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1.
Adv Exp Med Biol ; 1131: 27-72, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646506

RESUMO

Ca2+, Na+ and K+- permeable ion channels as well as GPCRs linked to Ca2+ release are important drug targets. Accordingly, high-throughput fluorescence plate reader assays have contributed substantially to drug discovery efforts and pharmacological characterization of these receptors and ion channels. This chapter describes some of the basic properties of the fluorescent dyes facilitating these assay approaches as well as general methods for establishment and optimisation of fluorescence assays for ion channels and Gq-coupled GPCRs.


Assuntos
Bioensaio , Canais Iônicos , Receptores Acoplados a Proteínas-G , Animais , Bioensaio/tendências , Descoberta de Drogas , Corantes Fluorescentes/metabolismo , Humanos , Canais Iônicos/análise , Receptores Acoplados a Proteínas-G/análise
2.
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
3.
Chemistry ; 25(55): 12795-12800, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376182

RESUMO

The controllable ion transport in the photoreceptors of rod cells is essentially important for the light detection and information transduction in visual systems. Herein, inspired by the photochromism-regulated ion transport in rod cells with stacking structure, layered ion channels have been developed with a visual photochromic function induced by the alternate irradiation with visible and UV light. The layered structure is formed by stacking spiropyran-modified montmorillonite 2D nanosheets on the surface of an alumina nanoporous membrane. The visual photochromism resulting from the photoisomerization of spiropyran chromophores reversibly regulates the ion transport through layered ion channels. Furthermore, the cooperation of photochromism and pH value achieves multiple switchable states of layered ion channels for the controllable ion transport mimicking the biological process of the visual cycle. The ion transport properties of these states are explained quantitatively by a theoretical calculation based on the Poisson and Nernst-Plank (PNP) equations.


Assuntos
Benzopiranos/química , Indóis/química , Canais Iônicos/química , Transporte de Íons/fisiologia , Nitrocompostos/química , Células Fotorreceptoras Retinianas Cones/química , Células Fotorreceptoras Retinianas Cones/metabolismo , Raios Ultravioleta
4.
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
5.
Medicine (Baltimore) ; 98(32): e16782, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393404

RESUMO

INTRODUCTION: Over the past 10 years, epilepsy genetics has made dramatic progress. This study aimed to analyze the knowledge structure and the advancement of epilepsy genetics over the past decade based on co-word analysis of medical subject headings (MeSH) terms. METHODS: Scientific publications focusing on epilepsy genetics from the PubMed database (January 2009-December 2018) were retrieved. Bibliometric information was analyzed quantitatively using Bibliographic Item Co-Occurrence Matrix Builder (BICOMB) software. A knowledge social network analysis and publication trend based on the high-frequency MeSH terms was built using VOSviewer. RESULTS: According to the search strategy, a total of 5185 papers were included. Among all the extracted MeSH terms, 86 high-frequency MeSH terms were identified. Hot spots were clustered into 5 categories including: "ion channel diseases," "beyond ion channel diseases," "experimental research & epigenetics," "single nucleotide polymorphism & pharmacogenetics," and "genetic techniques". "Epilepsy," "mutation," and "seizures," were located at the center of the knowledge network. "Ion channel diseases" are typically in the most prominent position of epilepsy genetics research. "Beyond ion channel diseases" and "genetic techniques," however, have gradually grown into research cores and trends, such as "intellectual disability," "infantile spasms," "phenotype," "exome," " deoxyribonucleic acid (DNA) copy number variations," and "application of next-generation sequencing." While ion channel genes such as "SCN1A," "KCNQ2," "SCN2A," "SCN8A" accounted for nearly half of epilepsy genes in MeSH terms, a number of additional beyond ion channel genes like "CDKL5," "STXBP1," "PCDH19," "PRRT2," "LGI1," "ALDH7A1," "MECP2," "EPM2A," "ARX," "SLC2A1," and more were becoming increasingly popular. In contrast, gene therapies, treatment outcome, and genotype-phenotype correlations were still in their early stages of research. CONCLUSION: This co-word analysis provides an overview of epilepsy genetics research over the past decade. The 5 research categories display publication hot spots and trends in epilepsy genetics research which could consequently supply some direction for geneticists and epileptologists when launching new projects.


Assuntos
Bibliometria , Epilepsia/genética , Medical Subject Headings/estatística & dados numéricos , Epigenômica/métodos , Humanos , Canais Iônicos/genética , Mutação , Testes Farmacogenômicos/métodos , Fenótipo , Convulsões/genética
6.
Br J Anaesth ; 123(3): 335-349, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31303268

RESUMO

Systemic administration of the local anaesthetic lidocaine is antinociceptive in both acute and chronic pain states, especially in acute postoperative and chronic neuropathic pain. These effects cannot be explained by its voltage-gated sodium channel blocking properties alone, but the responsible mechanisms are still elusive. This narrative review focuses on available experimental evidence of the molecular mechanisms by which systemic lidocaine exerts its clinically documented analgesic effects. These include effects on the peripheral nervous system and CNS, where lidocaine acts via silencing ectopic discharges, suppression of inflammatory processes, and modulation of inhibitory and excitatory neurotransmission. We highlight promising objectives for future research to further unravel these antinociceptive mechanisms, which subsequently may facilitate the development of new analgesic strategies and therapies for acute and chronic pain.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos/farmacologia , Anestésicos Locais/farmacologia , Dor Crônica/tratamento farmacológico , Lidocaína/farmacologia , Terapia de Alvo Molecular/métodos , Dor Aguda/metabolismo , Analgésicos/uso terapêutico , Anestésicos Locais/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Dor Crônica/metabolismo , Humanos , Canais Iônicos/efeitos dos fármacos , Lidocaína/uso terapêutico , Transmissão Sináptica/efeitos dos fármacos
8.
Adv Exp Med Biol ; 1140: 359-375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31347058

RESUMO

Ion channels are intrinsic membrane proteins that form gated ion permeable pores across biological membranes. Depending on the type, ion channels exhibit sensitivities to a diverse range of stimuli including changes in membrane potential, binding by diffusible ligands, changes in temperature and direct mechanical force. The purpose of these proteins is to facilitate the passive diffusion of ions down their respective electrochemical gradients into and out of the cell, and between intracellular compartments. In doing so, ion channels can affect transmembrane potentials and regulate the intracellular homeostasis of the important second messenger, Ca2+, modulating a multitude of cell signaling systems in the process. The ion channels of the plasma membrane are of particular clinical interest due to their regulation of cell excitability and cytosolic Ca2+ levels, and the fact that they are particularly amenable to manipulation by exogenously applied drugs and toxins. A critical step in improving the pharmacopeia of chemicals available that influence the activity of ion channels is understanding how their three-dimensional structure relates to their function. Historically, elucidation of the structure of membrane proteins has been slow relative to that for soluble proteins, due to limitations inherent in the most widely used methods, in particular X-ray crystallography. Over the course of the last decade, starting with significant advances in X-ray crystallography followed by the more recent, and profound, surge in the use of single particle cryo-electron microscopy (cryo-EM), a slew of high resolution ion channel structures have been resolved. Overshadowed during this period have been the equally marked advances in mass spectrometry, pushing this method to the fore as an important complimentary approach to studying the structure and function of ion channels. In addition to revealing the subtle conformational changes in ion channel structure that accompany gating and permeation, mass spectrometry is already being used effectively for identifying tissue-specific posttranslational modifications and mRNA splice variants. Furthermore, the use of mass spectrometry for high throughput proteomics analysis, which has proven so successful for soluble proteins, is already providing valuable insight into the functional interactions of ion channels within the context of the macromolecular signaling complexes that they inhabit in vivo. In this chapter, the potential for mass spectrometry as a complementary approach to the study of ion channel structure and function will be reviewed with examples of its application.


Assuntos
Canais Iônicos/fisiologia , Espectrometria de Massas , Transdução de Sinais , Membrana Celular , Microscopia Crioeletrônica , Cristalografia por Raios X , Proteômica
9.
Adv Exp Med Biol ; 1124: 77-101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183823

RESUMO

The peristaltic pressure waves in the renal pelvis that propel urine expressed by the kidney into the ureter towards the bladder have long been considered to be 'myogenic', being little affected by blockers of nerve conduction or autonomic neurotransmission, but sustained by the intrinsic release of prostaglandins and sensory neurotransmitters. In uni-papilla mammals, the funnel-shaped renal pelvis consists of a lumen-forming urothelium and a stromal layer enveloped by a plexus of 'typical' smooth muscle cells (TSMCs), in multi-papillae kidneys a number of minor and major calyces fuse into a large renal pelvis. Electron microscopic, electrophysiological and Ca2+ imaging studies have established that the pacemaker cells driving pyeloureteric peristalsis are likely to be morphologically distinct 'atypical' smooth muscle cells (ASMCs) that fire Ca2+ transients and spontaneous transient depolarizations (STDs) which trigger propagating nifedipine-sensitive action potentials and Ca2+ waves in the TSMC layer. In uni-calyceal kidneys, ASMCs predominately locate on the serosal surface of the proximal renal pelvis while in multi-papillae kidneys they locate within the sub-urothelial space. 'Fibroblast-like' interstitial cells (ICs) located in the sub-urothelial space or adventitia are a mixed population of cells, having regional and species-dependent expression of various Cl-, K+, Ca2+ and cationic channels. ICs display asynchronous Ca2+ transients that periodically synchronize into bursts that accelerate ASMC Ca2+ transient firing. This review presents current knowledge of the architecture of the proximal renal pelvis, the role Ca2+ plays in renal pelvis peristalsis and the mechanisms by which ICs may sustain/accelerate ASMC pacemaking.


Assuntos
Cálcio/fisiologia , Células Intersticiais de Cajal/fisiologia , Canais Iônicos/fisiologia , Pelve Renal/fisiologia , Contração Muscular , Peristaltismo , Animais , Ureter
10.
Adv Exp Med Biol ; 1124: 103-119, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183824

RESUMO

The ureter acts as a functional syncytium and is controlled by a propagating plateau-type action potential (AP) which gives rise to a wave of contraction (ureteral peristalsis) via a process called excitation-contraction (E-C)coupling. The second messenger Ca2+ activates Ca2+/calmodulin-dependent myosin light chain kinase-dependent phosphorylation of 20-kDa regulatory light chains of myosin which leads to ureteric contraction. Ca2+ entry from the extracellular space via voltage-gated L-type Ca2+ channels (VGCCs) provides the major source of activator Ca2+, responsible for generation of both the AP and a Ca2+ transient that appears as an intercellular Ca2+ wave. The AP, inward Ca2+ current, Ca2+ transient and twitch contraction are all fully blocked by the selective L-type Ca2+ channel blocker nifedipine. Ca2+ entry via VGCCs, coupled to activation of Ca2+-sensitive K+ (KCa) or Cl- (ClCa) channels, acts as a negative or positive feedback mechanism, respectively, to control excitability and the amplitude and duration of the plateau component of the AP, Ca2+ transient and twitch contraction. The ureter, isolated from the pelvis, is not spontaneously active. However, spontaneous activity can be initiated in the proximal and distal ureter by a variety of biological effectors such as neurotransmitters, paracrine, endocrine and inflammatory factors. Applied agonists depolarise ureteric smooth muscles cells to threshold of AP activation, initiating propagating intercellular AP-mediated Ca2+ waves to produce antegrade and/or retrograde ureteric peristalsis. Several mechanisms have been proposed to describe agonist-induced depolarization of ureteric smooth muscle, which include suppression of K+ channels, stimulation of ClCa current and activation of non-selective cation receptor/store operated channels.


Assuntos
Sinalização do Cálcio , Canais Iônicos/fisiologia , Contração Muscular , Músculo Liso/fisiologia , Peristaltismo , Ureter/fisiologia , Cálcio/fisiologia , Humanos
11.
Adv Exp Med Biol ; 1124: 171-194, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183827

RESUMO

The corpus cavernosum smooth muscle is important for both erection of the penis and for maintaining penile flaccidity. Most of the time, the smooth muscle cells are in a contracted state, which limits filling of the corpus sinuses with blood. Occasionally, however, they relax in a co-ordinated manner, allowing filling to occur. This results in an erection. When contractions of the corpus cavernosum are measured, it can be deduced that the muscle cells work together in a syncytium, for not only do they spontaneously contract in a co-ordinated manner, but they also synchronously relax. It is challenging to understand how they achieve this.In this review we will attempt to explain the activity of the corpus cavernosum, firstly by summarising current knowledge regarding the role of ion channels and how they influence tone, and secondly by presenting data on the intracellular Ca2+ signals that interact with the ion channels. We propose that spontaneous Ca2+ waves act as a primary event, driving transient depolarisation by activating Ca2+-activated Cl- channels. Depolarisation then facilitates Ca2+ influx via L-type voltage-dependent Ca2+ channels. We propose that the spontaneous Ca2+ oscillations depend on Ca2+ release from both ryanodine- and inositol trisphosphate (IP3)-sensitive stores and that modulation by signalling molecules is achieved mainly by interactions with the IP3-sensitive mechanism. This pacemaker mechanism is inhibited by nitric oxide (acting through cyclic GMP) and enhanced by noradrenaline. By understanding these mechanisms better, it might be possible to design new treatments for erectile dysfunction.


Assuntos
Sinalização do Cálcio , Canais Iônicos/fisiologia , Músculo Liso/fisiologia , Pênis/fisiologia , Cálcio/fisiologia , Humanos , Masculino , Ereção Peniana
12.
Adv Exp Med Biol ; 1124: 195-215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183828

RESUMO

Spontaneous myogenic contractions have been shown to be significantly upregulated in prostate tissue collected from men with Benign Prostatic Hyperplasia (BPH), an extremely common disorder of the ageing male. Although originally thought likely to be involved in 'housekeeping' functions, mixing prostatic secretions to prevent stagnation, these spontaneous myogenic contractions provide a novel opportunity to understand and treat BPH. This treatment potential differs from previous models, which focused exclusively on attenuating nerve-mediated neurogenic contractions. Previous studies in the rodent prostate have provided an insight into the mechanisms underlying the regulation of myogenic contractions. 'Prostatic Interstitial Cells' (PICs) within the prostate appear to generate pacemaker potentials, which arise from the summation of number of spontaneous transient depolarisations triggered by the spontaneous release of Ca2+ from internal stores and the opening of Ca2+-activated Cl- channels. Pacemaker potentials then conduct into neighbouring smooth muscle cells to generate spontaneous slow waves. These slow waves trigger the firing of 'spike-like' action potentials, Ca2+ entry and contraction, which are not attenuated by blockers of neurotransmission. However, these spontaneous prostatic contractions can be modulated by the autonomic nervous system. Here, we discuss the mechanisms underlying rodent and human prostate myogenic contractions and the actions of existing and novel pharmacotherapies for the treatment of BPH. Understanding the generation of human prostatic smooth muscle tone will confirm the mechanism of action of existing drugs, inform the identification and effectiveness of new pharmacotherapies, as well as predict patient outcomes.


Assuntos
Sinalização do Cálcio , Células Intersticiais de Cajal/fisiologia , Canais Iônicos/fisiologia , Contração Muscular , Músculo Liso/fisiologia , Animais , Cálcio/fisiologia , Humanos , Masculino , Hiperplasia Prostática
13.
Adv Exp Med Biol ; 1124: 217-231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183829

RESUMO

Seminal vesicles (SVs), a pair of male accessory glands, contract upon sympathetic nerve excitation during ejaculation while developing spontaneous phasic constrictions in the inter-ejaculatory storage phase. Recently, the fundamental role of the mucosa in generating spontaneous activity in SV of the guinea pig has been revealed. Stretching the mucosa-intact but not mucosa-denuded SV smooth muscle evokes spontaneous phasic contractions arising from action potential firing triggered by electrical slow waves and associated Ca2+ flashes. These spontaneous events primarily depend on sarco-endoplasmic reticulum (SR/ER) Ca2+ handling linked with the opening of Ca2+-activated chloride channels (CaCCs) resulting in the generation of slow waves. Slow waves in mucosa-intact SV smooth muscle are abolished upon blockade of gap junctions, suggesting that seminal smooth muscle cells are driven by cells distributed in the mucosa. In the SV mucosal preparations dissected free from the smooth muscle layer, a population of cells located just beneath the epithelium develop spontaneous Ca2+ transients relying on SR/ER Ca2+ handling. In the lamina propria of the SV mucosa, vimentin-immunoreactive interstitial cells including platelet-derived growth factor receptor α (PDGFRα)-immunoreactive cells are distributed, while known pacemaker cells in other smooth muscle tissues, e.g. c-Kit-positive interstitial cells or α-smooth muscle actin-positive atypical smooth muscle cells, are absent. The spontaneously-active subepithelial cells appear to drive spontaneous activity in SV smooth muscle either by sending depolarizing signals or by releasing humoral substances. Interstitial cells in the lamina propria may act as intermediaries of signal transmission from the subepithelial cells to the smooth muscle cells.


Assuntos
Células Intersticiais de Cajal/fisiologia , Membrana Mucosa/fisiologia , Contração Muscular , Músculo Liso/fisiologia , Glândulas Seminais/fisiologia , Animais , Sinalização do Cálcio , Cobaias , Canais Iônicos/fisiologia , Masculino , Miócitos de Músculo Liso/fisiologia
14.
Adv Exp Med Biol ; 1124: 297-312, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183832

RESUMO

Rhythmical contractility of blood vessels was first observed in bat wing veins by Jones (Philos Trans R Soc Lond 1852:142, 131-136), and subsequently described in arteries and arterioles of multiple vascular beds in several species. Despite an abundance of descriptive literature regarding the presence of vasomotion, to date we do not have an accurate picture of the cellular and ionic basis of these oscillations in tone, or the physiological relevance of the changes in pulsatile blood flow arising from vasomotion. This chapter reviews our current understanding of the cellular and ionic mechanisms underlying vasomotion in resistance arteries and arterioles. Focus is directed to the ion channels, changes in cytosolic Ca2+ concentration, and involvement of intercellular gap junctions in the development and synchronization of rhythmic changes in membrane potential and cytosolic Ca2+ concentration within the vessel wall that contribute to vasomotion. The physiological consequences of vasomotion are discussed with a focus on the cerebral vasculature, as recent advances show that rhythmic oscillations in cerebral arteriolar diameter appear to be entrained by cortical neural activity to increase the local supply of blood flow to active regions of the brain.


Assuntos
Artérias/fisiologia , Sinalização do Cálcio , Canais Iônicos/fisiologia , Músculo Liso Vascular/fisiologia , Animais , Arteríolas , Junções Comunicantes , Potenciais da Membrana , Fluxo Pulsátil
15.
Adv Exp Med Biol ; 1124: 329-356, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183834

RESUMO

The microvasculature is composed of arterioles, capillaries and venules. Spontaneous arteriolar constrictions reduce effective vascular resistance to enhance tissue perfusion, while spontaneous venular constrictions facilitate the drainage of tissue metabolites by pumping blood. In the venules of visceral organs, mural cells, i.e. smooth muscle cells (SMCs) or pericytes, periodically generate spontaneous phasic constrictions, Ca2+ transients and transient depolarisations. These events arise from spontaneous Ca2+ release from the sarco-endoplasmic reticulum (SR/ER) and the subsequent opening of Ca2+-activated chloride channels (CaCCs). CaCC-dependent depolarisation further activates L-type voltage-dependent Ca2+ channels (LVDCCs) that play a critical role in maintaining the synchrony amongst mural cells. Mural cells in arterioles or capillaries are also capable of developing spontaneous activity. Non-contractile capillary pericytes generate spontaneous Ca2+ transients primarily relying on SR/ER Ca2+ release. Synchrony amongst capillary pericytes depends on gap junction-mediated spread of depolarisations resulting from the opening of either CaCCs or T-type VDCCs (TVDCCs) in a microvascular bed-dependent manner. The propagation of capillary Ca2+ transients into arterioles requires the opening of either L- or TVDCCs again depending on the microvascular bed. Since the blockade of gap junctions or CaCCs prevents spontaneous Ca2+ transients in arterioles and venules but not capillaries, capillary pericytes appear to play a primary role in generating spontaneous activity of the microvasculature unit. Pericytes in capillaries where the interchange of substances between tissues and the circulation takes place may provide the fundamental drive for upstream arterioles and downstream venules so that the microvasculature network functions as an integrated unit.


Assuntos
Sinalização do Cálcio , Canais Iônicos/fisiologia , Microvasos/fisiologia , Pericitos/fisiologia , Arteríolas/fisiologia , Cálcio/fisiologia , Humanos , Microvasos/citologia , Vênulas/fisiologia
16.
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
17.
Cell Physiol Biochem ; 53(1): 36-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169990

RESUMO

BACKGROUND/AIMS: Ivabradine lowers the heart rate by inhibition of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels mediating the 'funny' pacemaker current If in the sinoatrial node. It is clinically approved for the treatment of heart failure and angina pectoris. Due to its proposed high selectivity for If administration of ivabradine is not associated with the side effects commonly observed following the application of other heart rate lowering agents. Recent evidence, however, has shown significant affinity of ivabradine towards Kv11.1 (ether-a-go-go related gene, ERG) potassium channels. Despite the inhibition of Kv11.1 channels by ivabradine, cardiac action potential (AP) duration and heart rate corrected QT interval (QTc) of the human electrocardiogram (ECG) were not prolonged. We thus surmised that compensatory mechanisms might counteract the drug's inhibitory action on Kv11.1. METHODS: The effects of ivabradine on human Kv11.1 and Kv7.1 potassium, Cav1.2 calcium, and Nav1.5 sodium channels, heterologously expressed in tsA-201 cells, were studied in the voltage-clamp mode of the whole cell patch clamp technique. In addition, changes in action potential parameters of human induced pluripotent stem cell (iPSC) derived cardiomyocytes upon application of ivabradine were studied with current-clamp experiments. RESULTS: Here we show that ivabradine exhibits significant affinity towards cardiac ion channels other than HCN. We demonstrate for the first time inhibition of human voltage-gated Nav1.5 sodium channels at therapeutically relevant concentrations. Within this study we also confirm recent findings of human Kv11.1 inhibition by low µM concentrations of ivabradine and observed no prolongation of ventricular-like APs in cardiomyocytes derived from iPSCs. CONCLUSION: Our results provide an explanation why ivabradine, despite its affinity for Kv11.1 channels, does not prolong the cardiac AP and QTc interval. Furthermore, our results suggest the inhibition of voltage-gated Nav1.5 sodium channels to underlie the recent observations of slowed atrioventricular conduction by increased atrial-His bundle intervals upon administration of ivabradine.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Canais Iônicos/metabolismo , Ivabradina/farmacologia , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo L/metabolismo , Linhagem Celular , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Canais Iônicos/antagonistas & inibidores , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/química , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Técnicas de Patch-Clamp
18.
Neuron ; 103(4): 598-616.e7, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31248728

RESUMO

Dorsal root ganglion (DRG) sensory neuron subtypes defined by their in vivo properties display distinct intrinsic electrical properties. We used bulk RNA sequencing of genetically labeled neurons and electrophysiological analyses to define ion channel contributions to the intrinsic electrical properties of DRG neuron subtypes. The transcriptome profiles of eight DRG neuron subtypes revealed differentially expressed and functionally relevant genes, including voltage-gated ion channels. Guided by these data, electrophysiological analyses using pharmacological and genetic manipulations as well as computational modeling of DRG neuron subtypes were undertaken to assess the functions of select voltage-gated potassium channels (Kv1, Kv2, Kv3, and Kv4) in shaping action potential (AP) waveforms and firing patterns. Our findings show that the transcriptome profiles have predictive value for defining ion channel contributions to sensory neuron subtype-specific intrinsic physiological properties. The distinct ensembles of voltage-gated ion channels predicted to underlie the unique intrinsic physiological properties of eight DRG neuron subtypes are presented.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Canais Iônicos/fisiologia , Células Receptoras Sensoriais/fisiologia , Potenciais de Ação , Vias Aferentes/fisiologia , Animais , Simulação por Computador , Gânglios Espinais/citologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Canais Iônicos/biossíntese , Canais Iônicos/genética , Mecanorreceptores/fisiologia , Camundongos , Camundongos Transgênicos , Modelos Neurológicos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Técnicas de Patch-Clamp , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , RNA/genética , Células Receptoras Sensoriais/química , Células Receptoras Sensoriais/classificação , Transcriptoma
19.
Nat Commun ; 10(1): 2695, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217422

RESUMO

Soft wearable electronics for underwater applications are of interest, but depend on the development of a waterproof, long-term sustainable power source. In this work, we report a bionic stretchable nanogenerator for underwater energy harvesting that mimics the structure of ion channels on the cytomembrane of electrocyte in an electric eel. Combining the effects of triboelectrification caused by flowing liquid and principles of electrostatic induction, the bionic stretchable nanogenerator can harvest mechanical energy from human motion underwater and output an open-circuit voltage over 10 V. Underwater applications of a bionic stretchable nanogenerator have also been demonstrated, such as human body multi-position motion monitoring and an undersea rescue system. The advantages of excellent flexibility, stretchability, outstanding tensile fatigue resistance (over 50,000 times) and underwater performance make the bionic stretchable nanogenerator a promising sustainable power source for the soft wearable electronics used underwater.


Assuntos
Fontes de Energia Elétrica , Nanotecnologia/métodos , Tecnologia de Sensoriamento Remoto/instrumentação , Dispositivos Eletrônicos Vestíveis , Animais , Materiais Biomiméticos/química , Membrana Celular/química , Dimetilpolisiloxanos/química , Electrophorus , Humanos , Canais Iônicos/química , Estrutura Molecular , Movimento , Nanopartículas/química , Oceanos e Mares , Trabalho de Resgate , Resistência à Tração , Tecnologia sem Fio
20.
Ecotoxicol Environ Saf ; 179: 160-166, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31039458

RESUMO

Non-selective cation channels (NSCCs) play important roles in uptake of heavy metals in plants. However, little information is available concerning the contribution of NSCCs to cadmium (Cd) transport in rice seedlings. Results from the hydroponic experiment showed that the inhibition of 2.7 µM Cd on the development of rice roots was alleviated by adding 0.1 mM gadolinium (Gd) in nutrient solution, companied by reduction of Cd content by 55.3% in roots and by 45.0% in shoots. Inhibition of Gd on Cd accumulation in cytoplasm fraction (F3) was much greater than that in cell walls (F1) and organelles (F2) in roots. After increasing concentrations of Mn and Zn in nutrient solution, adding 0.1 mM Gd resulted in reductions in Cd content by 89.1%, in micronutrients by 54.9% and in macronutrients by 5.4% in roots, respectively. Cd stress resulted in significant increase of PC2∼4 and free amino acids, but decrease of V-ATPase activity by 32.3% in roots. These results indicate that NSCCs make a great contribution to uptake of Cd in rice seedlings and opportunities for Cd to be transported by NSCCs can be efficiently reduced by blocking NSCCs and/or increasing essential microelements like Mn and Zn.


Assuntos
Cádmio/metabolismo , Gadolínio/farmacologia , Canais Iônicos/antagonistas & inibidores , Transporte de Íons/efeitos dos fármacos , Oryza/metabolismo , Plântula/metabolismo , Hidroponia , Oryza/efeitos dos fármacos , Oryza/crescimento & desenvolvimento , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento
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