Cellular mechanisms of transient contraction of coronary arterial smooth muscles in hypoxia: Role of intracellular Ca++

1989 ◽  
Vol 107 (1) ◽  
pp. 3-6
Author(s):  
A. I. Solov'ev ◽  
S. A. Bershtein ◽  
O. V. Bazilyuk
Keyword(s):  
Smooth Muscles ◽  
Cellular Mechanisms ◽  
Intracellular Ca

Genesis and Regulation of the Heart Automaticity

2008 ◽  
Vol 88 (3) ◽  
pp. 919-982 ◽  
Author(s):  
Matteo E. Mangoni ◽  
Joël Nargeot
Keyword(s):  
Ion Channels ◽  
Current Knowledge ◽  
Genetically Engineered ◽  
Cardiac Cells ◽  
Mouse Strains ◽  
Cellular Mechanisms ◽  
Cardiac Pacemaking ◽  
Intracellular Ca ◽  
Cardiac Automaticity

The heart automaticity is a fundamental physiological function in higher organisms. The spontaneous activity is initiated by specialized populations of cardiac cells generating periodical electrical oscillations. The exact cascade of steps initiating the pacemaker cycle in automatic cells has not yet been entirely elucidated. Nevertheless, ion channels and intracellular Ca2+ signaling are necessary for the proper setting of the pacemaker mechanism. Here, we review the current knowledge on the cellular mechanisms underlying the generation and regulation of cardiac automaticity. We discuss evidence on the functional role of different families of ion channels in cardiac pacemaking and review recent results obtained on genetically engineered mouse strains displaying dysfunction in heart automaticity. Beside ion channels, intracellular Ca2+ release has been indicated as an important mechanism for promoting automaticity at rest as well as for acceleration of the heart rate under sympathetic nerve input. The potential links between the activity of ion channels and Ca2+ release will be discussed with the aim to propose an integrated framework of the mechanism of automaticity.

scholarly journals Cellular mechanisms involved in CO2 and acid signaling in chemosensitive neurons

2004 ◽  
Vol 287 (6) ◽  
pp. C1493-C1526 ◽  
Author(s):  
Robert W. Putnam ◽  
Jessica A. Filosa ◽  
Nicola A. Ritucci
Keyword(s):  
Brain Stem ◽  
Neuronal Response ◽  
Taste Receptor ◽  
Cellular Mechanisms ◽  
Signaling Mechanisms ◽  
Intrapulmonary Chemoreceptors ◽  
Intracellular Ca ◽  
Different Levels ◽  
Carotid Body Glomus Cells

An increase in CO2/H+ is a major stimulus for increased ventilation and is sensed by specialized brain stem neurons called central chemosensitive neurons. These neurons appear to be spread among numerous brain stem regions, and neurons from different regions have different levels of chemosensitivity. Early studies implicated changes of pH as playing a role in chemosensitive signaling, most likely by inhibiting a K+ channel, depolarizing chemosensitive neurons, and thereby increasing their firing rate. Considerable progress has been made over the past decade in understanding the cellular mechanisms of chemosensitive signaling using reduced preparations. Recent evidence has pointed to an important role of changes of intracellular pH in the response of central chemosensitive neurons to increased CO2/H+ levels. The signaling mechanisms for chemosensitivity may also involve changes of extracellular pH, intracellular Ca2+, gap junctions, oxidative stress, glial cells, bicarbonate, CO2, and neurotransmitters. The normal target for these signals is generally believed to be a K+ channel, although it is likely that many K+ channels as well as Ca2+ channels are involved as targets of chemosensitive signals. The results of studies of cellular signaling in central chemosensitive neurons are compared with results in other CO2- and/or H+-sensitive cells, including peripheral chemoreceptors (carotid body glomus cells), invertebrate central chemoreceptors, avian intrapulmonary chemoreceptors, acid-sensitive taste receptor cells on the tongue, and pain-sensitive nociceptors. A multiple factors model is proposed for central chemosensitive neurons in which multiple signals that affect multiple ion channel targets result in the final neuronal response to changes in CO2/H+.

scholarly journals Mechanisms of the effect of systemic endotoxinemia on development and course of atherosclerosis at cell, systemic and body levels

2018 ◽  
pp. 12-22
Author(s):  
Д. П. Покусаева
Keyword(s):  
Cell Model ◽  
Smooth Muscles ◽  
Developed Countries ◽  
Systemic Circulation ◽  
Population Based ◽  
Cellular Mechanisms ◽  
Atherosclerosis Progression ◽  
A Cell ◽  
Different Strains

Осложнения атеросклероза, такие, как инсульт головного мозга и инфаркт миокарда, занимают ведущее место среди причин смерти в экономически развитых странах. Существует множество гипотез атерогенеза. Анализ научных публикаций позволил проследить эволюцию представлений о патогенезе болезней атеросклеротической природы, индукции атерогенеза, рисков его прогрессирования. Абсолютизация одного из них привела к доминированию холестериновой теории атеросклероза. Появление научных фактов, свидетельствующих об участии вирусов и грамотрицательных бактерий в прогрессировании атеросклероза, позволило рассматривать атерогенез с позиции воспаления (что подтверждено многочисленными исследованиями). Рассмотрены клеточные механизмы, пути активации макрофагов, действие воспалительных цитокинов на гладкомышечные клетки стенки артерии и эндотелиоциты с позиции воспалительной теории атеросклероза. На основании современных публикаций описываются точки приложения и механизмы воздействия эндотоксина при атерогенезе, как уникального липополисахарида, способного индуцировать воспаление. Эндотоксиновая концепция атерогенеза по своей сути является современным этапом развития воспалительной теории атеросклероза. Описаны механизмы его влияния на эндотелиоцит, моноцит и гладкомышечные клетки стенки артерии. Приведены примеры новейших исследований по изучению роли эндотоксина в патологии сердечно-сосудистых заболеваний на клеточной модели с участием подкожной вены человека, на модели животных с различными линиями нокаутных мышей. Приводятся данные исследований с участием человека, включая единственное популяционное исследование Брунек. Рассмотрены возможные пути взаимосвязи липидного обмена и обмена липополисахарида за счет единых механизмов транспорта. Проанализированы трудности изучения роли эндотоксина в патологии, которые связаны с недостаточной информативностью и точностью тест систем. Приводится сравнительная характеристика различных методов анализа концентрации липополисахарида в системном кровотоке и активности антиэндотоксинового иммунитета (АЭИ), такие, как ЛАЛ-тест, микро-ЛАЛ-тест, ЛПС-тест-ИФА, ELISA, тест ЕАА, метод СОИС-ИФА, ЕNA. Complications of atherosclerosis, such as stroke and myocardial infarction, has taken a lead among causes of death in developed countries. Multiple hypotheses of atherogenesis exist. The review of 60 reports enables tracking the evolution of understanding the pathogenesis of atherosclerotic diseases, induction of atherogenesis, and risks for atherosclerosis progression. Absolutization of one of them has resulted in predomination of the cholesteric theory of atherosclerosis. Emergence of evidence for participation of viruses and gram-negative bacteria in progression of atherosclerosis allowed atherogenesis to be considered from the standpoint of inflammation (as confirmed by numerous studies). This review focuses on cellular mechanisms, ways of macrophage activation, effects of inflammatory cytokines on arterial smooth muscle cells and endotheliocytes from a position of the inflammation theory of atherosclerosis. Based on current reports, atherogenic mechanisms of endotoxin effects are described as effects of a unique lipopolysaccharide capable for induction of inflammation. The endotoxin concept of atherogenesis is essentially a current stage of the inflammation theory of atherosclerosis. The author described mechanisms of the endotoxin effect on endotheliocytes, monocytes, and arterial smooth muscles cells. Examples of recent studies demonstrated the role of endotoxin in the pathology of cardiovascular diseases on a cell model with the human saphenous vein and on different strains of knockout mice. Data from human studies are presented, including the only population-based study by Bruneck. Possible interrelations of lipid and lipopolysaccharide metabolism based on single transport mechanisms are described. Difficulties of measuring endotoxin concentration in the systemic circulation are related with insufficient informative value and accuracy of available tests. Characteristics of different tests for measuring the LPS concentration and the activity of antiendotoxin immunity were compared, including the LAL-test, micro-LAL-test, LPS-test-ELISA, EAA test, SOIS-method, and ЕNA.

scholarly journals Role of impaired endothelial cell Ca2+ signaling in uteroplacental vascular dysfunction during diabetic rat pregnancy

2013 ◽  
Vol 304 (7) ◽  
pp. H935-H945 ◽  
Author(s):  
Natalia I. Gokina ◽  
Adrian D. Bonev ◽  
Alexander P. Gokin ◽  
Gabriela Goloman
Keyword(s):  
Endothelial Cell ◽  
Vascular Dysfunction ◽  
Maternal Blood ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Cellular Mechanisms ◽  
Citrate Buffer ◽  
Pregnant Rats ◽  
Intracellular Ca

Diabetes mellitus in pregnancy is associated with impaired endothelium-mediated dilatation of maternal arteries, although the underlying cellular mechanisms remain unknown. In this study, we hypothesized that diabetes during rat gestation attenuates agonist-induced uterine vasodilation through reduced endothelial cell (EC) Ca2+ elevations and impaired smooth muscle cell (SMC) hyperpolarization and SMC intracellular Ca2+ concentration ([Ca2+]i) responses. Diabetes was induced by an injection of streptozotocin to second-day pregnant rats and confirmed by the development of maternal hyperglycemia. Control rats were injected with a citrate buffer. Fura-2-based measurements of SMC [Ca2+]i or microelectrode recordings of SMC membrane potential were performed concurrently with dilator responses to ACh in uteroplacental arteries from control and diabetic pregnant rats. Basal levels of EC [Ca2+]i and ACh-induced EC [Ca2+]i elevations in pressurized vessels and small EC sheets were studied as well. Diabetes reduced ACh-induced vasodilation due to a markedly impaired EDHF-mediated response. Diminished vasodilation to ACh was associated with attenuated SMC hyperpolarization and [Ca2+]i responses. Basal levels of EC [Ca2+]i and ACh-induced EC [Ca2+]i elevations were significantly reduced by diabetes. In conclusion, these data demonstrate that reduced endothelium-mediated hyperpolarization contributes to attenuated uteroplacental vasodilation and SMC [Ca2+]i responses to ACh in diabetic pregnancy. Impaired endothelial Ca2+ signaling is in part responsible for endothelial dysfunction in the uterine resistance vasculature of diabetic rats. Pharmacological improvement of EC Ca2+ handling may provide an important strategy for the restoration of endothelial function and enhancement of maternal blood flow in human pregnancies complicated by diabetes.

The role of THOA in calcium sensitization in human myometrial smooth muscles

2007 ◽  
Vol 30 (4) ◽  
pp. 70
Author(s):  
Hector Aguilar ◽  
B. F. (Peter) Mitchell
Keyword(s):  
Smooth Muscle ◽  
Light Chain ◽  
Mammalian Cells ◽  
Myosin Light Chain ◽  
Smooth Muscles ◽  
Human Myometrium ◽  
Uterine Contractility ◽  
Western Blots ◽  
Intracellular Ca

Improved understanding of the regulation of contractions of uterine smooth muscle (myometrium) is essential to develop more successful strategies for prevention of premature birth, which remains the most common cause of infant death and disability. Oxytocin (OT) and prostaglandin (PG) F2a are potent myometrial stimulants which induce an increase in intracellular Ca++. This activates myosin light chain kinase (MLCK) and subsequently the cell’s contractile machinery. However, there is poor correlation between the rise in Ca++ and the strength of the myometrial contraction. Contractile strength greatly increases at the time of parturition partly due to Ca++-independent factors that sensitize the muscle to the rise in intracellular Ca++. In vascular smooth muscle, one key regulator in this process of Ca++ sensitization is the monomeric G-protein, RhoA which in turn activates Rho-associated kinase (ROK). Studies in the rat myometrium have shown that RhoA and ROK are involved in enhancing OT-induced contractions. The potential role of the RhoA/ROK system in uterine contractility at the time of parturition has not been investigated in the human myometrium or in human cell lines. We propose to investigate the role of RhoA/ROK in the human myometrium using molecular cloning techniques. We have constructed expression plasmids for wild type, dominant positive (constitutively active), and dominant negative (constitutively inactive) isoforms of RhoA and synthesized purified proteins using a bacterial (BL21) translation system. These constructs will be introduced into primary and immortalized human myocytes using the protein transduction domain (TAT) derived from the HIV virus, which is capable of introducing whole proteins into mammalian cells. RhoA activation/translocation to the plasma membrane will be visualized using real time confocal microscopy in experiments where the RhoA proteins have been tagged with green fluorescent protein (GFP). Following introduction of the normal and mutant G-proteins, the downstream targets of activated ROK will be assayed for phosphorylation status using near infrared (NIR) fluorescence imaging of western blots or in-cell westerns. These targets include the myosin binding subunit (MBS) of myosin light chain phosphatase (MLCP), and two peptide phosphatase inhibitors of MLCP, CPI-17 and PHI-1. In addition, we propose to measure ROK activity directly using a direct enzyme assay. We will monitor calcium transients using fluorescence microscopy to verify the calcium independence of our measurements. These experiments will determine the role of the RhoA/ROK system in the mechanisms that may determine human uterine contractility. This information may direct new strategies to prevent or treat preterm labour.

The action of catecholamines on guinea-pig taenia coli

1973 ◽  
Vol 265 (867) ◽  
pp. 115-121 ◽  
Keyword(s):  
Smooth Muscles ◽  
Underlying Mechanism ◽  
Taenia Coli ◽  
Cellular Mechanisms ◽  
Membrane Polarization ◽  
Tension Response ◽  
Intracellular Release ◽  
Pump Activity ◽  
Intracellular Ca ◽  
Stimulation Of

Observations of the effects of catecholamines on taenia coli indicate that the α and β actions are exerted on two different enzyme systems both involved in cellular mechanisms which regulate the intracellular Ca 2+ concentration, one by translocation of Ca within the cell and the other by removing Ca out of the cell. The β action reduces the tension response to m em brane excitation, probably by increased Ga uptake at intracellular stores, in all smooth muscles. The α effect is associated with a change in m em brane conductance resulting in hyperpolarization in some, including taenia coli, but depolarization in other smooth muscles. Nevertheless, the underlying mechanism may be the same, i.e. Ca release from intracellular stores and stimulation of Ca extrusion. This hypothesis is based on the assumption that the membrane permeability to K (and hence the membrane polarization and the degree of spontaneous activity) is largely determined by the amount of Ca bound at the inner surface of the plasma membrane. The change in membrane potential and membrane activity produced by the intracellular release of Ca caused by the α-adrenergic action will, therefore, depend on the ratio between the amount of Ca bound at the inside of the cell membrane and the rate of Ca pump activity in individual tissues.

Abstract 279: Mitochondrial Bioenergetic Signaling Drives Myofibroblast Transdifferentiation

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Alyssa A Lombardi ◽  
Ehtesham Arif ◽  
Timothy S Luongo ◽  
John W Elrod
Keyword(s):  
Cardiac Fibrosis ◽  
Contractile Function ◽  
Glycolytic Flux ◽  
Lv Function ◽  
Cellular Mechanisms ◽  
Adult Mice ◽  
Intracellular Ca ◽  
Fibrotic Diseases ◽  
Inducible Gene

When the heart is injured, quiescent fibroblasts differentiate into contractile, synthetic myofibroblasts. Initially fibrosis is reparative, but when chronic it becomes maladaptive and contributes to HF. Intracellular Ca 2+ ( i Ca 2+ ) signaling is reported to be necessary for myofibroblast transdifferentiation yet the role of mitochondrial Ca 2+ ( m Ca 2+ ) exchange has not been explored. The Mcu gene encodes the channel-forming subunit of the m Ca 2+ uniporter channel (MCUc) and is required for acute m Ca 2+ uptake. To examine the contribution of m Ca 2+ in cardiac fibrosis, we generated conditional, fibroblast-specific knockout mice by crossbreeding Mcu fl/fl mice with Col1a2-CreERT mice (Col1a2- Mcu -/- ), permitting tamoxifen-inducible gene deletion in adult mice. Col1a2- Mcu -/- mice and controls were subjected to ligation of the left coronary artery and cardiac function was examined by echocardiography. Loss of fibroblast Mcu worsened LV function and increased fibrosis, as evaluated by Mason’s trichrome staining and qPCR analysis of fibrotic gene expression. To examine the cellular mechanisms responsible for the increased fibrosis we isolated mouse embryonic fibroblasts (MEFs) from Mcu fl/fl mice and deleted Mcu with Cre-adenovirus. When challenged with pro-fibrotic ligands (TGF-β and AngII), Mcu -/- MEFs exhibited decreased m Ca 2+ uptake and enhanced i Ca 2+ transient amplitude. Loss of Mcu promoted myofibroblast transdifferentiation: increased α-SMA expression and contractile function (gel retraction) and decreased migration and proliferation. Mcu -/- MEFs were more glycolytic with increased phosphorylation (inactivation) of pyruvate dehydrogenase. Genetic activation of glycolysis with a Pfk2 mutant in WT MEFs promoted myofibroblast differentiation. Conversely, genetic inhibition of glycolytic flux ablated the increased transdifferentiation observed in Mcu -/- MEFs. Further, TGF-β and AngII altered the expression of regulatory MCUc components in WT MEFs. Our results suggest that alterations in m Ca 2+ uptake and bioenergetic pathways are necessary for myofibroblast transdifferentiation. Thus, energetic signaling represents a novel therapeutic target to impede HF progression and other progressive fibrotic diseases.

mTORC and PKCε in Regulation of Alcohol Use Disorder

2020 ◽  
Vol 20 (17) ◽  
pp. 1696-1708 ◽  
Author(s):  
Athirah Hanim ◽  
Isa Naina Mohamed ◽  
Rashidi M. Pakri Mohamed ◽  
Srijit Das ◽  
Norefrina Shafinaz Md Nor ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Alcohol Intake ◽  
Potential Role ◽  
Synaptic Proteins ◽  
Cellular Mechanisms ◽  
Kinase C ◽  
Protein Kinase C Epsilon ◽  
Seeking Behavior

Alcohol use disorder (AUD) is characterized by compulsive binge alcohol intake, leading to various health and social harms. Protein Kinase C epsilon (PKCε), a specific family of PKC isoenzyme, regulates binge alcohol intake, and potentiates alcohol-related cues. Alcohol via upstream kinases like the mammalian target to rapamycin complex 1 (mTORC1) or 2 (mTORC2), may affect the activities of PKCε or vice versa in AUD. mTORC2 phosphorylates PKCε at hydrophobic and turn motif, and was recently reported to be associated with alcohol-seeking behavior, suggesting the potential role of mTORC2-PKCε interactions in the pathophysiology of AUD. mTORC1 regulates translation of synaptic proteins involved in alcohol-induced plasticity. Hence, in this article, we aimed to review the molecular composition of mTORC1 and mTORC2, drugs targeting PKCε, mTORC1, and mTORC2 in AUD, upstream regulation of mTORC1 and mTORC2 in AUD and downstream cellular mechanisms of mTORCs in the pathogenesis of AUD.

scholarly journals Interactome Analysis of KIN (Kin17) Shows New Functions of This Protein

2021 ◽  
Vol 43 (2) ◽  
pp. 767-781
Author(s):  
Vanessa Pinatto Gaspar ◽  
Anelise Cardoso Ramos ◽  
Philippe Cloutier ◽  
José Renato Pattaro Junior ◽  
Francisco Ferreira Duarte Junior ◽  
...  
Keyword(s):  
Dna Replication ◽  
Protein Interactions ◽  
Ribosome Biogenesis ◽  
Cell Metabolism ◽  
Cell Types ◽  
Protein Protein Interactions ◽  
Cellular Mechanisms ◽  
Cancerous Cell ◽  
First Time

KIN (Kin17) protein is overexpressed in a number of cancerous cell lines, and is therefore considered a possible cancer biomarker. It is a well-conserved protein across eukaryotes and is ubiquitously expressed in all cell types studied, suggesting an important role in the maintenance of basic cellular function which is yet to be well determined. Early studies on KIN suggested that this nuclear protein plays a role in cellular mechanisms such as DNA replication and/or repair; however, its association with chromatin depends on its methylation state. In order to provide a better understanding of the cellular role of this protein, we investigated its interactome by proximity-dependent biotin identification coupled to mass spectrometry (BioID-MS), used for identification of protein–protein interactions. Our analyses detected interaction with a novel set of proteins and reinforced previous observations linking KIN to factors involved in RNA processing, notably pre-mRNA splicing and ribosome biogenesis. However, little evidence supports that this protein is directly coupled to DNA replication and/or repair processes, as previously suggested. Furthermore, a novel interaction was observed with PRMT7 (protein arginine methyltransferase 7) and we demonstrated that KIN is modified by this enzyme. This interactome analysis indicates that KIN is associated with several cell metabolism functions, and shows for the first time an association with ribosome biogenesis, suggesting that KIN is likely a moonlight protein.

scholarly journals Hippocampal Interneurons are Required for Trace Eyeblink Conditioning in Mice

2021 ◽  
Author(s):  
Wei-Wei Zhang ◽  
Rong-Rong Li ◽  
Jie Zhang ◽  
Jie Yan ◽  
Qian-Hui Zhang ◽  
...  
Keyword(s):  
Eyeblink Conditioning ◽  
Pyramidal Cells ◽  
Conditioned Eyeblink ◽  
Cellular Mechanisms ◽  
Sustained Activity ◽  
Early Acquisition ◽  
Freely Moving ◽  
Trace Eyeblink Conditioning

AbstractWhile the hippocampus has been implicated in supporting the association among time-separated events, the underlying cellular mechanisms have not been fully clarified. Here, we combined in vivo multi-channel recording and optogenetics to investigate the activity of hippocampal interneurons in freely-moving mice performing a trace eyeblink conditioning (tEBC) task. We found that the hippocampal interneurons exhibited conditioned stimulus (CS)-evoked sustained activity, which predicted the performance of conditioned eyeblink responses (CRs) in the early acquisition of the tEBC. Consistent with this, greater proportions of hippocampal pyramidal cells showed CS-evoked decreased activity in the early acquisition of the tEBC. Moreover, optogenetic suppression of the sustained activity in hippocampal interneurons severely impaired acquisition of the tEBC. In contrast, suppression of the sustained activity of hippocampal interneurons had no effect on the performance of well-learned CRs. Our findings highlight the role of hippocampal interneurons in the tEBC, and point to a potential cellular mechanism subserving associative learning.

Sign in / Sign up

Export Citation Format

Share Document