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1.
Phys Rev Lett ; 124(4): 048102, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32058787

RESUMO

Experiments have suggested that bacterial mechanosensitive channels separate into 2D clusters, the role of which is unclear. By developing a coarse-grained computer model we find that clustering promotes the channel closure, which is highly dependent on the channel concentration and membrane stress. This behaviour yields a tightly regulated gating system, whereby at high tensions channels gate individually, and at lower tensions the channels spontaneously aggregate and inactivate. We implement this positive feedback into the model for cell volume regulation, and find that the channel clustering protects the cell against excessive loss of cytoplasmic content.


Assuntos
Canais Iônicos/química , Canais Iônicos/metabolismo , Modelos Biológicos , Modelos Químicos , Escherichia coli/citologia , Escherichia coli/metabolismo , Ativação do Canal Iônico , Mecanotransdução Celular
2.
Cell Physiol Biochem ; 54(1): 15-26, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31916734

RESUMO

BACKGROUND/AIMS: The primary cilium is a nanoscale membrane protrusion believed to act as a mechano-chemical sensor in a range of different cell types. Disruptions in its structure and signalling have been linked to a number of medical conditions, referred to as ciliopathies, but remain poorly understood due to lack of techniques capable of investigating signal transduction in cilia at nanoscale. Here we set out to use latest advances in nanopipette technology to address the question of ion channel distribution along the structure of primary cilium. METHODS: We used glass nanopipettes and Scanning Ion Conductance Microscopy (SICM) to image 3D topography of intact primary cilia in inner medullary collecting duct (IMCD) cells with nanoscale resolution. The high-resolution topographical images were then used to navigate the nanopipette along the structure of each cilium and perform spatially resolved single-channel recordings under precisely controlled mechanical and chemical stimulation. RESULTS: We have successfully obtained first single-channel recordings at specific locations of intact primary cilia. Our experiments revealed significant differences between the populations of channels present at the ciliary base, tip and within extra-ciliary regions in terms of mean conductance and sensitivity to membrane displacement as small as 100 nm. Ion channels at the base of cilium, where mechanical strain is expected to be the highest, appeared particularly sensitive to the mechanical displacement. CONCLUSION: Our results suggest the distribution of ion channels in the membrane of primary cilia is non-homogeneous. The relationship between the location and function of ciliary ion channels could be key to understanding signal transduction in primary cilia.


Assuntos
Membrana Celular/metabolismo , Cílios/metabolismo , Canais Iônicos/metabolismo , Nanotecnologia/métodos , Potenciais de Ação/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Mecanotransdução Celular , Camundongos
3.
Cell Physiol Biochem ; 53(S1): 11-43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31834993

RESUMO

Ion channels residing in the inner (IMM) and outer (OMM) mitochondrial membranes are emerging as noteworthy pharmacological targets in oncology. While these aspects have not been investigated for all of them, a role in cancer growth and/or metastasis and/or drug resistance has been shown at least for the IMM-residing Ca2+ uniporter complex and K+- selective mtKV1.3, mtIKCa, mtSKCa and mtTASK-3, and for the OMM Voltage-Dependent Anion Channel (mitochondrial porin). A special case is that of the Mitochondrial Permeability Transition Pore, a large pore which forms in the IMM of severely stressed cells, and which may be exploited to precipitate the death of cancerous cells. Here we briefly discuss the oncological relevance of mitochondria and their channels, and summarize the methods that can be adopted to selectively target these intracellular organelles. We then present an updated list of known mitochondrial channels, and review the pharmacology of those with proven relevance for cancer.


Assuntos
Antineoplásicos/química , Canais Iônicos/metabolismo , Mitocôndrias/metabolismo , Bibliotecas de Moléculas Pequenas/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Humanos , Canais Iônicos/química , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Canais de Potássio/química , Canais de Potássio/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Canais de Ânion Dependentes de Voltagem/química , Canais de Ânion Dependentes de Voltagem/metabolismo
4.
Cell Physiol Biochem ; 53(S1): 44-51, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31834994

RESUMO

The current basis of systemic treatment for pancreas cancer involves cytotoxic chemotherapy. Despite newer regimens, overall survival remains poor and this dilemma is further compounded by a lack of effective, novel therapeutic targets. Another challenge in treating pancreas cancer is the complex tumor microenvironment, which contains regulatory T cells, myeloid derived suppressor cells, and tumor associated macrophages that forms a barrier to standard therapies. Intracellular ion channels are ubiquitously expressed in all cells and their role in carcinogenesis is increasingly becoming elucidated. They play an integral role in each of the six "Hallmarks of Cancer" and are potential novel prognostic biomarkers and therapeutic targets for pancreas cancer. Although examined in various hematologic and gastrointestinal malignancies, there are limited data examining the prognostic role of specific ion channels in pancreas ductal adenocarcinoma. This review focuses on chloride (CLCA-1, CLIC1, CLIC3), calcium (TRPM7, TRPM8), and potassium (Kir3.1, KCa3.1, Kv11.1, Kv1.3) channels in pancreas cancer.


Assuntos
Canais Iônicos/metabolismo , Neoplasias Pancreáticas/patologia , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Canais de Cloreto/química , Canais de Cloreto/metabolismo , Ensaios Clínicos como Assunto , Humanos , Canais Iônicos/química , Neoplasias Pancreáticas/metabolismo , Canais de Potássio/química , Canais de Potássio/metabolismo , Prognóstico , Microambiente Tumoral
5.
Cell Physiol Biochem ; 53(S1): 63-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31860207

RESUMO

Mitochondria play a central role in cancer development, by contributing to most of the classical hallmarks of cancer, including sustained proliferation, metabolic re-programming, apoptosis resistance, invasion and induction of angiogenesis [1]. In addition, mitochondria affect also the function of anti- and pro-tumoral immune cells in the tumor microenvironment. Mitochondria harbor a plethora of regulated ion channels whose function is related to ion/ metabolite transport and to fine-tuning of mitochondrial membrane potential as well as of reactive oxygen species release. As a consequence, growing evidence link ion channels located both in the outer and inner mitochondrial membranes to several cancer hallmarks. The present review summarizes our recent knowledge about the participation and role of mitochondrial channels leading to acquisition of cancer hallmarks and thus to cancer progression.


Assuntos
Canais Iônicos/metabolismo , Mitocôndrias/patologia , Neoplasias/patologia , Animais , Apoptose , Proliferação de Células , Progressão da Doença , Humanos , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/patologia , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia
6.
Nat Commun ; 10(1): 4619, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601809

RESUMO

Lipid availability within transmembrane nano-pockets of ion channels is linked with mechanosensation. However, the effect of hindering lipid-chain penetration into nano-pockets on channel structure has not been demonstrated. Here we identify nano-pockets on the large conductance mechanosensitive channel MscL, the high-pressure threshold channel. We restrict lipid-chain access to the nano-pockets by mutagenesis and sulfhydryl modification, and monitor channel conformation by PELDOR/DEER spectroscopy. For a single site located at the entrance of the nano-pockets and distal to the channel pore we generate an allosteric response in the absence of tension. Single-channel recordings reveal a significant decrease in the pressure activation threshold of the modified channel and a sub-conducting state in the absence of applied tension. Threshold is restored to wild-type levels upon reduction of the sulfhydryl modification. The modification associated with the conformational change restricts lipid access to the nano-pocket, interrupting the contact between the membrane and the channel that mediates mechanosensitivity.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Canais Iônicos/química , Canais Iônicos/metabolismo , Regulação Alostérica , Proteínas de Bactérias/genética , Cisteína/genética , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Canais Iônicos/genética , Bicamadas Lipídicas/química , Lipídeos/química , Mutação , Conformação Proteica , Domínios Proteicos
7.
Cell Mol Life Sci ; 76(21): 4221-4232, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31584127

RESUMO

In the past two decades, transmembrane channel-like (TMC) proteins have attracted a significant amount of research interest, because mutations of Tmc1 lead to hereditary deafness. As evolutionarily conserved membrane proteins, TMC proteins are widely involved in diverse sensorimotor functions of many species, such as hearing, chemosensation, egg laying, and food texture detection. Interestingly, recent structural and physiological studies suggest that TMC channels may share a similar membrane topology with the Ca2+-activated Cl- channel TMEM16 and the mechanically activated OSCA1.2/TMEM63 channel. Namely, these channels form dimers and each subunit consists of ten transmembrane segments. Despite this important structural insight, a key question remains: what is the gating mechanism of TMC channels? The major technical hurdle to answer this question is that the reconstitution of TMC proteins as functional ion channels has been challenging in mammalian heterologous systems. Since TMC channels are conserved across taxa, genetic studies of TMC channels in model organisms such as C. elegans, Drosophila, and zebrafish may provide us critical information on the physiological function and regulation of TMCs. Here, we present a comparative overview on the diverse functions of TMC channels in different species.


Assuntos
Canais Iônicos/metabolismo , Animais , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Canais Iônicos/química , Canais Iônicos/genética , Mecanotransdução Celular , Mutação de Sentido Incorreto , Neurônios/metabolismo , Propriocepção , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
8.
Elife ; 82019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31588901

RESUMO

Mechanical loading, such as caused by exercise, stimulates bone formation by osteoblasts and increases bone strength, but the mechanisms are poorly understood. Osteocytes reside in bone matrix, sense changes in mechanical load, and produce signals that alter bone formation by osteoblasts. We report that the ion channel Piezo1 is required for changes in gene expression induced by fluid shear stress in cultured osteocytes and stimulation of Piezo1 by a small molecule agonist is sufficient to replicate the effects of fluid flow on osteocytes. Conditional deletion of Piezo1 in osteoblasts and osteocytes notably reduced bone mass and strength in mice. Conversely, administration of a Piezo1 agonist to adult mice increased bone mass, mimicking the effects of mechanical loading. These results demonstrate that Piezo1 is a mechanosensitive ion channel by which osteoblast lineage cells sense and respond to changes in mechanical load and identify a novel target for anabolic bone therapy.


Assuntos
Osso e Ossos/citologia , Osso e Ossos/fisiologia , Canais Iônicos/metabolismo , Osteócitos/metabolismo , Osteogênese , Estresse Mecânico , Animais , Linhagem Celular , Técnicas de Silenciamento de Genes , Canais Iônicos/administração & dosagem , Canais Iônicos/agonistas , Camundongos
9.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514419

RESUMO

This paper reports on the discovery of a novel three-membrane channel unit exhibiting very steep voltage dependence and strong cooperative behavior. It was reconstituted into planar phospholipid membranes formed by the monolayer method and studied under voltage-clamp conditions. The behavior of the novel channel-former, isolated from Escherichia coli, is consistent with a linearly organized three-channel unit displaying steep voltage-gating (a minimum of 14 charges in the voltage sensor) that rivals that of channels in mammalian excitable membranes. The channels also display strong cooperativity in that closure of the first channel permits the second to close and closure of the second channel permits closure of the third. All three have virtually the same conductance and selectivity, and yet the first and third close at positive potentials whereas the second closes at negative potentials. Thus, is it likely that the second channel-former is oriented in the membrane in a direction opposite to that of the other two. This novel structure is named "triplin." The extraordinary behavior of triplin indicates that it must have important and as yet undefined physiological roles.


Assuntos
Eletricidade , Escherichia coli/metabolismo , Canais Iônicos/metabolismo , Ativação do Canal Iônico , Cinética , Modelos Biológicos , Porinas/metabolismo
10.
Nat Commun ; 10(1): 4149, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515493

RESUMO

Studies of cellular mechano-signaling have often utilized static models that do not fully replicate the dynamics of living tissues. Here, we examine the time-dependent response of primary human mesenchymal stem cells (hMSCs) to cyclic tensile strain (CTS). At low-intensity strain (1 h, 4% CTS at 1 Hz), cell characteristics mimic responses to increased substrate stiffness. As the strain regime is intensified (frequency increased to 5 Hz), we characterize rapid establishment of a broad, structured and reversible protein-level response, even as transcription is apparently downregulated. Protein abundance is quantified coincident with changes to protein conformation and post-translational modification (PTM). Furthermore, we characterize changes to the linker of nucleoskeleton and cytoskeleton (LINC) complex that bridges the nuclear envelope, and specifically to levels and PTMs of Sad1/UNC-84 (SUN) domain-containing protein 2 (SUN2). The result of this regulation is to decouple mechano-transmission between the cytoskeleton and the nucleus, thus conferring protection to chromatin.


Assuntos
Núcleo Celular/metabolismo , Células-Tronco Mesenquimais/citologia , Proteínas Nucleares/metabolismo , Sequência de Aminoácidos , Fenômenos Biomecânicos , Forma do Núcleo Celular , Cromatina/metabolismo , Citoesqueleto/metabolismo , Dano ao DNA , Histonas/metabolismo , Humanos , Canais Iônicos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Modelos Biológicos , Membrana Nuclear/metabolismo , Proteínas Nucleares/química , Domínios Proteicos , Processamento de Proteína Pós-Traducional , Proteoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estresse Mecânico , Resistência à Tração
11.
Adv Gerontol ; 32(3): 357-363, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31512421

RESUMO

The aim of this work was to examine the content of Piezo1 in fibroblasts and blood vessels of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of Piezo1 in age-dependent changes in the number of fibroblasts and blood vessels in the dermis. Piezo1, proliferating cells nuclear antigen (PCNA), endothelial cells marker CD31 were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for Piezo1 in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of Piezo1 positive fibroblasts in dermis is increased sufficiently since 41 years old until 60-85 years old group. The content of Piezo1 in blood vessels in the human dermis is decreased sufficiently from 20 weeks of pregnancy until 40 years old. Age-related changes in the content of Piezo1 in fibroblasts and blood vessels is not associated with an age-related decrease in total number and percent of PCNA positive fibroblasts, the number of blood vessels in the dermis.


Assuntos
Vasos Sanguíneos , Derme , Fibroblastos , Canais Iônicos , Envelhecimento da Pele , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasos Sanguíneos/fisiologia , Criança , Pré-Escolar , Derme/irrigação sanguínea , Derme/citologia , Derme/embriologia , Derme/crescimento & desenvolvimento , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Lactente , Canais Iônicos/metabolismo , Masculino , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Gravidez , Antígeno Nuclear de Célula em Proliferação/metabolismo , Envelhecimento da Pele/fisiologia
12.
Int J Mol Sci ; 20(18)2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31540178

RESUMO

Ion channels contribute fundamental properties to cell membranes. Although highly diverse in conductivity, structure, location, and function, many of them can be regulated by common mechanisms, such as voltage or (de-)phosphorylation. Primarily considering ion channels involved in the nociceptive system, this review covers more novel and less known features. Accordingly, we outline noncanonical operation of voltage-gated sodium, potassium, transient receptor potential (TRP), and hyperpolarization-activated cyclic nucleotide (HCN)-gated channels. Noncanonical features discussed include properties as a memory for prior voltage and chemical exposure, alternative ion conduction pathways, cluster formation, and silent subunits. Complementary to this main focus, the intention is also to transfer knowledge between fields, which become inevitably more separate due to their size.


Assuntos
Canais Iônicos/metabolismo , Dor/etiologia , Dor/metabolismo , Animais , Suscetibilidade a Doenças , Descoberta de Drogas , Humanos , Ativação do Canal Iônico , Canais Iônicos/química , Canais Iônicos/genética , Dor/tratamento farmacológico
13.
Int J Nanomedicine ; 14: 5595-5609, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413565

RESUMO

Background: Platinum nanoparticles (PtNPs) have been considered a nontoxic nanomaterial and been clinically used in cancer chemotherapy. PtNPs can also be vehicle exhausts and environmental pollutants. These situations increase the possibility of human exposure to PtNPs. However, the potential biotoxicities of PtNPs including that on cardiac electrophysiology have been poorly understood. Methods: Ion channel currents of cardiomyocytes were recorded by patch clamp. Heart rhythm was monitored by electrocardiogram recording. Morphology and characteristics of PtNPs were examined by transmission electron microscopy, dynamic light scattering and electrophoretic light scattering analyses. Results: In cultured neonatal mice ventricular cardiomyocytes, PtNPs with diameters 5 nm (PtNP-5) and 70 nm (PtNP-70) concentration-dependently (10-9 - 10-5 g/mL) depolarized the resting potentials, suppressed the depolarization of action potentials and delayed the repolarization of action potentials. At the ion channel level, PtNPs decreased the current densities of INa, IK1 and Ito channels, but did not affect the channel activity kinetics. In vivo, PtNP-5 and PtNP-70 dose-dependently (3-10 mg/kg, i.v.) decreased the heart rate and induced complete atrioventricular conduction block (AVB) at higher doses. Both PtNP-5 and PtNP-70 (10-9 - 10-5 g/mL) did not significantly increase the generation of ROS and leak of lactate dehydrogenase (LDH) from cardiomyocytes within 5 mins after exposure except that only very high PtNP-5 (10-5 g/mL) slightly increased LDH leak. The internalization of PtNP-5 and PtNP-70 did not occur within 5 mins but occurred 1 hr after exposure. Conclusion: PtNP-5 and PtNP-70 have similar acute toxic effects on cardiac electrophysiology and can induce threatening cardiac conduction block. These acute electrophysiological toxicities of PtNPs are most likely caused by a nanoscale interference of PtNPs on ion channels at the extracellular side, rather than by oxidative damage or other slower biological processes.


Assuntos
Frequência Cardíaca/efeitos dos fármacos , Canais Iônicos/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Miócitos Cardíacos/metabolismo , Platina/toxicidade , Testes de Toxicidade Aguda , Animais , Animais Recém-Nascidos , Células Cultivadas , Eletrocardiografia , Endocitose/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Ventrículos do Coração/citologia , Ativação do Canal Iônico/efeitos dos fármacos , Cinética , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Platina/administração & dosagem
14.
PLoS Comput Biol ; 15(8): e1006662, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31437161

RESUMO

Pituitary endocrine cells fire action potentials (APs) to regulate their cytosolic Ca2+ concentration and hormone secretion rate. Depending on animal species, cell type, and biological conditions, pituitary APs are generated either by TTX-sensitive Na+ currents (INa), high-voltage activated Ca2+ currents (ICa), or by a combination of the two. Previous computational models of pituitary cells have mainly been based on data from rats, where INa is largely inactivated at the resting potential, and spontaneous APs are predominantly mediated by ICa. Unlike in rats, spontaneous INa-mediated APs are consistently seen in pituitary cells of several other animal species, including several species of fish. In the current work we develop a computational model of gonadotropin releasing cells in the teleost fish medaka (Oryzias latipes). The model stands out from previous modeling efforts by being (1) the first model of a pituitary cell in teleosts, (2) the first pituitary cell model that fires sponateous APs that are predominantly mediated by INa, and (3) the first pituitary cell model where the kinetics of the depolarizing currents, INa and ICa, are directly fitted to voltage-clamp data. We explore the firing properties of the model, and compare it to the properties of previous models that fire ICa-based APs. We put a particular focus on how the big conductance K+ current (IBK) modulates the AP shape. Interestingly, we find that IBK can prolong AP duration in models that fire ICa-based APs, while it consistently shortens the duration of the predominantly INa-mediated APs in the medaka gonadotroph model. Although the model is constrained to experimental data from gonadotroph cells in medaka, it may likely provide insights also into other pituitary cell types that fire INa-mediated APs.


Assuntos
Gonadotrofos/metabolismo , Modelos Biológicos , Oryzias/metabolismo , Potenciais de Ação , Animais , Cálcio/metabolismo , Biologia Computacional , Simulação por Computador , Feminino , Proteínas de Peixes/metabolismo , Gonadotropinas Hipofisárias/metabolismo , Canais Iônicos/metabolismo , Cinética , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo
15.
Int J Mol Sci ; 20(15)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344783

RESUMO

Investigations of information dynamics in eukaryotic cells focus almost exclusively on heritable information in the genome. Gene networks are modeled as "central processors" that receive, analyze, and respond to intracellular and extracellular signals with the nucleus described as a cell's control center. Here, we present a model in which cellular information is a distributed system that includes non-genomic information processing in the cell membrane that may quantitatively exceed that of the genome. Within this model, the nucleus largely acts a source of macromolecules and processes information needed to synchronize their production with temporal variations in demand. However, the nucleus cannot produce microsecond responses to acute, life-threatening perturbations and cannot spatially resolve incoming signals or direct macromolecules to the cellular regions where they are needed. In contrast, the cell membrane, as the interface with its environment, can rapidly detect, process, and respond to external threats and opportunities through the large amounts of potential information encoded within the transmembrane ion gradient. Our model proposes environmental information is detected by specialized protein gates within ion-specific transmembrane channels. When the gate receives a specific environmental signal, the ion channel opens and the received information is communicated into the cell via flow of a specific ion species (i.e., K+, Na+, Cl-, Ca2+, Mg2+) along electrochemical gradients. The fluctuation of an ion concentration within the cytoplasm adjacent to the membrane channel can elicit an immediate, local response by altering the location and function of peripheral membrane proteins. Signals that affect a larger surface area of the cell membrane and/or persist over a prolonged time period will produce similarly cytoplasmic changes on larger spatial and time scales. We propose that as the amplitude, spatial extent, and duration of changes in cytoplasmic ion concentrations increase, the information can be communicated to the nucleus and other intracellular structure through ion flows along elements of the cytoskeleton to the centrosome (via microtubules) or proteins in the nuclear membrane (via microfilaments). These dynamics add spatial and temporal context to the more well-recognized information communication from the cell membrane to the nucleus following ligand binding to membrane receptors. Here, the signal is transmitted and amplified through transduction by the canonical molecular (e.g., Mitogen Activated Protein Kinases (MAPK) pathways. Cytoplasmic diffusion allows this information to be broadly distributed to intracellular organelles but at the cost of loss of spatial and temporal information also contained in ligand binding.


Assuntos
Comunicação Celular/genética , Membrana Celular/genética , Núcleo Celular/genética , Células Eucarióticas , Cálcio/metabolismo , Citoplasma/genética , Citoesqueleto/genética , Genoma/genética , Canais Iônicos/genética , Canais Iônicos/metabolismo , Íons/metabolismo , Transdução de Sinais/genética
16.
Cells ; 8(7)2019 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261944

RESUMO

Influenza is a highly contagious virus that causes seasonal epidemics and unpredictable pandemics. Four influenza virus types have been identified to date: A, B, C, and D, where only A-C are known to infect humans. Influenza A (IAV) and B (IBV) viruses are responsible for seasonal influenza epidemics in humans and are responsible for up to a billion flu infections annually. The M2 protein is present in all influenza types and belongs to the class of viroporins (i.e., small proteins that form ion channels that increase membrane permeability in virus-infected cells). In influenza A and B, AM2 and BM2 are predominantly proton channels, although they also show some permeability to monovalent cations. In contrast, M2 proteins in influenza C (ICV) and D (IDV), CM2 and DM2, appear to be especially selective for chloride ions, with possibly some permeability to protons. These differences point to different biological roles for M2 in types A and B versus C and D, which is also reflected in their sequences. AM2 is by far the best characterized viroporin, and mechanistic details and rationale of its acid activation, proton selectivity, unidirectionality and relative low conductance are just beginning to be understood. The present review summarizes the biochemical and structural aspects of influenza viroporins and discusses the most relevant aspects of function, inhibition and interaction with the host.


Assuntos
Antivirais/farmacologia , Influenza Humana/virologia , Canais Iônicos/metabolismo , Orthomyxoviridae/patogenicidade , Proteínas da Matriz Viral/metabolismo , Antivirais/uso terapêutico , Cloretos/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Influenza Humana/tratamento farmacológico , Canais Iônicos/antagonistas & inibidores , Orthomyxoviridae/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Prótons , Proteínas da Matriz Viral/antagonistas & inibidores
17.
Int J Mol Sci ; 20(14)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31336748

RESUMO

Receptor-type ion channels are critical for detection of noxious stimuli in primary sensory neurons. Transient receptor potential (TRP) channels mediate pain sensations and promote a variety of neuronal signals that elicit secondary neural functions (such as calcitonin gene-related peptide [CGRP] secretion), which are important for physiological functions throughout the body. In this review, we focus on the involvement of TRP channels in sensing acute pain, inflammatory pain, headache, migraine, pain due to fungal infections, and osteo-inflammation. Furthermore, action potentials mediated via interactions between TRP channels and the chloride channel, anoctamin 1 (ANO1), can also generate strong pain sensations in primary sensory neurons. Thus, we also discuss mechanisms that enhance neuronal excitation and are dependent on ANO1, and consider modulation of pain sensation from the perspective of both cation and anion dynamics.


Assuntos
Anoctamina-1/metabolismo , Proteínas de Neoplasias/metabolismo , Manejo da Dor , Dor/metabolismo , Canais de Receptores Transientes de Potencial/metabolismo , Animais , Anoctamina-1/genética , Humanos , Canais Iônicos/metabolismo , Proteínas de Neoplasias/genética , Dor/etiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais , Canais de Receptores Transientes de Potencial/genética
18.
Molecules ; 24(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340554

RESUMO

Scorpions, a characteristic group of arthropods, are among the earliest diverging arachnids, dating back almost 440 million years. One of the many interesting aspects of scorpions is that they have venom arsenals for capturing prey and defending against predators, which may play a critical role in their evolutionary success. Unfortunately, however, scorpion envenomation represents a serious health problem in several countries, including Iran. Iran is acknowledged as an area with a high richness of scorpion species and families. The diversity of the scorpion fauna in Iran is the subject of this review, in which we report a total of 78 species and subspecies in 19 genera and four families. We also list some of the toxins or genes studied from five species, including Androctonus crassicauda, Hottentotta zagrosensis, Mesobuthus phillipsi, Odontobuthus doriae, and Hemiscorpius lepturus, in the Buthidae and Hemiscorpiidae families. Lastly, we review the diverse functions of typical toxins from the Iranian scorpion species, including their medical applications.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Antineoplásicos/química , Proteínas de Artrópodes/química , Venenos de Escorpião/química , Escorpiões/química , Animais , Peptídeos Catiônicos Antimicrobianos/biossíntese , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Proteínas de Artrópodes/biossíntese , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/uso terapêutico , Descoberta de Drogas/métodos , Expressão Gênica , Humanos , Canais Iônicos/agonistas , Canais Iônicos/antagonistas & inibidores , Canais Iônicos/metabolismo , Irã (Geográfico) , Metaloproteases/biossíntese , Metaloproteases/isolamento & purificação , Metaloproteases/toxicidade , Fosfolipases A2/biossíntese , Fosfolipases A2/isolamento & purificação , Fosfolipases A2/toxicidade , Filogenia , Picadas de Escorpião/fisiopatologia , Venenos de Escorpião/biossíntese , Venenos de Escorpião/isolamento & purificação , Escorpiões/classificação , Escorpiões/patogenicidade , Escorpiões/fisiologia , Inibidores de Serino Proteinase/biossíntese , Inibidores de Serino Proteinase/isolamento & purificação , Inibidores de Serino Proteinase/toxicidade , Especificidade da Espécie
19.
Ann Anat ; 225: 28-32, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31195095

RESUMO

Anterior cruciate ligament (ACL) tears is a devastating injury and one of the most common knee injuries experienced by athletes in the United States. Although patients reach maximal subjective improvement by one-year following ACL reconstruction, many patients often experience moderate to severe post-operative pain. Opioids, intra-articular injections, and regional anesthesia have been previously implemented to mediate post-operative pain. However, chronic opioid usage has become an epidemic in the United States. Alternative analgesic modalities, such as nerve blocks, have been implemented in clinical practice to provide adequate pain relief and minimize opioid usage. Periarticular injections targeted towards local neurological structures performed concomitantly with nerve blocks provides superior pain relief and satisfaction than isolated nerve blocks. Therefore, it is imperative for physicians to understand local neurological anatomy around the knee joint in order to provide adequate analgesia while minimizing opioid consumption. This purpose of this investigation is to summarize (1) neurogenic origins of pain generators and mediators in sites affected by ACL reconstruction and autograft harvest sites and (2) analgesia utilized in ACL reconstruction.


Assuntos
Reconstrução do Ligamento Cruzado Anterior , Ligamento Cruzado Anterior/anatomia & histologia , Articulação do Joelho/irrigação sanguínea , Articulação do Joelho/inervação , Dor Pós-Operatória/etiologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anestesia Local , Anestésicos Locais/administração & dosagem , Ligamento Cruzado Anterior/inervação , Ligamento Cruzado Anterior/cirurgia , Autoenxertos , Canais Iônicos/metabolismo , Mecanorreceptores/fisiologia , Bloqueio Nervoso , Neuropeptídeos/metabolismo , Neuropeptídeos/fisiologia , Nociceptividade/fisiologia , Nociceptores/fisiologia
20.
Cell Mol Life Sci ; 76(19): 3783-3800, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31165202

RESUMO

In the male reproductive tract, ionic equilibrium is essential to maintain normal spermatozoa production and, hence, the reproductive potential. Among the several ions, HCO3- and H+ have a central role, mainly due to their role on pH homeostasis. In the male reproductive tract, the major players in pH regulation and homeodynamics are carbonic anhydrases (CAs), HCO3- membrane transporters (solute carrier 4-SLC4 and solute carrier 26-SLC26 family transporters), Na+-H+ exchangers (NHEs), monocarboxylate transporters (MCTs) and voltage-gated proton channels (Hv1). CAs and these membrane transporters are widely distributed throughout the male reproductive tract, where they play essential roles in the ionic balance of tubular fluids. CAs are the enzymes responsible for the production of HCO3- which is then transported by membrane transporters to ensure the maturation, storage, and capacitation of the spermatozoa. The transport of H+ is carried out by NHEs, Hv1, and MCTs and is essential for the electrochemical balance and for the maintenance of the pH within the physiological limits along the male reproductive tract. Alterations in HCO3- production and transport of ions have been associated with some male reproductive dysfunctions. Herein, we present an up-to-date review on the distribution and role of the main intervenient on pH homeodynamics in the fluids throughout the male reproductive tract. In addition, we discuss their relevance for the establishment of the male reproductive potential.


Assuntos
Genitália Masculina/metabolismo , Concentração de Íons de Hidrogênio , Animais , Bicarbonatos/metabolismo , Anidrases Carbônicas/metabolismo , Fertilidade , Genitália Masculina/química , Homeostase , Humanos , Canais Iônicos/metabolismo , Bombas de Íon/metabolismo , Masculino , Transportadores de Ácidos Monocarboxílicos/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo
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