ativados pela Liberação de Cálcio/sangue , Canais de Cálcio Ativados pela Liberação de Cálcio/genética , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Humanos , Mutação , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo
2.
Adv Exp Med Biol ; 1131: 747-770, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646533

RESUMO

The pioneering work of Richard Altman on the presence of mitochondria in cells set in motion a field of research dedicated to uncovering the secrets of the mitochondria. Despite limitations in studying the structure and function of the mitochondria, advances in our understanding of this organelle prompted the development of potential treatments for various diseases, from neurodegenerative conditions to muscular dystrophy and cancer. As the powerhouses of the cell, the mitochondria represent the essence of cellular life and as such, a selective advantage for cancer cells. Much of the function of the mitochondria relies on Ca2+ homeostasis and the presence of effective Ca2+ signaling to maintain the balance between mitochondrial function and dysfunction and subsequently, cell survival. Ca2+ regulates the mitochondrial respiration rate which in turn increases ATP synthesis, but too much Ca2+ can also trigger the mitochondrial apoptosis pathway; however, cancer cells have evolved mechanisms to modulate mitochondrial Ca2+ influx and efflux in order to sustain their metabolic demand and ensure their survival. Therefore, targeting the mitochondrial Ca2+ signaling involved in the bioenergetic and apoptotic pathways could serve as potential approaches to treat cancer patients. This chapter will review the role of Ca2+ signaling in mediating the function of the mitochondria and its involvement in health and disease with special focus on the pathophysiology of cancer.


Assuntos
Sinalização do Cálcio , Cálcio , Mitocôndrias , Neoplasias , Apoptose , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Homeostase , Humanos , Mitocôndrias/fisiologia , Neoplasias/fisiopatologia
3.
Adv Exp Med Biol ; 1131: 1-6, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646504

RESUMO

Calcium signaling and its interacting networks are involved in mediating numerous processes including gene expression, excitation-contraction coupling, stimulus-secretion coupling, synaptic transmission, induction of synaptic plasticity, and embryonic development. Many structures, organelles, receptors, channels, calcium-binding proteins, pumps, transporters, enzymes, and transcription factors are involved in the generation and decoding of the different calcium signals in different cells. Powerful methods for measuring calcium concentrations, advanced statistical methods, and biophysical simulations are being used for modelling calcium signals. Calcium signaling is being studied in many cells, and in many model organisms to understand the mechanisms of many physiological processes, and the pathogenesis of many diseases, including cancers, diabetes, and neurodegenerative disorders. Studies in calcium signaling are being used for understanding the mechanisms of actions of drugs, and for discovery of new drugs for the prevention and treatment of many diseases.


Assuntos
Sinalização do Cálcio , Animais , Sinalização do Cálcio/fisiologia , Humanos
4.
Adv Exp Med Biol ; 1131: 163-182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646510

RESUMO

Calcium (Ca2+) buffering is part of an integrative crosstalk between different mechanisms and elements involved in the control of free Ca2+ ions persistence in the cytoplasm and hence, in the Ca2+-dependence of many intracellular processes. Alterations of Ca2+ homeostasis and signaling from systemic to subcellular levels also play a pivotal role in the pathogenesis of many diseases.Compared with Ca2+ sequestration towards intracellular Ca2+ stores, Ca2+ buffering is a rapid process occurring in a subsecond scale. Any molecule (or binding site) with the ability to bind Ca2+ ions could be considered, at least in principle, as a buffer. However, the term Ca2+ buffer is applied only to a small subset of Ca2+ binding proteins containing acidic side-chain residues.Ca2+ buffering in the cytoplasm mainly relies on mobile and immobile or fixed buffers controlling the diffusion of free Ca2+ ions inside the cytosol both temporally and spatially. Mobility of buffers depends on their molecular weight, but other parameters as their concentration, affinity for Ca2+ or Ca2+ binding and dissociation kinetics next to their diffusional mobility also contribute to make Ca2+ signaling one of the most complex signaling activities of the cell.The crosstalk between all the elements involved in the intracellular Ca2+ dynamics is a process of extreme complexity due to the diversity of structural and molecular elements involved but permit a highly regulated spatiotemporal control of the signal mediated by Ca2+ ions. The basis of modeling tools to study Ca2+ dynamics are also presented.


Assuntos
Sinalização do Cálcio , Cálcio , Citoplasma , Animais , Tampões (Química) , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Citoplasma/metabolismo , Humanos
5.
Nat Neurosci ; 22(10): 1731-1742, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31501572

RESUMO

Mitochondria vary in morphology and function in different tissues; however, little is known about their molecular diversity among cell types. Here we engineered MitoTag mice, which express a Cre recombinase-dependent green fluorescent protein targeted to the outer mitochondrial membrane, and developed an isolation approach to profile tagged mitochondria from defined cell types. We determined the mitochondrial proteome of the three major cerebellar cell types (Purkinje cells, granule cells and astrocytes) and identified hundreds of mitochondrial proteins that are differentially regulated. Thus, we provide markers of cell-type-specific mitochondria for the healthy and diseased mouse and human central nervous systems, including in amyotrophic lateral sclerosis and Alzheimer's disease. Based on proteomic predictions, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neuronal mitochondria. We also characterize cell-type differences in mitochondrial calcium buffering via the mitochondrial calcium uniporter (Mcu) and identify regulator of microtubule dynamics protein 3 (Rmdn3) as a determinant of endoplasmic reticulum-mitochondria proximity in Purkinje cells. Our approach enables exploring mitochondrial diversity in many in vivo contexts.


Assuntos
Encéfalo/citologia , Mitocôndrias/metabolismo , Neurônios/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Astrócitos/metabolismo , Sinalização do Cálcio/genética , Sinalização do Cálcio/fisiologia , Células Cultivadas , Cerebelo/citologia , Ácidos Graxos/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Membranas Mitocondriais/metabolismo , Proteômica , Células de Purkinje/metabolismo
6.
Hypertension ; 74(5): 1200-1214, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31542964

RESUMO

Endothelial cells line all blood vessels and are critical regulators of vascular tone. In hypertension, disruption of endothelial function alters the release of endothelial-derived vasoactive factors and results in increased vascular tone. Although the release of endothelial-derived vasodilators occurs in a Ca2+-dependent manner, little is known on how Ca2+ signaling is altered in hypertension. A key element to endothelial control of vascular tone is Ca2+ signals at specialized regions (myoendothelial projections) that connect endothelial cells and smooth muscle cells. This work describes disruption in the operation of this key Ca2+ signaling pathway in hypertension. We show that vascular reactivity to phenylephrine is increased in hypertensive (spontaneously hypertensive rat) when compared with normotensive (Wistar Kyoto) rats. Basal endothelial Ca2+ activity limits vascular contraction, but that Ca2+-dependent control is impaired in hypertension. When changes in endothelial Ca2+ levels are buffered, vascular contraction to phenylephrine increased, resulting in similar responses in normotension and hypertension. Local endothelial IP3(inositol trisphosphate)-mediated Ca2+ signals are smaller in amplitude, shorter in duration, occur less frequently, and arise from fewer sites in hypertension. Spatial control of endothelial Ca2+ signaling is also disrupted in hypertension: local Ca2+ signals occur further from myoendothelial projections in hypertension. The results demonstrate that the organization of local Ca2+ signaling circuits occurring at myoendothelial projections is disrupted in hypertension, giving rise to increased contractile responses.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Endotélio Vascular/metabolismo , Hipertensão/fisiopatologia , Fenilefrina/farmacologia , Receptores de Detecção de Cálcio/metabolismo , Animais , Sinalização do Cálcio/fisiologia , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Valores de Referência , Sensibilidade e Especificidade , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia
7.
Gut ; 68(9): 1676-1687, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31315892

RESUMO

BACKGROUND & OBJECTIVES: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Several types of chronic liver disease predispose to HCC, and several different signalling pathways have been implicated in its pathogenesis, but no common molecular event has been identified. Ca2+ signalling regulates the proliferation of both normal hepatocytes and liver cancer cells, so we investigated the role of intracellular Ca2+ release channels in HCC. DESIGN: Expression analyses of the type 3 isoform of the inositol 1, 4, 5-trisphosphate receptor (ITPR3) in human liver samples, liver cancer cells and mouse liver were combined with an evaluation of DNA methylation profiles of ITPR3 promoter in HCC and characterisation of the effects of ITPR3 expression on cellular proliferation and apoptosis. The effects of de novo ITPR3 expression on hepatocyte calcium signalling and liver growth were evaluated in mice. RESULTS: ITPR3 was absent or expressed in low amounts in hepatocytes from normal liver, but was expressed in HCC specimens from three independent patient cohorts, regardless of the underlying cause of chronic liver disease, and its increased expression level was associated with poorer survival. The ITPR3 gene was heavily methylated in control liver specimens but was demethylated at multiple sites in specimens of patient with HCC. Administration of a demethylating agent in a mouse model resulted in ITPR3 expression in discrete areas of the liver, and Ca2+ signalling was enhanced in these regions. In addition, cell proliferation and liver regeneration were enhanced in the mouse model, and deletion of ITPR3 from human HCC cells enhanced apoptosis. CONCLUSIONS: These results provide evidence that de novo expression of ITPR3 typically occurs in HCC and may play a role in its pathogenesis.


Assuntos
Carcinoma Hepatocelular/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Neoplasias Hepáticas/metabolismo , Adulto , Animais , Apoptose/fisiologia , Sinalização do Cálcio/fisiologia , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/fisiologia , Células Cultivadas , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Hepatócitos/metabolismo , Humanos , Receptores de Inositol 1,4,5-Trifosfato/deficiência , Receptores de Inositol 1,4,5-Trifosfato/genética , Fígado/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Regeneração Hepática/fisiologia , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Análise de Sobrevida
8.
Nat Commun ; 10(1): 2659, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201323

RESUMO

In contrast to the plasma membrane, the vacuole membrane has not yet been associated with electrical excitation of plants. Here, we show that mesophyll vacuoles from Arabidopsis sense and control the membrane potential essentially via the K+-permeable TPC1 and TPK channels. Electrical stimuli elicit transient depolarization of the vacuole membrane that can last for seconds. Electrical excitability is suppressed by increased vacuolar Ca2+ levels. In comparison to wild type, vacuoles from the fou2 mutant, harboring TPC1 channels insensitive to luminal Ca2+, can be excited fully by even weak electrical stimuli. The TPC1-loss-of-function mutant tpc1-2 does not respond to electrical stimulation at all, and the loss of TPK1/TPK3-mediated K+ transport affects the duration of TPC1-dependent membrane depolarization. In combination with mathematical modeling, these results show that the vacuolar K+-conducting TPC1 and TPK1/TPK3 channels act in concert to provide for Ca2+- and voltage-induced electrical excitability to the central organelle of plant cells.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Canais de Cálcio/metabolismo , Potenciais da Membrana/fisiologia , Vacúolos/fisiologia , Proteínas de Arabidopsis/genética , Canais de Cálcio/genética , Sinalização do Cálcio/fisiologia , Membranas Intracelulares/fisiologia , Mutação com Perda de Função , Células do Mesofilo/citologia , Células do Mesofilo/fisiologia , Plantas Geneticamente Modificadas , Potássio/metabolismo , Canais de Potássio/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo
9.
Neuron ; 103(3): 432-444.e3, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31221559

RESUMO

Subtypes of nucleus accumbens medium spiny neurons (MSNs) promote dichotomous outcomes in motivated behaviors. However, recent reports indicate enhancing activity of either nucleus accumbens (NAc) core MSN subtype augments reward, suggesting coincident MSN activity may underlie this outcome. Here, we report a collateral excitation mechanism in which high-frequency, NAc core dopamine 1 (D1)-MSN activation causes long-lasting potentiation of excitatory transmission (LLP) on dopamine receptor 2 (D2)-MSNs. Our mechanistic investigation demonstrates that this form of plasticity requires release of the excitatory peptide substance P from D1-MSNs and robust cholinergic interneuron activation through neurokinin receptor stimulation. We also reveal that D2-MSN LLP requires muscarinic 1 receptor activation, intracellular calcium signaling, and GluR2-lacking AMPAR insertion. This study uncovers a mechanism for shaping NAc core activity through the transfer of excitatory information from D1-MSNs to D2-MSNs and may provide a means for altering goal-directed behavior through coordinated MSN activity.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Potenciação de Longa Duração/fisiologia , Núcleo Accumbens/fisiologia , Substância P/metabolismo , Potenciais de Ação/fisiologia , Animais , Aprepitanto/farmacologia , Sinalização do Cálcio/fisiologia , Neurônios Colinérgicos/fisiologia , Neurônios Dopaminérgicos/efeitos da radiação , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Interneurônios/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Motivação , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Núcleo Accumbens/citologia , Estimulação Luminosa , Piperidinas/farmacologia , Receptor Muscarínico M1/fisiologia , Receptores de AMPA/fisiologia , Receptores de Dopamina D1/análise , Receptores de Dopamina D2/análise , Receptores da Neurocinina-1/fisiologia
10.
Life Sci ; 231: 116567, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202839

RESUMO

AIMS: Metabotropic glutamate receptor 5 (mGluR5), a member of group I mGluR, exerts its effect via elevation of intracellular Ca2+ level. We here characterized Ca2+ signals in the tsA201 cells transfected with mGluR5 and investigated the role of passages for mGluR5-induced Ca2+ signals in synaptic plasticity. MAIN METHODS: Using a genetically encoded Ca2+ indicator, GCamp2, Ca2+ signals were reliably induced by bath application of (S)-3,5-dihydroxyphenylglycine, the group I mGluR agonist, in the tsA201 cells transfected with mGluR5. Using whole-cell recordings in the substantia gelatinosa (SG) neurons of the spinal trigeminal subnucleus caudalis (Vc), excitatory postsynaptic currents were recorded by stimulating the trigeminal tract. KEY FINDINGS: Ca2+ signals were mediated by "classical" or "canonical" transient receptor potential (TRPC) channels, particularly TRPC1/3/4/6, but not TRPC5, naturally existing in the tsA201 cells. Interestingly, the induction of Ca2+ signals was independent of the phospholipase C signaling pathway; instead, it critically involves the cyclic adenosine diphosphate ribose/ryanodine receptor-dependent signaling pathway and only partially protein kinase C. On the other hand, both TRPC3 and TRPC4 mediated mGluR1/5-induced long-lasting potentiation of excitatory synaptic transmission from the trigeminal primary afferents to the SG neurons of the Vc. SIGNIFICANCE: This study demonstrates that endogenous TRPC channels contribute to mGluR5-induced Ca2+ signals in tsA201 cells and synaptic plasticity at excitatory synapses.


Assuntos
Sinalização do Cálcio/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Receptor de Glutamato Metabotrópico 5/metabolismo , Canais de Cátion TRPC/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores , Feminino , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Sinapses/metabolismo , Transmissão Sináptica , Nervo Trigêmeo/metabolismo , Núcleo Espinal do Trigêmeo/metabolismo
11.
Neuron ; 103(1): 92-101.e6, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31097361

RESUMO

The dorsomedial striatum (DMS) is critically involved in motor control and reward processing, but the specific neural circuit mediators are poorly understood. Recent evidence highlights the extensive connectivity of low-threshold spiking interneurons (LTSIs) within local striatal circuitry; however, the in vivo function of LTSIs remains largely unexplored. We employed fiber photometry to assess LTSI calcium activity in a range of DMS-mediated behaviors, uncovering specific reward-related activity that is down-modulated during goal-directed learning. Using two mechanistically distinct manipulations, we demonstrated that this down-modulation of LTSI activity is critical for acquisition of novel contingencies, but not for their modification. In contrast, continued LTSI activation slowed instrumental learning. Similar manipulations of fast-spiking interneurons did not reproduce these effects, implying a specific function of LTSIs. Finally, we revealed a role for the γ-aminobutyric acid (GABA)ergic functions of LTSIs in learning. Together, our data provide new insights into this striatal interneuron subclass as important gatekeepers of goal-directed learning.


Assuntos
Corpo Estriado/fisiologia , Metas , Interneurônios/fisiologia , Aprendizagem/fisiologia , Animais , Apetite , Sinalização do Cálcio/fisiologia , Condicionamento Operante/fisiologia , Fenômenos Eletrofisiológicos/fisiologia , Camundongos , Camundongos Knockout , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Recompensa , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/fisiologia , Ácido gama-Aminobutírico/fisiologia
12.
Cell Prolif ; 52(4): e12623, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115100

RESUMO

L-type voltage-gated calcium ion channels (L-VGCCs) have been demonstrated to be the mediator of several significant intracellular activities in excitable cells, such as neurons, chromaffin cells and myocytes. Recently, an increasing number of studies have investigated the function of L-VGCCs in non-excitable cells, particularly stem cells. However, there appear to be no systematic reviews of the relationship between L-VGCCs and stem cells, and filling this gap is prescient considering the contribution of L-VGCCs to the proliferation and differentiation of several types of stem cells. This review will discuss the possible involvement of L-VGCCs in stem cells, mainly focusing on osteogenesis mediated by mesenchymal stem cells (MSCs) from different tissues and neurogenesis mediated by neural stem/progenitor cells (NSCs). Additionally, advanced applications that use these channels as the target for tissue engineering, which may offer the hope of tissue regeneration in the future, will also be explored.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Cálcio/metabolismo , Células-Tronco/metabolismo , Animais , Sinalização do Cálcio/fisiologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Humanos , Osteogênese/fisiologia , Engenharia Tecidual/métodos
13.
Nat Commun ; 10(1): 2299, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127110

RESUMO

Ca2+ coordinates diverse cellular processes, yet how function-specific signals arise is enigmatic. We describe a cell-wide network of distinct cytoplasmic nanocourses with the nucleus at its centre, demarcated by sarcoplasmic reticulum (SR) junctions (≤400 nm across) that restrict Ca2+ diffusion and by nanocourse-specific Ca2+-pumps that facilitate signal segregation. Ryanodine receptor subtype 1 (RyR1) supports relaxation of arterial myocytes by unloading Ca2+ into peripheral nanocourses delimited by plasmalemma-SR junctions, fed by sarco/endoplasmic reticulum Ca2+ ATPase 2b (SERCA2b). Conversely, stimulus-specified increases in Ca2+ flux through RyR2/3 clusters selects for rapid propagation of Ca2+ signals throughout deeper extraperinuclear nanocourses and thus myocyte contraction. Nuclear envelope invaginations incorporating SERCA1 in their outer nuclear membranes demarcate further diverse networks of cytoplasmic nanocourses that receive Ca2+ signals through discrete RyR1 clusters, impacting gene expression through epigenetic marks segregated by their associated invaginations. Critically, this circuit is not hardwired and remodels for different outputs during cell proliferation.


Assuntos
Sinalização do Cálcio/fisiologia , Citosol/metabolismo , Animais , Membrana Celular/metabolismo , Proliferação de Células/fisiologia , Células Cultivadas , Masculino , Células Musculares/fisiologia , Contração Muscular/fisiologia , Músculo Esquelético/citologia , Músculo Esquelético/fisiologia , Membrana Nuclear/metabolismo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
14.
Nat Rev Gastroenterol Hepatol ; 16(8): 479-496, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31138897

RESUMO

The incidence of acute pancreatitis continues to increase worldwide, and it is one of the most common gastrointestinal causes for hospital admission in the USA. In the past decade, substantial advancements have been made in our understanding of the pathophysiological mechanisms of acute pancreatitis. Studies have elucidated mechanisms of calcium-mediated acinar cell injury and death and the importance of store-operated calcium entry channels and mitochondrial permeability transition pores. The cytoprotective role of the unfolded protein response and autophagy in preventing sustained endoplasmic reticulum stress, apoptosis and necrosis has also been characterized, as has the central role of unsaturated fatty acids in causing pancreatic organ failure. Characterization of these pathways has led to the identification of potential molecular targets for future therapeutic trials. At the patient level, two classification systems have been developed to classify the severity of acute pancreatitis into prognostically meaningful groups, and several landmark clinical trials have informed management strategies in areas of nutritional support and interventions for infected pancreatic necrosis that have resulted in important changes to acute pancreatitis management paradigms. In this Review, we provide a summary of recent advances in acute pancreatitis with a special emphasis on pathophysiological mechanisms and clinical management of the disorder.


Assuntos
Pancreatite/diagnóstico , Pancreatite/terapia , Doença Aguda , Animais , Sinalização do Cálcio/fisiologia , Gerenciamento Clínico , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Mutação , Apoio Nutricional/métodos , Pancreatite/etiologia , Pancreatite/fisiopatologia , Índice de Gravidade de Doença , Terminologia como Assunto , Tripsinogênio/metabolismo
15.
Int J Mol Sci ; 20(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897737

RESUMO

In plant cells, calcium (Ca2+) serves as a versatile intracellular messenger, participating in several fundamental and important biological processes. Recent studies have shown that the actin cytoskeleton is not only an upstream regulator of Ca2+ signaling, but also a downstream regulator. Ca2+ has been shown to regulates actin dynamics and rearrangements via different mechanisms in plants, and on this basis, the upstream signaling encoded within the Ca2+ transient can be decoded. Moreover, actin dynamics have also been proposed to act as an upstream of Ca2+, adjust Ca2+ oscillations, and establish cytosolic Ca2+ ([Ca2+]cyt) gradients in plant cells. In the current review, we focus on the advances in uncovering the relationship between the actin cytoskeleton and calcium in plant cells and summarize our current understanding of this relationship.


Assuntos
Citoesqueleto de Actina/classificação , Citoesqueleto de Actina/metabolismo , Sinalização do Cálcio/fisiologia , Células Vegetais/metabolismo , Tubo Polínico/metabolismo
16.
Chaos ; 29(2): 023125, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30823735

RESUMO

In this study, we analyze a nonlinear map model of intracellular calcium (Ca) and voltage in cardiac cells. In this model, Ca release from the sarcoplasmic reticulum (SR) occurs at spatially distributed dyadic junctions that are diffusively coupled. At these junctions, release occurs with a probability that depends on key variables such as the SR load and the diastolic interval. Using this model, we explore how nonlinearity and stochasticity determine the spatial distribution of Ca release events within a cardiac cell. In particular, we identify a novel synchronization transition, which occurs at rapid pacing rates, in which the global Ca transient transitions from a period 2 response to a period 1 response. In the global period 2 response dyadic junctions fire in unison, on average, on alternate beats, while in the period 1 regime, Ca release at individual dyads is highly irregular. A close examination of the spatial distribution of Ca reveals that in the period 1 regime, the system coarsens into spatially out-of-phase regions with a length scale much smaller than the system size, but larger than the spacing between dyads. We have also explored in detail the coupling to membrane voltage. We study first the case of positive coupling, where a large Ca transient promotes a long action potential duration (APD). Here, the coupling to voltage synchronizes Ca release so that the system exhibits a robust period 2 response that is independent of initial conditions. On the other hand, in the case of negative coupling, where a large Ca transient tends to shorten the APD, we find a multitude of metastable states which consist of complex spatially discordant alternans patterns. Using an analogy to equilibrium statistical mechanics, we show that the spatial patterns observed can be explained by a mapping to the Potts model, with an additional term that accounts for a global coupling of spin states. Using this analogy, we argue that Ca cycling in cardiac cells exhibits complex spatiotemporal patterns that emerge via first or second order phase transitions. These results show that voltage and Ca can interact in order to induce complex subcellular responses, which can potentially lead to heart rhythm disorders.


Assuntos
Potenciais de Ação/fisiologia , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Modelos Cardiovasculares , Miócitos Cardíacos/metabolismo , Retículo Sarcoplasmático/metabolismo , Humanos
17.
Proc Natl Acad Sci U S A ; 116(12): 5775-5784, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30819882

RESUMO

Close appositions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are a general feature of all cells and are abundant in neurons. A function of these appositions is lipid transport between the two adjacent bilayers via tethering proteins that also contain lipid transport modules. However, little is known about the properties and dynamics of these proteins in neurons. Here we focused on TMEM24/C2CD2L, an ER-localized SMP domain containing phospholipid transporter expressed at high levels in the brain, previously shown to be a component of ER-PM contacts in pancreatic ß-cells. TMEM24 is enriched in neurons versus glial cells and its levels increase in parallel with neuronal differentiation. It populates ER-PM contacts in resting neurons, but elevations of cytosolic Ca2+ mediated by experimental manipulations or spontaneous activity induce its transient redistribution throughout the entire ER. Dissociation of TMEM24 from the plasma membrane is mediated by phosphorylation of an array of sites in the C-terminal region of the protein. These sites are only partially conserved in C2CD2, the paralogue of TMEM24 primarily expressed in nonneuronal tissues, which correspondingly display a much lower sensitivity to Ca2+ elevations. ER-PM contacts in neurons are also sites where Kv2 (the major delayed rectifier K+ channels in brain) and other PM and ER ion channels are concentrated, raising the possibility of a regulatory feedback mechanism between neuronal excitability and lipid exchange between the ER and the PM.


Assuntos
Sinalização do Cálcio/fisiologia , Proteínas de Membrana/metabolismo , Neurônios/fisiologia , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Humanos , Lipídeos , Mamíferos/metabolismo , Proteínas de Membrana/fisiologia , Camundongos , Neurônios/metabolismo , Fosfolipídeos/metabolismo , Fosforilação , Cultura Primária de Células , Sinaptotagminas/metabolismo
18.
Int J Mol Sci ; 20(4)2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30823575

RESUMO

Astrocytes are abundant cells in the brain that regulate multiple aspects of neural tissue homeostasis by providing structural and metabolic support to neurons, maintaining synaptic environments and regulating blood flow. Recent evidence indicates that astrocytes also actively participate in brain functions and play a key role in brain disease by responding to neuronal activities and brain insults. Astrocytes become reactive in response to injury and inflammation, which is typically described as hypertrophy with increased expression of glial fibrillary acidic protein (GFAP). Reactive astrocytes are frequently found in many neurological disorders and are a hallmark of brain disease. Furthermore, reactive astrocytes may drive the initiation and progression of disease processes. Recent improvements in the methods to visualize the activity of reactive astrocytes in situ and in vivo have helped elucidate their functions. Ca2+ signals in reactive astrocytes are closely related to multiple aspects of disease and can be a good indicator of disease severity/state. In this review, we summarize recent findings concerning reactive astrocyte Ca2+ signals. We discuss the molecular mechanisms underlying aberrant Ca2+ signals in reactive astrocytes and the functional significance of aberrant Ca2+ signals in neurological disorders.


Assuntos
Astrócitos/metabolismo , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Doenças do Sistema Nervoso/metabolismo , Animais , Humanos , Camundongos , Ratos
19.
Exp Mol Pathol ; 107: 129-140, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30763573

RESUMO

INTRODUCTION: The tumor-promoting rearrangement of the lungs facilitates the process of cancer cell survival in a foreign microenvironment and enables their protection against immune defense. The study aimed to define the fingerprint of the early rearrangement of the lungs via the proteomic profiling of the lung tissue in the experimental model of tumor metastasis in a murine 4T1 mammary adenocarcinoma. MATERIALS AND METHODS: The studies were performed on 7-8-week-old BALB/c female mice. Viable 4T1 cancer cells were orthotopically inoculated into the right mammary fat pad. The experiment was performed in the early phase of the tumor metastasis one and two weeks after cancer cell inoculation. The comparative analysis of protein profiles was carried out with the aid of the two-dimensional difference in gel electrophoresis (2D-DIGE). Proteins, of which expression differed significantly, were identified using nano-liquid chromatography coupled to a high-resolution mass spectrometry (nanoLC/hybrid ion trap- Orbitrap XL Discovery). RESULTS: Palpable primary tumors were noted in the 2nd week after cancer cell inoculation. The investigated period preceded the formation of numerous macrometastases in the lungs, however the metastasis-promoting changes were visible very early. Primary tumor-induced inflammation developed in the lungs as early as after the 1st week and progressed during the 2nd week, accompanied by increased concentration of 2-OH-E+, an oxidative stress marker, and imbalance in nitric oxide metabolites, pointing to endothelium dysfunction. The early proteomic changes in the lungs in the 1st week after 4T1 cell inoculation resulted in the reorganization of lung tissue structure [actin, cytoplasmic 1 (Actb), tubulin beta chain (Tubb5), lamin-B1 (Lmnb1), serine protease inhibitor A3K (Serpina3k)] and activation of defense mechanisms [selenium-binding protein 1 (Selenbp1), endoplasmin (Hsp90b1), stress 70 protein, mitochondrial (Hspa9), heat shock protein HSP 90-beta (Hsp90ab1)], but also modifications in metabolic pathways [glucose-6-phosphate 1-dehydrogenase X (G6pdx), ATP synthase subunit beta, mitochondrial (Atp5b), L-lactate dehydrogenase B chain (Ldhb)]. Further development of the solid tumor after the 2nd week following cancer cell inoculation, secretion of prolific tumor-derived factors as well as the presence of the increasing number of circulating cancer cells and extravasation processes further impose reorganization of the lung tissue [Actb, vimentin (Vim), clathrin light chain A (Clta)], altering additional metabolic pathways [annexin A5 (Anxa5), Rho GDP-dissociation inhibitor 2 (Arhgdib), complement 1 Q subcomponent-binding protein, mitochondrial (C1qbp), 14-3-3 protein zeta/delta (Ywhaz), peroxiredoxin-6 (Prdx6), chitinase-like protein 4 (Chi3l4), reticulocalbin-1 (Rcn1), EF-hand domain-containing protein D2 (Efhd2), calumenin (Calu)]. Interestingly, many of differentially expressed proteins were involved in calcium homeostasis (Rcn1, Efhd2, Calu, Actb, Vim, Lmnb1, Clta, Tubb5, Serpina3k, Hsp90b1, Hsp90ab1, Hspa9. G6pdx, Atp5b, Anxa5, Arhgdib, Ywhaz). CONCLUSION: The analysis enabled revealing the importance of calcium signaling during the early phase of metastasis development, early cytoskeleton and extracellular matrix reorganization, activation of defense mechanisms and metabolic adaptations. It seems that the tissue response is an interplay between pro- and anti-metastatic mechanisms accompanied by inflammation, oxidative stress and dysfunction of the barrier endothelial cells.


Assuntos
Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Metástase Neoplásica/fisiopatologia , Animais , Sinalização do Cálcio/fisiologia , Feminino , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Proteômica
20.
Plant Mol Biol ; 99(6): 517-534, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30710226

RESUMO

KEY MESSAGE: Transcription factor MYB59 is involved in plant growth and stress responses by acting as negative regulator of Ca signalling and homeostasis. The Arabidopsis thaliana transcription factor MYB59 is induced by cadmium (Cd) and plays a key role in the regulation of cell cycle progression and root elongation, but its mechanism of action is poorly understood. We investigated the expression of MYB59 and differences between wild-type plants, the myb59 mutant and MYB59-overexpressing lines (obtained by transformation in the mutant genotype) during plant growth and in response to various forms of stress. We also compared the transcriptomes of wild-type and myb59 mutant plants to determine putative MYB59 targets. The myb59 mutant has longer roots, smaller leaves and smaller cells than wild-type plants and responds differently to stress in germination assay. Transcriptomic analysis revealed the upregulation in the myb59 mutant of multiple genes involved in calcium (Ca) homeostasis and signalling, including those encoding calmodulin-like proteins and Ca transporters. Notably, MYB59 was strongly induced by Ca deficiency, and the myb59 mutant was characterized by higher levels of cytosolic Ca in root cells and showed a modest alteration of Ca transient frequency in guard cells, associated with the absence of Ca-induced stomatal closure. These results indicate that MYB59 negatively regulates Ca homeostasis and signalling during Ca deficiency, thus controlling plant growth and stress responses.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Sinalização do Cálcio/fisiologia , Desenvolvimento Vegetal , Fatores de Transcrição/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Ligação ao Cálcio , Ciclo Celular , Citosol/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Germinação , Homeostase , Mutação , Reguladores de Crescimento de Planta/genética , Reguladores de Crescimento de Planta/metabolismo , Folhas de Planta/crescimento & desenvolvimento , Raízes de Plantas/crescimento & desenvolvimento , Plantas Geneticamente Modificadas , Fatores de Transcrição/genética , Transcriptoma
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