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1.
Acta Neurochir Suppl ; 127: 11-13, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407056

RESUMO

In the 1960s Professor Setsuro Ebashi, a physiologist from the University of Tokyo, discovered calcium ion plays a pivotal role in muscle contraction for the first time. However, he was confounded by icy neglect of the society of physiologists. The International Conference on Physiology was held in Boston in 1962, and Dr. Ebashi and his coworker Dr. Anne Mary Weber gave a talk about calcium signal which is a key mechanism for regulating muscle contraction. Every single attendant stood against their theory and even laughed at them.


Assuntos
Contração Muscular , Vasoconstrição , Cálcio , História do Século XX , Humanos , Japão , Masculino , Pesquisa/história
2.
Gene ; 722: 144101, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31479714

RESUMO

The catadromous species, eels, invariably exposed to variable Ca2+ concentrations circumstance i.e., lagoon or ocean. They need to maintain Ca2+ homeostasis by exchanging Ca2+ under different culture conditions. To understand the effects of environmental Ca2+ to fish, three types of genes coding for voltage-dependent L-type calcium channels (cacnb1, 2, 3) were cloned by screening an A. marmorata cDNA library. Tissue distribution analysis of Western blot showed that Cacnb1, 2, 3 had a significantly high expression in gill; while mRNA results showed the expressions of cacnb1 and cacnb3 were predominated in skin tissue but only cacnb2 was expressed in intestine. Serum osmolality and Ca2+ concentrations of A.marmorata were increased in a high calcium environment while reduced in a low calcium environment within 7 days; however, they were not significantly different among Ca2+ treatments after the eels were acclimated for 7 days. We also examined the influence of ambient Ca2+ levels on cacnbs expression of eels. With the increasing of exposure time, mRNA and protein expressions of cacnb1 were up-regulated in high level of Ca2+ (10 mM) and down-regulated in deficient Ca2+ (0 mM) compared to the control Ca2+ (2 mM). However, the opposite results were observed in cacnb2 and cacnb3. Notably, the cacnb2 expression was not significant different among Ca2+ treatments on day 7. Our study provided the insightful evidence that cacnbs play important roles in maintaining Ca2+ homeostasis of fish.


Assuntos
Anguilla/metabolismo , Canais de Cálcio Tipo L/metabolismo , Cálcio/fisiologia , Aclimatação , Anguilla/sangue , Anguilla/genética , Animais , Cálcio/sangue , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo L/genética , Clonagem Molecular , Brânquias/metabolismo , Concentração Osmolar , RNA Mensageiro/metabolismo , Distribuição Tecidual
3.
Adv Exp Med Biol ; 1131: 321-336, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646516

RESUMO

Ryanodine receptor calcium release channels (RyRs) play central roles in controlling intracellular calcium concentrations in excitable and non-excitable cells. RyRs are located in the sarcoplasmic or endoplasmic reticulum, intracellular Ca2+ storage compartment, and release Ca2+ during cellular action potentials or in response to other cellular stimuli. Mammalian cells express three structurally related isoforms of RyR. RyR1 and RyR2 are the major RyR isoforms in skeletal and cardiac muscle, respectively, and RyR3 is expressed in various tissues along with the other two isoforms. A prominent feature of RyRs is that the Ca2+ release channel activities of RyRs are regulated by calcium ions; therefore, intracellular Ca2+ release controls positive- and negative-feedback phenomena through the RyRs. RyR channel activities are also regulated by Ca2+ indirectly, i.e. through Ca2+ binding proteins at both cytosolic and sarco/endoplasmic reticulum luminal sides. Here, I summarize Ca2+-dependent feedback regulation of RyRs including recent progress in the structure/function aspects.


Assuntos
Cálcio , Regulação da Expressão Gênica , Canal de Liberação de Cálcio do Receptor de Rianodina , Animais , Cálcio/metabolismo , Citosol/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/química , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Relação Estrutura-Atividade
4.
Adv Exp Med Biol ; 1131: 337-370, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646517

RESUMO

The sarcoplasmic/endoplasmic reticulum (SR/ER) is the main intracellular calcium (Ca2+) pool in muscle and non-muscle eukaryotic cells, respectively. The reticulum accumulates Ca2+ against its electrochemical gradient by the action of sarco/endoplasmic reticulum calcium ATPases (SERCA pumps), and the capacity of this Ca2+ store is increased by the presence of Ca2+ binding proteins in the lumen of the reticulum. A diversity of physical and chemical signals, activate the main Ca2+ release channels, i.e. ryanodine receptors (RyRs) and inositol (1, 4, 5) trisphosphate receptors (IP3Rs), to produce transient elevations of the cytoplasmic calcium concentration ([Ca2+]i) while the reticulum is being depleted of Ca2+. This picture is incomplete because it implies that the elements involved in the Ca2+ release process are acting alone and independently of each other. However, it appears that the Ca2+ released by RyRs and IP3Rs is trapped in luminal Ca2+ binding proteins (Ca2+ lattice), which are associated with these release channels, and the activation of these channels appears to facilitate that the trapped Ca2+ ions become available for release. This situation makes the initial stage of the Ca2+ release process a highly efficient one; accordingly, there is a large increase in the [Ca2+]i with minimal reductions in the bulk of the free luminal SR/ER [Ca2+] ([Ca2+]SR/ER). Additionally, it has been shown that active SERCA pumps are required for attaining this highly efficient Ca2+ release process. All these data indicate that Ca2+ release by the SR/ER is a highly regulated event and not just Ca2+ coming down its electrochemical gradient via the open release channels. One obvious advantage of this sophisticated Ca2+ release process is to avoid depletion of the ER Ca2+ store and accordingly, to prevent the activation of ER stress during each Ca2+ release event.


Assuntos
Cálcio , Retículo Endoplasmático , Retículo Sarcoplasmático , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Retículo Endoplasmático/metabolismo , Humanos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
5.
Adv Exp Med Biol ; 1131: 371-394, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646518

RESUMO

Ca2+ signals are probably the most common intracellular signaling cellular events, controlling an extensive range of responses in virtually all cells. Many cellular stimuli, often acting at cell surface receptors, evoke Ca2+ signals by mobilizing Ca2+ from intracellular stores. Inositol trisphosphate (IP3) was the first messenger shown to link events at the plasma membrane to release Ca2+ from the endoplasmic reticulum (ER), through the activation of IP3-gated Ca2+ release channels (IP3 receptors). Subsequently, two additional Ca2+ mobilizing messengers were discovered, cADPR and NAADP. Both are metabolites of pyridine nucleotides, and may be produced by the same class of enzymes, ADP-ribosyl cyclases, such as CD38. Whilst cADPR mobilizes Ca2+ from the ER by activation of ryanodine receptors (RyRs), NAADP releases Ca2+ from acidic stores by a mechanism involving the activation of two pore channels (TPCs). In addition, other pyridine nucleotides have emerged as intracellular messengers. ADP-ribose and 2'-deoxy-ADPR both activate TRPM2 channels which are expressed at the plasma membrane and in lysosomes.


Assuntos
Cálcio , ADP-Ribose Cíclica , Piridinas , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Retículo Endoplasmático/metabolismo , Humanos , Espaço Intracelular/metabolismo , NADP/metabolismo , Piridinas/química , Piridinas/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
6.
Adv Exp Med Biol ; 1131: 395-443, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646519

RESUMO

The aim of this chapter is to discuss evidence concerning the many roles of calcium ions, Ca2+, in cell signaling pathways that control heart function. Before considering details of these signaling pathways, the control of contraction in ventricular muscle by Ca2+ transients accompanying cardiac action potentials is first summarized, together with a discussion of how myocytes from the atrial and pacemaker regions of the heart diverge from this basic scheme. Cell signaling pathways regulate the size and timing of the Ca2+ transients in the different heart regions to influence function. The simplest Ca2+ signaling elements involve enzymes that are regulated by cytosolic Ca2+. Particularly important examples to be discussed are those that are stimulated by Ca2+, including Ca2+-calmodulin-dependent kinase (CaMKII), Ca2+ stimulated adenylyl cyclases, Ca2+ stimulated phosphatase and NO synthases. Another major aspect of Ca2+ signaling in the heart concerns actions of the Ca2+ mobilizing agents, inositol trisphosphate (IP3), cADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate, (NAADP). Evidence concerning roles of these Ca2+ mobilizing agents in different regions of the heart is discussed in detail. The focus of the review will be on short term regulation of Ca2+ transients and contractile function, although it is recognized that Ca2+ regulation of gene expression has important long term functional consequences which will also be briefly discussed.


Assuntos
Sinalização do Cálcio , Coração , Animais , Cálcio/metabolismo , ADP-Ribose Cíclica , Coração/fisiologia , Humanos , Contração Muscular/fisiologia , NADP
7.
Adv Exp Med Biol ; 1131: 445-469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646520

RESUMO

Store-operated Ca2+ entry (SOCE) is a ubiquitous mechanism for Ca2+ influx in mammalian cells with important physiological implications. Since the discovery of SOCE more than three decades ago, the mechanism that communicates the information about the amount of Ca2+ accumulated in the intracellular Ca2+ stores to the plasma membrane channels and the nature of these channels have been matters of intense investigation and debate. The stromal interaction molecule-1 (STIM1) has been identified as the Ca2+ sensor of the intracellular Ca2+ compartments that activates the store-operated channels. STIM1 regulates two types of store-dependent channels: the Ca2+ release-activated Ca2+ (CRAC) channels, formed by Orai1 subunits, that conduct the highly Ca2+ selective current I CRAC and the cation permeable store-operated Ca2+ (SOC) channels, which consist of Orai1 and TRPC1 proteins and conduct the non-selective current I SOC. While the crystal structure of Drosophila CRAC channel has already been solved, the architecture of the SOC channels still remains unclear. The dynamic interaction of STIM1 with the store-operated channels is modulated by a number of proteins that either support the formation of the functional STIM1-channel complex or protect the cell against Ca2+ overload.


Assuntos
Canais de Cálcio , Cálcio , Transporte de Íons , Animais , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Sinalização do Cálcio , Transporte de Íons/genética , Molécula 1 de Interação Estromal/metabolismo
8.
Adv Exp Med Biol ; 1131: 471-487, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646521

RESUMO

All seven canonical transient potential receptor (TRPC1-7) channel members are expressed in mammalian airway smooth muscle cells (ASMCs). Among this family, TRPC3 channel plays an important role in the control of the resting [Ca2+]i and agonist-induced increase in [Ca2+]i. This channel is significantly upregulated in molecular expression and functional activity in airway diseases. The upregulated channel significantly augments the resting [Ca2+]i and agonist-induced increase in [Ca2+]i, thereby exerting a direct and essential effect in airway hyperresponsiveness. The increased TRPC3 channel-mediated Ca2+ signaling also results in the transcription factor nuclear factor-κB (NF-κB) activation via protein kinase C-α (PKCα)-dependent inhibitor of NFκB-α (IκBα) and calcineurin-dependent IκBß signaling pathways, which upregulates cyclin-D1 expression and causes cell proliferation, leading to airway remodeling. TRPC3 channel may further interact with intracellular release Ca2+ channels, Orai channels and Ca2+-sensing stromal interaction molecules, mediating important cellular responses in ASMCs and the development of airway diseases.


Assuntos
Cálcio , Miócitos de Músculo Liso , Canais de Cátion TRPC , Animais , Calcineurina/metabolismo , Cálcio/metabolismo , Proliferação de Células/genética , Humanos , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/fisiologia , Sistema Respiratório/fisiopatologia , Canais de Cátion TRPC/metabolismo
9.
Adv Exp Med Biol ; 1131: 489-504, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646522

RESUMO

Store-Operated Ca2+ Entry (SOCE) is an important Ca2+ influx pathway expressed by several excitable and non-excitable cell types. SOCE is recognized as relevant signaling pathway not only for physiological process, but also for its involvement in different pathologies. In fact, independent studies demonstrated the implication of essential protein regulating SOCE, such as STIM, Orai and TRPCs, in different pathogenesis and cell disorders, including cardiovascular disease, muscular dystrophies and angiogenesis. Compelling evidence showed that dysregulation in the function and/or expression of isoforms of STIM, Orai or TRPC play pivotal roles in cardiac hypertrophy and heart failure, vascular remodeling and hypertension, skeletal myopathies, and angiogenesis. In this chapter, we summarized the current knowledge concerning the mechanisms underlying abnormal SOCE and its involvement in some diseases, as well as, we discussed the significance of STIM, Orai and TRPC isoforms as possible therapeutic targets for the treatment of angiogenesis, cardiovascular and skeletal muscle diseases.


Assuntos
Cálcio , Doenças Cardiovasculares , Doenças Musculares , Neovascularização Patológica , Cálcio/metabolismo , Canais de Cálcio , Sinalização do Cálcio , Doenças Cardiovasculares/fisiopatologia , Humanos , Transporte de Íons , Doenças Musculares/fisiopatologia , Neovascularização Patológica/fisiopatologia
10.
Adv Exp Med Biol ; 1131: 505-517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646523

RESUMO

Cancer cells acquire the ability to modify the calcium signaling network by altering the expression and functions of cation channels, pumps or transporters. Calcium signaling pathways are involved in proliferation, angiogenesis, invasion, immune evasion, disruption of cell death pathways, ECM remodelling, epithelial-mesenchymal transition (EMT) and drug resistance. Among cation channels, a pivotal role is played by the Transient Receptor Potential non-selective cation-permeable receptors localized in plasma membrane, endoplasmic reticulum, mitochondria and lysosomes. Several findings indicate that the dysregulation in calcium signaling induced by TRP channels is responsible for cancer growth, metastasis and chemoresistance. Drug resistance represents a major limitation in the application of current therapeutic regimens and several efforts are spent to overcome it. Here we describe the ability of Transient Receptor Potential Channels to modify, by altering the intracellular calcium influx, the cancer cell sensitivity to chemotherapeutic drugs.


Assuntos
Sinalização do Cálcio , Neoplasias , Canais de Receptores Transientes de Potencial , Antineoplásicos/uso terapêutico , Cálcio/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Canais de Receptores Transientes de Potencial/genética , Canais de Receptores Transientes de Potencial/metabolismo
11.
Adv Exp Med Biol ; 1131: 519-535, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646524

RESUMO

The multifunctional Ca2+/calmodulin-dependent protein kinase type 2 (CaMK-II) was first discovered in brain tissue and shown to have a central role in long term potentiation, responding to Ca2+ elevations through voltage dependent channels. CaMK-II has a unique molecular mechanism that enables it to remain active in proportion to the degree (frequency and amplitude) of Ca2+ elevations, long after such elevations have subsided. Ca2+ is also a rapid activator of early development and CaMK-II is expressed and activated in early development. Using biochemical, pharmacological and genetic approaches, the functions of CaMK-II overlap remarkably well with those for Ca2+ elevations, post-fertilization. Conclusion. Activated CaMK-II plays a central role in decoding Ca2+ signals to activate specific events during early development; a majority of the known functions of elevated Ca2+ act though CaMK-II.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Potenciação de Longa Duração , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Crescimento e Desenvolvimento/fisiologia , Humanos , Potenciação de Longa Duração/fisiologia
12.
Adv Exp Med Biol ; 1131: 537-545, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646525

RESUMO

Calcium signaling plays an important role in gene expression. At the transcriptional level, this may underpin mammalian neuronal synaptic plasticity. Calcium influx into the postsynaptic neuron via: N-methyl-D-aspartate (NMDA) receptors activates small GTPase Rac1 and other Rac guanine nucleotide exchange factors, and stimulates calmodulin-dependent kinase kinase (CaMKK) and CaMKI; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors that are not impermeable to calcium ions, that is, those lacking the glutamate receptor-2 subunits, leads to activation of Ras guanine nucleotide-releasing factor proteins, which is coupled with activation of the mitogen-activated protein kinases/extracellular signal-regulated kinases signaling cascade; L-type voltage-gated calcium channels activates signaling pathways involving CaMKII, downstream responsive element antagonist modulator and distinct microdomains. Key members of these signaling cascades then translocate into the nucleus, where they alter the expression of genes involved in neuronal synaptic plasticity. At the post-transcriptional level, intracellular calcium level changes can change alternative splicing patterns; in the mammalian brain, alterations in calcium signaling via NMDA receptors is associated with exon silencing of the CI cassette of the NMDA R1 receptor (GRIN1) transcript by UAGG motifs in response to neuronal excitation. Regulation also occurs at the translational level; transglutaminase-2 (TG2) mediates calcium ion-regulated crosslinking of Y-box binding protein-1 (YB-1) translation-regulatory protein in TGFß1-activated myofibroblasts; YB-1 binds smooth muscle α-actin mRNA and regulates its translational activity. Calcium signaling is also important in epigenetic regulation, for example in respect of changes in cytosine bases. Targeting calcium signaling may provide therapeutically useful options, for example to induce epigenetic reactivation of tumor suppressor genes in cancer patients.


Assuntos
Sinalização do Cálcio , Regulação da Expressão Gênica , Animais , Cálcio/metabolismo , Epigênese Genética , Regulação da Expressão Gênica/fisiologia , Humanos , Neurônios/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo
13.
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
14.
Adv Exp Med Biol ; 1131: 625-648, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646528

RESUMO

Free Calcium (Ca2+) is an important and universal signalling entity in all cells, red blood cells included. Although mature mammalian red blood cells are believed to not contain organelles as Ca2+ stores such as the endoplasmic reticulum or mitochondria, a 20,000-fold gradient based on a intracellular Ca2+ concentration of approximately 60 nM vs. an extracellular concentration of 1.2 mM makes Ca2+-permeable channels a major signalling tool of red blood cells. However, the internal Ca2+ concentration is tightly controlled, regulated and maintained primarily by the Ca2+ pumps PMCA1 and PMCA4. Within the last two decades it became evident that an increased intracellular Ca2+ is associated with red blood cell clearance in the spleen and promotes red blood cell aggregability and clot formation. In contrast to this rather uncontrolled deadly Ca2+ signals only recently it became evident, that a temporal increase in intracellular Ca2+ can also have positive effects such as the modulation of the red blood cells O2 binding properties or even be vital for brief transient cellular volume adaptation when passing constrictions like small capillaries or slits in the spleen. Here we give an overview of Ca2+ channels and Ca2+-regulated channels in red blood cells, namely the Gárdos channel, the non-selective voltage dependent cation channel, Piezo1, the NMDA receptor, VDAC, TRPC channels, CaV2.1, a Ca2+-inhibited channel novel to red blood cells and i.a. relate these channels to the molecular unknown sickle cell disease conductance Psickle. Particular attention is given to correlation of functional measurements with molecular entities as well as the physiological and pathophysiological function of these channels. This view is in constant progress and in particular the understanding of the interaction of several ion channels in a physiological context just started. This includes on the one hand channelopathies, where a mutation of the ion channel is the direct cause of the disease, like Hereditary Xerocytosis and the Gárdos Channelopathy. On the other hand it applies to red blood cell related diseases where an altered channel activity is a secondary effect like in sickle cell disease or thalassemia. Also these secondary effects should receive medical and pharmacologic attention because they can be crucial when it comes to the life-threatening symptoms of the disease.


Assuntos
Canais de Cálcio , Animais , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Eritrócitos/fisiologia , Doenças Hematológicas/fisiopatologia , Humanos , Mutação
15.
Adv Exp Med Biol ; 1131: 681-697, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646530

RESUMO

Neurons are long-lived post-mitotic cells that possess an elaborate system of endosomes and lysosomes (endolysosomes) for protein quality control. Relatively recently, endolysosomes were recognized to contain high concentrations (400-600 µM) of readily releasable calcium. The release of calcium from this acidic organelle store contributes to calcium-dependent processes of fundamental physiological importance to neurons including neurotransmitter release, membrane excitability, neurite outgrowth, synaptic remodeling, and cell viability. Pathologically, disturbances of endolysosome structure and/or function have been noted in a variety of neurodegenerative disorders including Alzheimer's disease (AD) and HIV-1 associated neurocognitive disorder (HAND). And, dysregulation of intracellular calcium has been implicated in the neuropathogenesis of these same neurological disorders. Thus, it is important to better understand mechanisms by which calcium is released from endolysosomes as well as the consequences of such release to inter-organellar signaling, physiological functions of neurons, and possible pathological consequences. In doing so, a path forward towards new therapeutic modalities might be facilitated.


Assuntos
Cálcio , Lisossomos , Doenças Neurodegenerativas , Neurônios , Cálcio/metabolismo , Sinalização do Cálcio , Endossomos/fisiologia , Humanos , Lisossomos/patologia , Lisossomos/fisiologia , Doenças Neurodegenerativas/fisiopatologia , Neurônios/fisiologia
16.
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
17.
Adv Exp Med Biol ; 1131: 719-746, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646532

RESUMO

It is generally accepted that interorganellar contacts are central to the control of cellular physiology. Virtually, any intracellular organelle can come into proximity with each other and, by establishing physical protein-mediated contacts within a selected fraction of the membrane surface, novel specific functions are acquired. Endoplasmic reticulum (ER) contacts with mitochondria are among the best studied and have a major role in Ca2+ and lipid transfer, signaling, and membrane dynamics.Their functional (and structural) diversity, their dynamic nature as well as the growing number of new players involved in the tethering concurred to make their monitoring difficult especially in living cells. This review focuses on the most established examples of tethers/modulators of the ER-mitochondria interface and on the roles of these contacts in health and disease by specifically dissecting how Ca2+ transfer occurs and how mishandling eventually leads to disease. Additional functions of the ER-mitochondria interface and an overview of the currently available methods to measure/quantify the ER-mitochondria interface will also be discussed.


Assuntos
Cálcio , Retículo Endoplasmático , Mitocôndrias , Doenças Neurodegenerativas , Cálcio/metabolismo , Sinalização do Cálcio , Retículo Endoplasmático/metabolismo , Humanos , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Transdução de Sinais
18.
Adv Exp Med Biol ; 1131: 771-797, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646534

RESUMO

In this article, we present an overview of simulation strategies in the context of subcellular domains where calcium-dependent signaling plays an important role. The presentation follows the spatial and temporal scales involved and represented by each algorithm. As an exemplary cell type, we will mainly cite work done on striated muscle cells, i.e. skeletal and cardiac muscle. For these cells, a wealth of ultrastructural, biophysical and electrophysiological data is at hand. Moreover, these cells also express ubiquitous signaling pathways as they are found in many other cell types and thus, the generalization of the methods and results presented here is straightforward.The models considered comprise the basic calcium signaling machinery as found in most excitable cell types including Ca2+ ions, diffusible and stationary buffer systems, and calcium regulated calcium release channels. Simulation strategies can be differentiated in stochastic and deterministic algorithms. Historically, deterministic approaches based on the macroscopic reaction rate equations were the first models considered. As experimental methods elucidated highly localized Ca2+ signaling events occurring in femtoliter volumes, stochastic methods were increasingly considered. However, detailed simulations of single molecule trajectories are rarely performed as the computational cost implied is too large. On the mesoscopic level, Gillespie's algorithm is extensively used in the systems biology community and with increasing frequency also in models of microdomain calcium signaling. To increase computational speed, fast approximations were derived from Gillespie's exact algorithm, most notably the chemical Langevin equation and the τ-leap algorithm. Finally, in order to integrate deterministic and stochastic effects in multiscale simulations, hybrid algorithms are increasingly used. These include stochastic models of ion channels combined with deterministic descriptions of the calcium buffering and diffusion system on the one hand, and algorithms that switch between deterministic and stochastic simulation steps in a context-dependent manner on the other. The basic assumptions of the listed methods as well as implementation schemes are given in the text. We conclude with a perspective on possible future developments of the field.


Assuntos
Sinalização do Cálcio , Cálcio , Simulação por Computador , Algoritmos , Animais , Cálcio/metabolismo , Canais de Cálcio , Fenômenos Eletrofisiológicos , Humanos , Modelos Biológicos , Processos Estocásticos
19.
Adv Exp Med Biol ; 1131: 799-826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646535

RESUMO

Transient rises and falls of the intracellular calcium concentration have been observed in numerous cell types and under a plethora of conditions. There is now a growing body of evidence that these whole-cell calcium oscillations are stochastic, which poses a significant challenge for modelling. In this review, we take a closer look at recently developed statistical approaches to calcium oscillations. These models describe the timing of whole-cell calcium spikes, yet their parametrisations reflect subcellular processes. We show how non-stationary calcium spike sequences, which e.g. occur during slow depletion of intracellular calcium stores or in the presence of time-dependent stimulation, can be analysed with the help of so-called intensity functions. By utilising Bayesian concepts, we demonstrate how values of key parameters of the statistical model can be inferred from single cell calcium spike sequences and illustrate what information whole-cell statistical models can provide about the subcellular mechanistic processes that drive calcium oscillations. In particular, we find that the interspike interval distribution of HEK293 cells under constant stimulation is captured by a Gamma distribution.


Assuntos
Sinalização do Cálcio , Cálcio , Modelos Biológicos , Teorema de Bayes , Cálcio/metabolismo , Canais de Cálcio , Células HEK293 , Humanos
20.
Adv Exp Med Biol ; 1131: 827-855, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646536

RESUMO

Calcium (Ca2+) is a universal signaling ion, whose major informational role shaped the evolution of signaling pathways, enabling cellular communications and responsiveness to both the intracellular and extracellular environments. Elaborate Ca2+ regulatory networks have been well characterized in eukaryotic cells, where Ca2+ regulates a number of essential cellular processes, ranging from cell division, transport and motility, to apoptosis and pathogenesis. However, in bacteria, the knowledge on Ca2+ signaling is still fragmentary. This is complicated by the large variability of environments that bacteria inhabit with diverse levels of Ca2+. Yet another complication arises when bacterial pathogens invade a host and become exposed to different levels of Ca2+ that (1) are tightly regulated by the host, (2) control host defenses including immune responses to bacterial infections, and (3) become impaired during diseases. The invading pathogens evolved to recognize and respond to the host Ca2+, triggering the molecular mechanisms of adhesion, biofilm formation, host cellular damage, and host-defense resistance, processes enabling the development of persistent infections. In this review, we discuss: (1) Ca2+ as a determinant of a host environment for invading bacterial pathogens, (2) the role of Ca2+ in regulating main events of host colonization and bacterial virulence, and (3) the molecular mechanisms of Ca2+ signaling in bacterial pathogens.


Assuntos
Bactérias , Cálcio , Interações entre Hospedeiro e Microrganismos , Virulência , Bactérias/patogenicidade , Infecções Bacterianas/microbiologia , Infecções Bacterianas/fisiopatologia , Cálcio/metabolismo , Humanos , Virulência/fisiologia
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