Signaling in Muscle Contraction

Kuo, Ivana Y.; Ehrlich, Barbara E.

doi:10.1101/cshperspect.a006023

Cited by 286 publications

(242 citation statements)

References 61 publications

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“…Previous studies have demonstrated that imiquimod induces rises in [Ca 2ϩ ] i in sensory neurons (24), and PC12 and F11 cell lines (20), with the latter study highlighting a role for the inositol triphosphate (IP 3 ) receptor activation in this process. Contractions by histamine and carbachol, both of which were reversed by imiquimod, primarily rely on IP 3 signaling and release of ERderived Ca 2ϩ to induce contraction (25). Imiquimod may disrupt this pathway either through binding to and blocking the IP 3 receptor (19), or emptying of ER pools, as demonstrated in this study.…”

Section: Discussionmentioning

confidence: 90%

The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation

Larsson

Manson

Starkhammar

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Their recently reported ability to rapidly relax airways has further increased their interest in the treatment of pulmonary disease. However, the mechanisms behind this effect are not fully understood. The present study, therefore, aimed to determine whether airway smooth muscle (ASM)-dependent mechanisms could be identified. TLR7 agonists were added to guinea pig airways following precontraction with carbachol in vitro or histamine in vivo. Pharmacological inhibitors were used to dissect conventional pathways of bronchodilation; tetrodotoxin was used or bilateral vagotomy was performed to assess neuronal involvement. Human ASM cells (HASMCs) were employed to determine the effect of TLR7 agonists on intracellular Ca 2ϩ ([Ca 2ϩ ]i) mobilization. The well-established TLR7 agonist imiquimod rapidly relaxed precontracted airways in vitro and in vivo. This relaxation was demonstrated to be independent of nitric oxide, carbon monoxide, and cAMP signaling, as well as neuronal activity. A limited role for prostanoids could be detected. Imiquimod induced [Ca 2ϩ ]i release from endoplasmic reticulum stores in HASMCs, inhibiting histamine-induced [Ca 2ϩ ]i. The TLR7 antagonist IRS661 failed to inhibit relaxation, and the structurally dissimilar agonist CL264 did not relax airways or inhibit [Ca 2ϩ ]i. This study shows that imiquimod acts directly on ASM to induce bronchorelaxation, via a TLR7-independent release of [Ca 2ϩ ]i. The effect is paralleled by other bronchorelaxant compounds, like chloroquine, which, like imiquimod, but unlike CL264, contains the chemical structure quinoline. Compounds with quinoline moieties may be of interest in the development of multifunctional drugs to treat pulmonary disease. asthma; bronchodilation; imiquimod; quinoline; toll-like receptor 7

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Section: Discussionmentioning

confidence: 90%

The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation

Larsson

Manson

Starkhammar

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Increased intracellular free Ca 2+ concentration ([Ca 2+ ] i ) is essential for the activity of Nox5,18, 19, 20 as evidenced in cell‐culture studies where ROS are not synthesized in Ca 2+ ‐free buffer or from cells with truncation of the N‐terminal region of Nox5 21. This is of particular significance in vascular smooth muscle cells (VSMCs), given that increased [Ca 2+ ] i is the major trigger for vascular contraction 22, 23. Nox5 is expressed in all vascular cell types, including endothelial cells, VSMCs, and perivascular adventitial fibroblast,12, 14, 24 and plays a role in angiotensin II (Ang II)‐ and endothelin‐1 (ET‐1)‐mediated redox signaling 25.…”

mentioning

confidence: 99%

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

Montezano

Camargo

Persson

et al. 2018

JAHA

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BackgroundNADPH Oxidase 5 (Nox5) is a calcium‐sensitive superoxide‐generating Nox. It is present in lower forms and higher mammals, but not in rodents. Nox5 is expressed in vascular cells, but the functional significance remains elusive. Given that contraction is controlled by calcium and reactive oxygen species, both associated with Nox5, we questioned the role of Nox5 in pro‐contractile signaling and vascular function.Methods and ResultsTransgenic mice expressing human Nox5 in a vascular smooth muscle cell–specific manner (Nox5 mice) and Rhodnius prolixus, an arthropod model that expresses Nox5 endogenoulsy, were studied. Reactive oxygen species generation was increased systemically and in the vasculature and heart in Nox5 mice. In Nox5‐expressing mice, agonist‐induced vasoconstriction was exaggerated and endothelium‐dependent vasorelaxation was impaired. Vascular structural and mechanical properties were not influenced by Nox5. Vascular contractile responses in Nox5 mice were normalized by N‐acetylcysteine and inhibitors of calcium channels, calmodulin, and endoplasmic reticulum ryanodine receptors, but not by GKT137831 (Nox1/4 inhibitor). At the cellular level, vascular changes in Nox5 mice were associated with increased vascular smooth muscle cell [Ca2+]i, increased reactive oxygen species and nitrotyrosine levels, and hyperphosphorylation of pro‐contractile signaling molecules MLC20 (myosin light chain 20) and MYPT1 (myosin phosphatase target subunit 1). Blood pressure was similar in wild‐type and Nox5 mice. Nox5 did not amplify angiotensin II effects. In R. prolixus, gastrointestinal smooth muscle contraction was blunted by Nox5 silencing, but not by VAS2870 (Nox1/2/4 inhibitor).ConclusionsNox5 is a pro‐contractile Nox isoform important in redox‐sensitive contraction. This involves calcium‐calmodulin and endoplasmic reticulum–regulated mechanisms. Our findings define a novel function for vascular Nox5, linking calcium and reactive oxygen species to the pro‐contractile molecular machinery in vascular smooth muscle cells.

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“…However, there are no studies to support the association of smaller genes with skin development. The categorization on the basis of published work has its advantages, but there is often overlapping of functions within these categories, for example, calcium signalling also happens in the muscle [84] and immune system [85], Wnt signalling pathway also has a role in cancer [86], TGF-beta signalling pathway can also be associated with the immune system [87], among others. In spite of this, our findings lead us to believe there is a disparity in gene sizes for genes that have a role or are present in tissues with very little to almost no development pos-natally (like neuron) and genes (not involved in housekeeping) that are quite frequently expressed during a human’s whole lifetime (like in skin development and immune response) or involved in providing functions with fast responses.…”

Section: Discussionmentioning

confidence: 99%

Gene size matters: What determines gene length in the human genome?

Lopes

Altab

Raina

et al. 2020

Preprint

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While it is expected for gene length to be influenced by factors such as intron number and evolutionary conservation, we have yet to fully understand the connection between gene length and function in the human genome.In this study, we show that, as expected, there is a strong positive correlation between gene length and the number of SNPs, introns and protein size. Amongst tissue specific genes, we find that the longest genes are expressed in blood vessels, nerve, thyroid, cervix uteri and brain, while the smallest genes are expressed within the pancreas, skin, stomach, vagina and testis. We report, as shown previously, that natural selection suppresses changes for genes with longer lengths and promotes changes for smaller genes. We also observed that longer genes have a significantly higher number of co-expressed genes and protein-protein interactions. In the functional analysis, we show that bigger genes are often associated with neuronal development, while smaller genes tend to play roles in skin development and in the immune system. Furthermore, pathways related to cancer, neurons and heart diseases tend to have longer genes, with smaller genes being present in pathways related to immune response and neurodegenerative diseases.We hypothesise that longer genes tend to be associated with functions that are important early in life, while smaller genes play a role in functions that are important throughout the organisms’ whole life, like the immune system which require fast responses.Author SummaryEven though the human genome has been fully sequenced, we still do not fully grasp all of its nuances. One such nuance is the length of the genes themselves. Why are certain genes longer than others? Is there a common function shared by longer/smaller genes? What exactly makes gene longer? We tried answering these questions using a variety of analysis. We found that, while there was not a particular strong factor in genes that influenced their size, there could be an influence of several gene characteristics in determining the length of a gene. We also found that longer genes are linked with the development of neurons, cancer, heart diseases and muscle cells, while smaller genes seem to be mostly related with the immune system and the development of the skin. This led us to believe that, whether the gene has an important function early in our life, or throughout our whole lives, or even if the function requires a rapid response, that its gene size will be influenced accordingly.

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Signaling in Muscle Contraction

Cited by 286 publications

References 61 publications

The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation

The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

Gene size matters: What determines gene length in the human genome?

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