Microfilaments form tracks for the activity of myosin and serve together intracellular “muscles” for maintenance of cabinet shape, movement, and also contractility.

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From: Ten Cate's oral Histology (Eighth Edition), 2013

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James M. Crawford, ... Prodromos Hytiroglou, in Macsween's Pathology the the Liver (Seventh Edition), 2018

Microfilaments

Microfilaments room double-stranded molecules of polymerized fibrous (F) actin; the monomeric form of the protein is globular (G) actin; and these two develops exist in equilibrium in the cell. The microfilaments are present in majority and type a three-dimensional (3D) intracellular meshwork. Over there is considerable intracellular binding and cross-linking with various other intracellular proteins, such as myosin, lamin and also spectrin. The filaments are greatly located at the cabinet periphery; they attach to the plasma membrane and extend into microvilli. They are particularly concentrated in the pericanalicular zone, developing a pericanalicular web,177 and attach come the junctional complexes which border the canaliculus. 4 main functions are postulated because that the contractile microfilaments the the hepatocyte: (1) translocation that intracellular vesicles implicated in bile secretion, especially by insertion and also removal the canalicular plasma membrane transport proteins; (2) coordinated contraction, creating peristaltic activity in the canaliculus;178 (3) with microtubules, transmembrane control over the topography that intrinsic proteins in the phospholipid bilayer of the cabinet membrane, for this reason influencing the protein mosaic and functional differentiation that a particular membrane domain;179 and (4) feasible modulation of the structure and tightness that the ‘tight junction’, therefore regulating the permeability of the paracellular pathway.180,181 The sensible roles for microfilaments involve cell membrane motility, endo- and exocytosis, secretion and vesicle transfer.


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Elaine M. Keohane, in Rodak's Hematology (Sixth Edition), 2020

Microfilaments and also intermediate filaments

Actin microfilaments are double-stranded, linked solid structures approximately 5 come 7 nm in diameter. They associate with myosin to enable cell motility, contraction, and intracellular transport. They find near the nucleus and also assist in cell division. They additionally locate near the plasma membrane and administer cytoskeletal support.

Intermediate filaments, through a diameter of around 8 come 10 nm, self-assemble into larger bundles.2 They room the many durable facet of the cytoskeleton and carry out structural stability for the cells, specifically those subjected to more physical stress, such together the epidermal class of skin.1 Examples encompass the keratins and also lamins.


Steven G. Thomas, in Platelets (Fourth Edition), 2019

The Actin Cytoskeleton in relaxing Platelets

Actin microfilaments (referred to as filamentous actin or F-actin) room polymers the the actin monomer (globular actin or G-actin) which, like tubulin dimers, polymerize in a head-to-tail manner. However, in contrast to microtubules, actin filaments room thin versatile fibers of around 7 nm in diameter. Actin filaments are dynamic, polarized frameworks with unique ends that differ in your affinities because that ATP tied actin (known together plus and also minus ends). The plus and also minus ends of actin filament are periodically referred to as the barbed and pointed ends, respectively, v this nomenclature arising from patterns seen in electron microscopy research studies of actin filaments bound come myosin head domains.147 A huge number that actin-binding proteins have been established which manage actin filament assembly and function in cells, and Table 3.2 highlights those which have actually been determined in platelets.

There are six genes encoding different isoforms that the actin monomer protein (3 α-, 1 β-, and 2 γ-actin genes). α-Actin is expressed specifically in muscle cells, with β- and γ-actin being the develops expressed in nonmuscle cells, and also it has been shown that platelets save β-actin and also γ1-actin in a proportion of 5:1 at the protein level.148,149 The actin isoforms are highly conserved and also differ by just a couple of amino acids, mostly at the N-terminus.150 The definition of these differences in between isoforms has been the evaluation elsewhere,151 however in platelets, back it has actually been suggested that annexin V binding preferentially come γ-actin in activated platelets, that is unclear whether β- and also γ-actin behave differently.


Platelets contain roughly 2 million copies of the actin monomer every platelet, making it the most abundant platelet protein at a concentration of roughly 0.55 mM (around 15% of complete platelet protein).152,153 In a resting platelet about 40% that the actin is polymerized into between 2000 and also 5000 actin filaments. A relationship of this actin filaments are associated with the spectrin membrane skeleton (see section “The Spectrin Membrane Skeleton in relaxing Platelets”); however, a large proportion form the cytoplasmic actin network (Fig. 3.6). Over 98% of this filaments have their barbed ends capped by the capping protein capZ and adducin i m sorry are numerous in platelets and also bind to barbed ends through nanomolar affinity.54,128,154,155 A large number the the pointed ends of these actin filaments are capped by the Arp2/3 complex; Arp2/3 is current at about 2 μM in platelets, with about 30% being linked with the cytoskeleton.57,58 as the Arp2/3 complicated is able to nucleate brand-new filaments native the next of currently filaments,130 it is likely that that is important for the development of the resting platelet cytoplasm actin network as well as protecting filaments native depolymerization. In enhancement to the barbed and pointed end binding proteins, the network of actin filaments is crosslinked via a variety of actin-binding proteins. This duty is performed mainly by filamin (FLN) and α-actinin in platelets, together both protein are highly expressed.53



Fig. 3.6. Cytoskeletal organization of the resting platelet. (A) Electron micrograph of a platelet treated with Taxol prior to detergent extraction showing the microtubules (T) in ~ the periphery of the disc and also a meshwork the actin filaments (MF) transparent the platelet. An amorphous class of submembrane filaments (SMF) is visible wherein the plasma membrane would certainly be discovered in the undamaged cell (magnification × 22,000). (B) diverted microtubule coil and the actin cytoskeleton in a resting platelet that has had actually its membrane skeleton gotten rid of (magnification × 22,000). Dashboard A courtesy that Jim White. Dashboard B courtesy the Alice Pollitt and John Hartwig.


FLN is a homodimer that creates a versatile “V” shape, through the vertex gift the association site in between the two FLN molecules and the end of the “V” comprise actin binding regions. Thus, FLN can form a versatile bridge in between two adjacent actin filaments.71 However, FLN can likewise bind to a wide variety of companion proteins, which as such links the actin cytoskeleton to signaling molecules, receptors, kinases, and also phosphatases.71,129,156 In the paper definition of the resting platelet, FLN forms vital interactions through the cytoplasmic tails that GPIbα and also β-integrins,157–161 i beg your pardon play crucial functions in the linking that the platelet surface to the basic actin network and also brings FLN binding partner close come the plasma membrane. Thus, these linkages may be necessary for the adhesion of GPIb-IX-V to VWF and capture that platelets at high shear.162 α-actinin is an antiparallel homodimer that forms a brief rod-shaped molecule through actin binding areas at either end giving that the capacity to cross link actin filaments.163 In contrast to FLN, α-actinin reasons the actin filaments to be bundled much closer together and also is less flexible.


The duty of the resting platelet actin cytoskeleton is because of this mainly to provide structural support for the platelet together it travels approximately the circulation and also is subjected to a range of shear forces. The meshwork the filaments gives a procession onto i beg your pardon organelles and other structural materials can attach164 and furthermore, v its relations with the spectrin membrane skeleton and surface receptor can aid to manage interactions that the platelet during record from flow. This is shown in FLN knockout mouse models, which screen aberrant platelet duty downstream the GPIb-IX-V and the integrin GPIIb-IIIa165,166 and also in both human and mouse platelets lacking the GPIbα receptor, which have a phenotype that membrane deformability consistent with a loss of actin-membrane linkage.162,167 Recently, patients with macrothrombocytopenia due to mutations in the α-actinin-1 gene have been reported, yet they have a low bleeding propensity and no details tests the cytoskeletal function were carry out in this platelets.168–171 as α-actinin majority actin really differently than does FLN, the is not likely that the 2 proteins would give rise come a similar phenotype, yet it would certainly be interesting to establish the role of α-actinin in resting platelet structure. A number of other actin-binding proteins have been shown to be crucial for platelet production and also platelet activation (e.g., Ref. 172), yet their role, if any, in the maintain of resting platelet framework is uncertain. Fig. 3.7 shows a schematic that the organization of the three cytoskeletons in the resting platelet.



Duncan de Souza, ... Victor C. Baum, in Smith's Anesthesia because that Infants and also Children (Eighth Edition), 2011

Cytoskeleton

An intracellular building of microtubules and also microfilaments web links the contractile elements, T-tubules, sarcolemma, mitochondria, and also nucleus. This scaffolding organizes the subcellular components that take part in cabinet signaling and enables transmission that the pressure of contraction to be used to the myocyte. Mutations in number of of these have the right to be responsible for number of familial cardiomyopathic conditions. The cytoskeleton not just undergoes change with myocardial development, but microfilaments also play a function in the adaptive solution to mechanical loading of the love (Small et al., 1992; valve der Loop et al., 1995; Schroder et al., 2002). One of the most necessary roles of the cytoskeleton is to link the thick filaments. Titin, the biggest protein in the human, extends from the Z-disc to the M-line that the sarcomere. It both set the special filament and has a spring-like role that identify passive tension. Titin isoforms room under developmental regulation, v fetal myocardium having the much more compliant N2BA isoform, which is then changed with the stiffer isoforms. The counter of isoforms is varieties dependent, but it correlates through the shift from the more compliant fetal myocardial cells (when studied gotten rid of from the neighboring matrix) to the less compliant cell of the adult.


AOIFE P. BOYD, male R. CORNELIS, in ethics of bacter Pathogenesis, 2001

1. YOPE

YopE root cause disruption the the actin microfilament framework of the host cell <181>. The organize cell rounds up and detaches from the extracellular matrix, a phenomenon referred to as cytotoxicity <148, 193>. Actin is responsible for preserving the form of cells, and disruption that actin therefore leads come cellular amorphism and the round off up. Together the actin is linked to surface-located moving adhesion factors, there would additionally be subsequent detachment of cells. The actin disruption contributes come the capability of Yersinia to resist phagocytosis <181, 194>. The yes, really enzyme activity and the target of YopE within the eukaryotic bio cell continue to be to it is in identified. In enhancement to YopE, three other Yops have a cytotoxic impact on cultured epithelial cells, namely, YopH, YopO, and also YopT (see further).


Frederick R. Singer, in Endocrinology (Sixth Edition), 2010

SLOW VIRUS INFECTION

The presence of osteoclast nuclear and cytoplasmic microfilaments basically identical in framework to nucleocapsids that the Paramyxoviridae virus family initially argued the opportunity that Paget's disease was led to by a sluggish virus infection.21,22 succeeding immunochemical studies24,25 and sequence analysis of nucleocapsid transcripts26-28 have added support come the hypothesis, although no all studies have been confident for a famous presence.113,114

The many compelling evidence to assistance a viral duty in Paget's disease comes from research studies in transgenic mice in i m sorry bone histology usual of the condition was induced through inserting the measles virus nucleocapsid gene right into precursor cell of the osteoclast lineage.115 In a separate study of transgenic mice, insertion of a mutated murine SQSTM1 gene right into the endogenous mouse SQSTM1 gene raised the osteoclastogenic potential of the bone microenvironment however produced no histologic evidence of Paget's disease.116

The findings of clinical studies combined with those of recent studies designed to construct an pet model that Paget's disease continue to assistance the viral theory of Paget's disease. Integration of genetic and viral interactions may develop a greater understanding the the reasons of the disease.


Magdalini Sachana, ... Alan J. Hargreaves, in Reproductive and also Developmental Toxicology (Second Edition), 2017

Cytoskeleton

The cytoskeleton is a complicated interconnected protein filamentous meshwork, consisting of three distinctive interconnected arrays of microtubules (MTs), microfilaments (MFs), and intermediate filaments (IFs). That plays a an essential role in a selection of developmentally important phenomena in the nervous system, consisting of the regulation that mitosis, cell differentiation, cabinet migration, and also neurite outgrowth (Hargreaves, 1997; Bezanilla et al., 2015). These roles, in turn, room dependent ~ above the regulation that the truth of the cytoskeleton. MTs and also MFs are developed by the polymerization that tubulin dimers or actin monomers in a nucleotide-dependent fashion (Hargreaves, 1997; Bezanilla et al., 2015). In mammalian cells, MTs exhibition a property well-known as dynamic instability, by which some MT subpopulations may rapidly shrink, whereas rather undergo fast growth, preserving a consistent polymer mass (Mitchison and also Kirschner, 1988). GTP binding is forced for MT assembly; that hydrolysis to GDP occurs soon after incorporation of tubulin dimers and the cultivation ends that MTs space stabilized by a “cap” of tubulin subunits v nonhydrolyzed GTP (Carlier et al., 1984). MF assembly and also dynamics, ~ above the other hand, are dependent ~ above the binding and also hydrolysis that ATP, respectively (Gungabissoon and also Bamburg, 2003).

In neural development, MTs, MFs, and their connected functions space modulated by interactions through a variety of accessory protein that can stabilize, destabilize, act together motor proteins, or connect MTs and also MFs to other cytoskeletal elements and membranes. Developmentally crucial MT-associated protein (MAPs) encompass MAP 1b, MAP 2, tau, and stathmin, which stabilize development cones, dendritic and axonal MTs in arising neurons or increase MT dynamics by upregulating GTP hydrolysis at the GTP cap, dong (Kosik and Finch, 1987; Mack et al., 2000; Ohkawa et al., 2007). The binding the MAPs to MTs is regulated by miscellaneous protein kinases consisting of MT affinity regulation kinases (MARKs) and calmodulin kinase (Biernat et al., 2002; Ohkawa et al., 2007). The engine proteins kinesin and also dynein additionally play vital roles in the regulation the MT-dependent phenomena, including development of the mitotic spindle, chromosome alignment/segregation, intracellular transport (e.g., axonal transport), and neurite outgrowth (Schliwa and Woehlke, 2003). As the duties of MTs are dependent on the correct regulation of MT dynamics and MAP interactions, neurotoxins the interfere through this procedure might it is in potential developmental toxins.

Of the actin-binding proteins, cofilin is of details neurodevelopmental importance as that regulates actin dynamics in the development cone of arising neurites, the binding of i m sorry is blocked as soon as phosphorylated by the neurodevelopmentally crucial LIM kinase and Slingshot phosphatase (Endo et al., 2003). The dynamic nature of MFs are closely regulated transparent neural development, enabling them to perform key developmental functions such as the formation of the contractile ring at the end of mitosis, the regulation of cabinet migration and growth cone advance.


IFs room biochemically much much more stable than MTs and also MFs. Therefore they pat a more structural or supportive role. However, prefer MTs and MFs they are modulated to some level by your phosphorylation state (Omary et al., 2006). IFs certain to the nervous mechanism include:

Glial fibrillary acidic protein (GFAP) and peripherin, i beg your pardon are found mainly in astrocytes and peripheral neurons, respectively.

Neurofilaments (NFs), which comprise a triplet that polypeptides known as the neurofilament hefty (NFH; 200 kDa), tool (NFM; 120–150 kDa), and light (NFL; 70 kDa) chains, i beg your pardon are discovered in many neurons and enriched in axons.


In summary, the complexity and developmental prestige of the cytoskeleton renders it a most likely target for DNTs. Indeed, in vitro toxicity research studies have shown that a range of cytoskeletal proteins might be target by DNTs. This can occur in a number of ways, which room summarized in Table 15.2. The remainder of this section will emphasis on cytoskeletal targets identified in cellular research studies of neural cell differentiation.


Table 15.2. Means in which Developmental Neurotoxins deserve to Target the Cytoskeleton


TargetCharacteristics of toxicity Agent
Core protein1.

Agents that may bind directly to the polymer-forming subunit and also interfere through dynamics, integrity, or assembly the the network

2.

Agents that affect the expression that nerve-specific cytoskeletal core proteins, such together β-type III tubulin, GFAP, and NFs

3.

Agents that have the capability to modulate the cytoskeleton via disruption of Ca2+ homeostasis

Cytoskeleton-associated proteinsAgents that impact the protein level and/or gene expression of regulatory proteins such as MAPs and ABPs
Phosphorylation standing of cytoskeletal proteinsAgents that influence the activities of kinases that modulate the binding that regulatory proteins and/or main point proteins
Free SH groupsAgents the block
*
SH groups directly or induce your oxidation indirectly

ABP, actin binding protein; GFAP, glial fibrillary acidic protein; MAP, microtubule-associated protein; NF, neurofilament.


Heavy Metals

Reduced phosphorylation state of actin depolymerizing factor/cofilin, yet no change in the level of total cofilin or actin, was demonstrated in proteomic researches of distinguishing primary cultures of computer mouse CGCs exposed come subcytotoxic level of MeHg chloride (Vendrell et al., 2010). This would potentially an outcome in magnified binding that cofilin come actin and also increased MF dynamics.

Various research studies on mitotic tumor cabinet lines and purified MTs argued that MeHg was capable of disrupting the MT network and preventing MT assembly, dong (Vogel et al., 1985; Miura et al., 1999). Making use of in vitro breakthrough assays, MT disruption was found in cultured cell induced to differentiate into a neuronal phenotype (Graff et al., 1997) and the immunological detection of neuron-specific β-tubulin was used to show the disruption the MTs and reduced numbers of neurons in MeHg-treated NSCs (Tamm et al., 2006).

Studies v organic command compounds have likewise shown disruption that the MT network utilizing polymerization assays v purified MTs and also in vitro cellular models, arguing a direct interaction that disrupts the assembly and/or distribution of MTs (Zimmermann et al., 1985a). Zimmermann et al. (1985b) additionally found the triethyl lead had a straight effect on purified NFs and also disrupted NFs in cultured cells, return no such effect has yet been reported for MeHg. Furthermore, these authors detect no apparent effect ~ above the MF network (Zimmermann et al., 1985a), suggesting that the two heavy metals may have some differences in your cytoskeletal toxicity.

It is recognized that plenty of heavy metals are qualified of disrupting the cytoskeleton in nonneural cultured cell (Chou, 1989), although not all of them have actually been experiment in arising neural cell models. However, the demonstration that exposure to sublethal levels of arsenic inhibits the outgrowth that neurites by differentiating PC12 and also N2a cells and also that this involves upregulation the the mRNA levels for NFM and NFL however downregulation of those because that tubulin and also tau in the latter, argues that cytoskeletal organization is a most likely target because that this toxin in occurring neurons (Frankel et al., 2009; Aung et al., 2013).

In a additional report the was additionally suggested the measurement the the levels of mRNA matching to specific cytoskeletal proteins could be a an extremely sensitive an approach for detecting exposure to neurodevelopmentally toxic metals using in vitro models (Hogberg et al., 2010). However, it should be borne in mind that a detectable (or lack of) impact using this strategy may not necessarily reflect the same readjust at the protein level and is unable to demonstrate changes due come posttranslational changes such together proteolytic degradation and phosphorylation.

Organic Solvents

Solvents such together ethanol and toluene have additionally been shown to disrupt cytoskeletal proteins in cultured neural cells. For example, MF disassembly was displayed to be affiliated in the capability of ethanol come inhibit NMDA receptor activity in major neural cultures (Popp and Dertien, 2008). Toluene is likewise known come disrupt NMDA receptor task but a similar effect on MFs has not yet been demonstrated (Bale et al., 2007). On the various other hand, the improvement of neurite outgrowth in distinguishing PC12 cell by chronic ethanol exposure was connected with enhanced MT polymerization, return the specific mechanism continues to be unknown (Reiter-Funk and Dohrman, 2005). In a research with cultured computer mouse embryo cells, the ability of toluene come inhibit astrocyte differentiation was demonstrated by reduced GFAP expression following chronic exposure come environmentally relevant levels that solvent (Yamaguchi et al., 2002). By contrast, ethanol exposure was discovered to boost GFAP expression in cultured differentiating NSCs, consistent with amplified differentiation/proliferation the astrocytes under the problems tested (Tateno et al., 2005).

Pesticides

Exposure of separating neuronal and/or glial cell to sublethal neurite inhibitory concentrations of the organophosphorothioate pesticide DZN and CPF has been displayed to impact the level of cytoskeletal proteins. In ~ a molecular level, exposure to DZN and also CPF had actually no impact on MT organization or the levels of tubulin, but did reason reduced reactivity the antibodies with MAP1B and NFH, in addition to NFH aggregation in the cell body (Sachana et al., 2001, 2005; Flaskos et al., 2007). Furthermore, return DZN had actually no impact on the levels of actin detect on western blots, it induced upregulation that the actin binding protein cofilin, which regulates MF dynamics in the advancing expansion cone (Harris et al., 2009). The levels of phosphorylated cofilin (p-cofilin) detected immunologically were additionally upregulated but to a considerably lower degree than complete cofilin, suggesting a reduction in the overall level that cofilin phosphorylation and increased MF dynamics under these speculative conditions. That is no yet known whether CPF induces the exact same effects. The neurite inhibitory impacts of CPF on separating C6 glioma cell were associated with lessened levels of MAP1B but not MAP 2c (transiently expressed throughout early development) or tubulin (Sachana et al., 2008).

However, research studies of the results of the acutely toxic (in regards to acetylcholinesterase activity inhibition) oxon metabolites that DZN and CPF (DZO and also CPO, respectively) top top C6 cell differentiation imply that both agents inhibit astrocyte differentiation, as established by diminished levels the the astrocyte mite GFAP (Sidiropoulou et al., 2009b). In both cases, impaired neurite outgrowth was connected with decreased levels the antibody reactivity through α-tubulin and MAP1B, arguing reduced synthetic and/or increased deterioration of these MT protein (Sachana et al., 2008; Sidiropoulou et al., 2009b). In contrast, the level of MAP 2c in CPO- (Sachana et al., 2008) and DZO- (Sidiropoulou et al., 2009b) cure cells were not considerably affected. The validity the the neural cytoskeleton as a target because that CPF and also CPO was more strengthened through the demonstration of a direct binding communication of both compounds with tubulin and also by their capacity to inhibit MT assembly and also to interfere v kinesin-dependent MT motility assays in vitro (Gearhart et al., 2007; Prendergast et al., 2007). In separating N2a cells, neurite inhibitory concentration of DZO had actually no result on total tubulin or NFH levels however did induce a reduction in the level of MAP1B and the neuron-specific βIII-tubulin isoform, together with increased phosphorylation that NFH (Sidiropoulou et al., 2009a; Sachana et al., 2014). ~ above the various other hand, exposure of separating N2a cell to CPO was connected with diminished levels that NFH however with the remaining NFH had actually a greater phosphorylation state 보다 the control; GAP-43 protein level were also reduced (Flaskos et al., 2011). These data suggest that, return cytoskeletal transforms may represent good biomarkers of impact in to move models that development, chemically associated compounds may affect these proteins in different ways in a path concomitant v their potency as a developmental toxin.

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Polychlorinated Biphenyls

Few studies have been released showing straight effects of PCBs top top the neural cytoskeleton utilizing in vitro models. However, the capacity of sublethal concentration of numerous PCBs to (1) inhibit differentiation, induce cellular hypertrophy, and impair the development of contractile filaments in a separating skeletal muscle myocyte cell heat (Coletti et al., 2001), (2) perturb calcium homeostasis in cultured rat CGCs (Kodavanti et al., 1993), and also (3) promote neurite outgrowth in distinguishing PC12 cells (Angus and Contreras, 1994) suggest underlying molecular effects on cytoskeletal targets. A research of the impacts of PCBs top top the proteome that primary societies of CGCs revealed a number of congener-specific alterations in the level of cytoskeletal protein (Brunelli et al., 2012). For example, 13 days' exposure come 1 μM PCB180 led to approximately threefold palliation in the level of actin-related protein 2/3 (ARP2/3) and a threefold rise in MAP2, contrasted with untreated control cells. The very same study uncovered an roughly 12-fold increase and a 1.5-fold to decrease in the level of α-actinin 1 and α-internexin, respectively, complying with exposure come 0.1 μM PCB138. These alters could reflect the disruption of various cytoskeleton-mediated events affiliated in the expansion and advancement of neurites.