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Fulltext Unearthing the role of septins in viral infections

Khairat JE, Hatta MNA, Abdullah N, Azman AS, Calvin SYM, Syed Hassan S

Biosci Rep, 2024 Mar 29;44(3).
PMID: 38372298 DOI: 10.1042/BSR20231827

Septin proteins are a subfamily of closely related GTP-binding proteins conserved in all species except for higher plants and perform essential biological processes. Septins self-assemble into heptameric or octameric complexes and form higher-order structures such as filaments, rings, or gauzes by end-to-end binding. Their close association with cell membrane components makes them central in regulating critical cellular processes. Due to their organisation and properties, septins function as diffusion barriers and are integral in providing scaffolding to support the membrane's curvature and stability of its components. Septins are also involved in vesicle transport and exocytosis through the plasma membrane by co-localising with exocyst protein complexes. Recently, there have been emerging reports of several human and animal diseases linked to septins and abnormalities in their functions. Most of our understanding of the significance of septins during microbial diseases mainly pertains to their roles in bacterial infections but not viruses. This present review focuses on the known roles of septins in host-viral interactions as detailed by various studies.

Matched MeSH terms: Cytoskeleton/metabolism
Thermal noise due to surface-charge effects within the Debye layer of endogenous structures in dendrites

Poznanski RR

Phys Rev E Stat Nonlin Soft Matter Phys, 2010 Feb;81(2 Pt 1):021902.
PMID: 20365590

An assumption commonly used in cable theory is revised by taking into account electrical amplification due to intracellular capacitive effects in passive dendritic cables. A generalized cable equation for a cylindrical volume representation of a dendritic segment is derived from Maxwell's equations under assumptions: (i) the electric-field polarization is restricted longitudinally along the cable length; (ii) extracellular isopotentiality; (iii) quasielectrostatic conditions; and (iv) homogeneous medium with constant conductivity and permittivity. The generalized cable equation is identical to Barenblatt's equation arising in the theory of infiltration in fissured strata with a known analytical solution expressed in terms of a definite integral involving a modified Bessel function and the solution to a linear one-dimensional classical cable equation. Its solution is used to determine the impact of thermal noise on voltage attenuation with distance at any particular time. A regular perturbation expansion for the membrane potential about the linear one-dimensional classical cable equation solution is derived in terms of a Green's function in order to describe the dynamics of free charge within the Debye layer of endogenous structures in passive dendritic cables. The asymptotic value of the first perturbative term is explicitly evaluated for small values of time to predict how the slowly fluctuating (in submillisecond range) electric field attributed to intracellular capacitive effects alters the amplitude of the membrane potential. It was found that capacitive effects are almost negligible for cables with electrotonic lengths L>0.5 , contributes up to 10% of the signal for cables with electrotonic lengths in the range between 0.25

Matched MeSH terms: Cytoskeleton/metabolism; Cytoskeleton/chemistry
Orbital fluid shear stress promotes osteoblast metabolism, proliferation and alkaline phosphates activity in vitro

Aisha MD, Nor-Ashikin MN, Sharaniza AB, Nawawi H, Froemming GR

Exp Cell Res, 2015 Sep 10;337(1):87-93.
PMID: 26163894 DOI: 10.1016/j.yexcr.2015.07.002

Prolonged disuse of the musculoskeletal system is associated with reduced mechanical loading and lack of anabolic stimulus. As a form of mechanical signal, the multidirectional orbital fluid shear stress transmits anabolic signal to bone forming cells in promoting cell differentiation, metabolism and proliferation. Signals are channeled through the cytoskeleton framework, directly modifying gene and protein expression. For that reason, we aimed to study the organization of Normal Human Osteoblast (NHOst) cytoskeleton with regards to orbital fluid shear (OFS) stress. Of special interest were the consequences of cytoskeletal reorganization on NHOst metabolism, proliferation, and osteogenic functional markers. Cells stimulated at 250 RPM in a shaking incubator resulted in the rearrangement of actin and tubulin fibers after 72 h. Orbital shear stress increased NHOst mitochondrial metabolism and proliferation, simultaneously preventing apoptosis. The ratio of RANKL/OPG was reduced, suggesting that orbital shear stress has the potential to inhibit osteoclastogenesis and osteoclast activity. Increase in ALP activity and OCN protein production suggests that stimulation retained osteoblast function. Shear stress possibly generated through actin seemed to hold an anabolic response as osteoblast metabolism and functional markers were enhanced. We hypothesize that by applying orbital shear stress with suitable magnitude and duration as a non-drug anabolic treatment can help improve bone regeneration in prolonged disuse cases.

Matched MeSH terms: Cytoskeleton/metabolism; Cytoskeleton/ultrastructure
Fulltext Piezoresistive effects in controllable defective HFTCVD graphene-based flexible pressure sensor

Mohammad Haniff MA, Muhammad Hafiz S, Wahid KA, Endut Z, Wah Lee H, Bien DC, et al.

Sci Rep, 2015;5:14751.
PMID: 26423893 DOI: 10.1038/srep14751

In this work, the piezoresistive effects of defective graphene used on a flexible pressure sensor are demonstrated. The graphene used was deposited at substrate temperatures of 750, 850 and 1000 °C using the hot-filament thermal chemical vapor deposition method in which the resultant graphene had different defect densities. Incorporation of the graphene as the sensing materials in sensor device showed that a linear variation in the resistance change with the applied gas pressure was obtained in the range of 0 to 50 kPa. The deposition temperature of the graphene deposited on copper foil using this technique was shown to be capable of tuning the sensitivity of the flexible graphene-based pressure sensor. We found that the sensor performance is strongly dominated by the defect density in the graphene, where graphene with the highest defect density deposited at 750 °C exhibited an almost four-fold sensitivity as compared to that deposited at 1000 °C. This effect is believed to have been contributed by the scattering of charge carriers in the graphene networks through various forms such as from the defects in the graphene lattice itself, tunneling between graphene islands, and tunneling between defect-like structures.

Matched MeSH terms: Cytoskeleton
Potentiality of MWCNT on 3D-printed bio-inspired spherical-roof cubic core under quasi-static loading

Ma Q, Rejab MRM, Hassan SA, Hu H, Kumar AP

J Mech Behav Biomed Mater, 2022 Dec;136:105514.
PMID: 36215770 DOI: 10.1016/j.jmbbm.2022.105514

Sandwich panel is increasingly used as lightweight energy absorbing components, which provides excellent crashworthiness performance with the three-dimensional periodic core. This paper investigates 3D-printed bio-inspired spherical-roof cubic cores with multi-walled carbon nanotubes (MWCNT) and foam-filled cores under quasi-static loading. The proposed bio-inspired spherical-roof cubic cores with 1.5 mm wall thickness were manufactured using the fused filament fabrication process, which used 70% polylactic acid (PLA) and 30% carbon fiber filament. Moreover, four groups of 3D-printed bio-inspired spherical-roof cubic cores were compared and analyzed on compressive properties and failure behavior. Experimental results were shown that foam-filled double bio-inspired spherical-roof cubic core with MWCNT was the maximum Fpeak with 1.92 kN, which provided a much more stable plateau load and better energy-absorbing characteristics. In addition, it is conducted that a double bio-inspired spherical-roof cubic core with four notches core is considered as the potential energy-absorbing core.

Matched MeSH terms: Cytoskeleton
Fulltext Interaction between Flavivirus and Cytoskeleton during Virus Replication

Foo KY, Chee HY

Biomed Res Int, 2015;2015:427814.
PMID: 26347881 DOI: 10.1155/2015/427814

Flaviviruses are potentially human pathogens that cause major epidemics worldwide. Flavivirus interacts with host cell factors to form a favourable virus replication site. Cell cytoskeletons have been observed to have close contact with flaviviruses, which expands the understanding of cytoskeleton functions during virus replication, although many detailed mechanisms are still unclear. The interactions between the virus and host cytoskeletons such as actin filaments, microtubules, and intermediate filaments have provided insight into molecular alterations during the virus infection, such as viral entry, in-cell transport, scaffold assembly, and egress. This review article focuses on the utilization of cytoskeleton by Flavivirus and the respective functions during virus replication.

Matched MeSH terms: Cytoskeleton/metabolism*
Simulium hiroyukii, a new species of the subgenus Gomphostilbia (Diptera: Simuliidae) from Mount Murud, Sarawak, Malaysia

Ya'cob Z, Takaoka H, Sofian-Azirun M

Zootaxa, 2015;3911(3):424-32.
PMID: 25661622 DOI: 10.11646/zootaxa.3911.3.8

Simulium (Gomphostilbia) hiroyukii is described based on females, males, pupae and larvae collected in Mount Murud, Sarawak, Malaysia. This new species is assigned to the Simulium darjeelingense species-group of the subgenus Gomphostilbia, and is characterized by the darkened fore coxae and the pupal gill with eight long filaments, of which middle and dorsal triplets have elongated primary and secondary stalks, respectively.

Matched MeSH terms: Cytoskeleton
Investigation of the links between heterocyst and biohydrogen production by diazotrophic cyanobacterium A. variabilis ATCC 29413

Salleh SF, Kamaruddin A, Uzir MH, Karim KA, Mohamed AR

Arch Microbiol, 2016 Mar;198(2):101-13.
PMID: 26521065 DOI: 10.1007/s00203-015-1164-6

This work investigates the effect of heterocyst toward biohydrogen production by A. variabilis. The heterocyst frequency was artificially promoted by adding an amino acid analog, in this case DL-7-azatryptophan into the growth medium. The frequency of heterocyst differentiation was found to be proportional to the concentration of azatryptophan (0-25 µM) in the medium. Conversely, the growth and nitrogenase activity were gradually suppressed. In addition, there was also a distinct shortening of the cells filaments and detachment of heterocyst from the vegetative cells. Analysis on the hydrogen production performance revealed that both the frequency and distribution of heterocyst in the filaments affected the rate of hydrogen production. The highest hydrogen production rate and yield (41 µmol H2 mg chl a(-1) h(-1) and 97 mL H2 mg chl a(-1), respectively) were achieved by cells previously grown in 15 µM of azatryptophan with 14.5 % of heterocyst frequency. The existence of more isolated heterocyst has been shown to cause a relative loss in nitrogenase activity thus lowering the hydrogen production rate.

Matched MeSH terms: Cytoskeleton
Mechano-cytoskeleton remodeling mechanism and molecular docking studies on nanosurface technology: Titania nanotube arrays

Mydin RBSMN, Mahboob A, Sreekantan S, Saharudin KA, Qazem EQ, Hazan R, et al.

Biotechnol Appl Biochem, 2023 Jun;70(3):1072-1084.
PMID: 36567620 DOI: 10.1002/bab.2421

In biomedical implant technology, nanosurface such as titania nanotube arrays (TNA) could provide better cellular adaptation, especially for long-term tissue acceptance response. Mechanotransduction activities of TNA nanosurface could involve the cytoskeleton remodeling mechanism. However, there is no clear insight into TNA mechano-cytoskeleton remodeling activities, especially computational approaches. Epithelial cells have played critical interface between biomedical implant surface and tissue acceptance, particularly for long-term interaction. Therefore, this study investigates genomic responses that are responsible for cell-TNA mechano-stimulus using epithelial cells model. Findings suggested that cell-TNA interaction may improve structural and extracellular matrix (ECM) support on the cells as an adaptive response toward the nanosurface topography. More specifically, the surface topography of the TNA might improve the cell polarity and adhesion properties via the interaction of the plasma membrane and intracellular matrix responses. TNA nanosurface might engross the cytoskeleton remodeling activities for multidirectional cell movement and cellular protrusions on TNA nanosurface. These observations are supported by the molecular docking profiles that determine proteins' in silico binding mechanism on TNA. This active cell-surface revamping would allow cells to adapt to develop a protective barrier toward TNA nanosurface, thus enhancing biocompatibility properties distinctly for long-term interaction. The findings from this study will be beneficial toward nano-molecular knowledge of designing functional nanosurface technology for advanced medical implant applications.

Matched MeSH terms: Cytoskeleton
Improvement of early cell adhesion on Thai silk fibroin surface by low energy plasma

Amornsudthiwat P, Mongkolnavin R, Kanokpanont S, Panpranot J, Wong CS, Damrongsakkul S

Colloids Surf B Biointerfaces, 2013 Nov 1;111:579-86.
PMID: 23893032 DOI: 10.1016/j.colsurfb.2013.07.009

Low energy plasma has been introduced to treat the surface of Thai silk fibroin which should be enhanced for cell adhesion due to its native hydrophobic surface. Plasma surface treatment could introduce desirable hydrophilic functionalities on the surface without using any chemicals. In this work, nitrogen glow discharge plasma was generated by a low energy AC50Hz power supply system. The plasma operating conditions were optimized to reach the highest nitrogen active species by using optical emission spectroscopy. X-ray photoelectron spectroscopy (XPS) revealed that amine, hydroxyl, ether, and carboxyl groups were induced on Thai silk fibroin surface after plasma treatment. The results on Fourier transform infrared attenuated total reflection (FTIR-ATR) spectroscopy confirmed that the plasma treated effects were only on the outermost layer since there was no change in the bulk chemistry. The surface topography was insignificantly changed from the detection with atomic force microscopy (AFM). The plasma-treated effects were the improved surface wettability and cell adhesion. After a 90-s treatment, the water contact angle was at 20°, while the untreated surface was at 70°. The early cell adhesion of L929 mouse fibroblast was accelerated. L929 cells only took 3h to reach 100% cell adhesion on 90 s N2 plasma-treated surface, while there was less than 50% cell adhesion on the untreated Thai silk fibroin surface after 6h of culture. The cell adhesion results were in agreement with the cytoskeleton development. L929 F-actin was more evident on 90 s N2 plasma-treated surface than others. It could be concluded that a lower energy AC50Hz plasma system enhanced early L929 mouse fibroblast adhesion on Thai silk fibroin surface without any significant change in surface topography and bulk chemistry.

Matched MeSH terms: Cytoskeleton/drug effects; Cytoskeleton/metabolism
Fulltext Ultrastructural Study on the Antibacterial Activity of Artonin E versus Streptomycin against Staphylococcus aureus Strains

Zajmi A, Mohd Hashim N, Noordin MI, Khalifa SA, Ramli F, Mohd Ali H, et al.

PLoS One, 2015;10(6):e0128157.
PMID: 26030925 DOI: 10.1371/journal.pone.0128157

Staphylococci are facultative anaerobes, perfectly spherical un-encapsulated cocci, with a diameter not exceeding 1 micrometer in diameter. Staphylococcus aureus are generally harmless and remain confined to the skin unless they burrow deep into the body, causing life-threatening infections in bones, joints, bloodstream, heart valves and lungs. Among the 20 medically important staphylococci species, Staphylococcus aureus is one of the emerging human pathogens. Streptomycin had its highest potency against Staphylococcus infections despite the likelihood of getting a resistant type of staphylococcus strains. Methicillin-resistant S. aureus (MRSA) is the persister type of Staphylococcus aureus and was evolved after decades of antibiotic misuse. Inadequate penetration of the antibiotic is one of the principal factors related to success/failure of the therapy. The active drug needs to reach the bacteria at concentrations necessary to kill or suppress the pathogen's growth. In turn the effectiveness of the treatment relied on the physical properties of Staphylococcus aureus. Thus understanding the cell integrity, shape and roughness is crucial to the overall influence of the therapeutic agent on S. aureus of different origins. Hence our experiments were designed to clarify ultrastructural changes of S. aureus treated with streptomycin (synthetic compound) in comparison to artonin E (natural compound). In addition to the standard in vitro microbial techniques, we used transmission electron microscopy to study the disrupted cell architecture under antibacterial regimen and we correlate this with scanning electron microscopy (SEM) to compare results of both techniques.

Matched MeSH terms: Cytoskeleton/drug effects; Cytoskeleton/ultrastructure
Fulltext In vitro treatment of lipopolysaccharide increases invasion of Pasteurella multocida serotype B:2 into bovine aortic endothelial cells

Yap SK, Zakaria Z, Othman SS, Omar AR

J Vet Sci, 2018 Mar 31;19(2):207-215.
PMID: 28693312 DOI: 10.4142/jvs.2018.19.2.207

Pasteurella multocida serotype B:2 causes hemorrhagic septicemia in cattle and buffalo. The invasion mechanism of the bacterium when invading the bloodstream is unclear. This study aimed to characterize the effects of immunomodulatory molecules, namely dexamethasone and lipopolysaccharide, on the invasion efficiency of P. multocida serotype B:2 toward bovine aortic endothelial cells (BAECs) and the involvement of actin microfilaments in the invasion mechanism. The results imply that treatment of BAECs with lipopolysaccharide at 100 ng/mL for 24 h significantly increases the intracellular bacteria number per cell (p ＜ 0.01) compared with those in untreated and dexamethasone-treated cells. The lipopolysaccharide-treated cells showed a significant decrease in F-actin expression and an increase in G-actin expression (p ＜ 0.001), indicating actin depolymerization of BAECs. However, no significant differences were detected in the invasion efficiency and actin filament reorganization between the dexamethasone-treated and untreated cells. Transmission electron microscopy showed that P. multocida B:2 resided in a vacuolar compartment of dexamethasone-treated and untreated cells, whereas the bacteria resided in cellular membrane of lipopolysaccharide-treated cells. The results suggest that lipopolysaccharide destabilizes the actin filaments of BAECs, which could facilitate the invasion of P. multocida B:2 into BAECs.

Matched MeSH terms: Actin Cytoskeleton/drug effects; Actin Cytoskeleton/microbiology
Simulium ledangense, a new species of the Simulium feuerborni species-group of the subgenus Nevermannia (Diptera: Simuliidae) from Mount Ledang, Peninsular Malaysia

Ya'cob Z, Takaoka H, Sofian-Azirun M

Zootaxa, 2014;3881(3):228-36.
PMID: 25543632 DOI: 10.11646/zootaxa.3881.3.2

Simulium (Nevermannia) ledangense sp. nov. is described from females, males, pupae and mature larvae from Peninsular Malaysia. This new species is assigned to the Simulium feuerborni species-group of the subgenus Nevermannia, and is characterized by the pupa having a very long stalk of the ventral paired gill filaments, which is almost five times longer than the interspiracular trunk and female tergites of segments 2 and 5 to 7 shiny. Taxonomic notes are given to distinguish this new species from three known species of the S. feuerborni species-group from Malaysia.

Matched MeSH terms: Cytoskeleton
A new species of the Simulium (Simulium) variegatum species-group (Diptera: Simuliidae) from Thailand

Takaoka H, Srisuka W, Saeung A

Acta Trop, 2019 Mar;191:155-161.
PMID: 30611713 DOI: 10.1016/j.actatropica.2019.01.002

A new species of black fly, Simulium (Simulium) luculentum, is described from specimens collected in Thailand, and is assigned to the Simulium variegatum species-group of the subgenus Simulium Latreille. This new species is distinguished from most members of this species group in the female by the mid femur and tibia entirely yellowish; and in the pupa by the gill with six filaments, which are somewhat inflated basally. This species represents the fifth member of the S. variegatum species-group recorded from Thailand.

Matched MeSH terms: Cytoskeleton
Fulltext Microtubular Dysfunction and Male Infertility

Gunes S, Sengupta P, Henkel R, Alguraigari A, Sinigaglia MM, Kayal M, et al.

World J Mens Health, 2020 Jan;38(1):9-23.
PMID: 30350487 DOI: 10.5534/wjmh.180066

Microtubules are the prime component of the cytoskeleton along with microfilaments. Being vital for organelle transport and cellular divisions during spermatogenesis and sperm motility process, microtubules ascertain functional capacity of sperm. Also, microtubule based structures such as axoneme and manchette are crucial for sperm head and tail formation. This review (a) presents a concise, yet detailed structural overview of the microtubules, (b) analyses the role of microtubule structures in various male reproductive functions, and (c) presents the association of microtubular dysfunctions with male infertility. Considering the immense importance of microtubule structures in the formation and maintenance of physiological functions of sperm cells, this review serves as a scientific trigger in stimulating further male infertility research in this direction.

Matched MeSH terms: Actin Cytoskeleton
Fulltext The role of reactive oxygen species in pressure-dependent myogenic tone

Satirah Zainalabidin, Coats, Paul, Wadsworth, Roger M.

Jurnal Sains Kesihatan Malaysia, 2012;10(1):1-11.
MyJurnal

Myogenic tone is the response of the vascular smooth muscle to an increase in intraluminal pressure with vasoconstriction and with vasodilation when the pressure is decreased. Such myogenic tone contributes a level of physiological basal tone in response to neurohumoral stimuli. In spite of myogenic tone discovery by Sir William Bayliss 100 years ago, questions still remain regarding the underlying signaling mechanism of the myogenic response. Studies have shown that increased intraluminal pressure or wall tension leads to membrane depolarization, voltage-operated calcium channel (VOCC), stretch-activated cation (SAC) channels, extracelullar matrix (ECM) and actin cytoskeleton. Recently, evidence has shown a potential role for reactive oxygen species (ROS) as a key signalling mediator in the genesis of myogenic tone. The identification of the primary mechanosensors in the initiation of pressure-dependent myogenic tone is essential as these components could be potential therapeutical targets in the future.

Matched MeSH terms: Actin Cytoskeleton
Fulltext Alteration of cell cytoskeleton and functions of cell recovery of normal human osteoblast cells caused by factors associated with real space flight

Kapitonova MY, Salim N, Othman S, Muhd Kamauzaman TM, Ali AM, Nawawi HM, et al.

Malays J Pathol, 2013 Dec;35(2):153-63.
PMID: 24362479 MyJurnal

Experiments involving short-term space flight have shown an adverse effect on the physiology, morphology and functions of cells investigated. The causes for this effect on cells are: microgravity, temperature fluctuations, mechanical stress, hypergravity, nutrient restriction and others. However, the extent to which these adverse effects can be repaired by short-term space flown cells when recultured in conditions of normal gravity remains unclear. Therefore this study aimed to investigate the effect of short-term spaceflight on cytoskeleton distribution and recovery of cell functions of normal human osteoblast cells. The ultrastructure was evaluated using ESEM. Fluorescent staining was done using Hoechst, Mito Tracker CMXRos and Tubulin Tracker Green for cytoskeleton. Gene expression of cell functions was quantified using qPCR. As a result, recovered cells did not show any apoptotic markers when compared with control. Tubulin volume density (p<0.001) was decreased significantly when compared to control, while mitochondria volume density was insignificantly elevated. Gene expression for IL-6 (p<0.05) and sVCAM-1 (p<0.001) was significantly decreased while alkaline phosphatase (p<0.001), osteocalcin and sICAM (p<0.05) were significantly increased in the recovered cells compared to the control ones. The changes in gene and protein expression of collagen 1A, osteonectin, osteoprotegerin and beta-actin, caused by short-term spaceflight, were statistically not significant. These data indicate that short term space flight causes morphological changes in osteoblast cells which are consistent with hypertrophy, reduced cell differentiation and increased release of monocyte attracting proteins. The long-term effect of these changes on bone density and remodeling requires more detailed studies.

Matched MeSH terms: Cytoskeleton/ultrastructure*
Asiaticoside Inhibits TNF-α-Induced Endothelial Hyperpermeability of Human Aortic Endothelial Cells

Fong LY, Ng CT, Zakaria ZA, Baharuldin MT, Arifah AK, Hakim MN, et al.

Phytother Res, 2015 Oct;29(10):1501-8.
PMID: 26171791 DOI: 10.1002/ptr.5404

The increase in endothelial permeability often promotes edema formation in various pathological conditions. Tumor necrosis factor-alpha (TNF-α), a pro-atherogenic cytokine, impairs endothelial barrier function and causes endothelial dysfunction in early stage of atherosclerosis. Asiaticoside, one of the triterpenoids derived from Centella asiatica, is known to possess antiinflammatory activity. In order to examine the role of asiaticoside in preserving the endothelial barrier, we assessed its effects on endothelial hyperpermeability and disruption of actin filaments evoked by TNF-α in human aortic endothelial cells (HAEC). TNF-α caused an increase in endothelial permeability to fluorescein isothiocyanate (FITC)-dextran. Asiaticoside pretreatment significantly suppressed TNF-α-induced increased permeability. Asiaticoside also prevented TNF-α-induced actin redistribution by suppressing stress fiber formation. However, the increased F to G actin ratio stimulated by TNF-α was not changed by asiaticoside. Cytochalasin D, an actin depolymerizing agent, was used to correlate the anti-hyperpermeability effect of asiaticoside with actin cytoskeleton. Surprisingly, asiaticoside failed to prevent cytochalasin D-induced increased permeability. These results suggest that asiaticoside protects against the disruption of endothelial barrier and actin rearrangement triggered by TNF-α without a significant change in total actin pool. However, asiaticoside seems to work by other mechanisms to maintain the integrity of endothelial barrier rather than stabilizing the F-actin organization.

Matched MeSH terms: Actin Cytoskeleton/drug effects
Fulltext Contribution of Coiled-Coil Assembly to Ca2+/Calmodulin-Dependent Inactivation of TRPC6 Channel and its Impacts on FSGS-Associated Phenotypes

Polat OK, Uno M, Maruyama T, Tran HN, Imamura K, Wong CF, et al.

J Am Soc Nephrol, 2019 09;30(9):1587-1603.
PMID: 31266820 DOI: 10.1681/ASN.2018070756

BACKGROUND: TRPC6 is a nonselective cation channel, and mutations of this gene are associated with FSGS. These mutations are associated with TRPC6 current amplitude amplification and/or delay of the channel inactivation (gain-of-function phenotype). However, the mechanism of the gain-of-function in TRPC6 activity has not yet been clearly solved.
METHODS: We performed electrophysiologic, biochemical, and biophysical experiments to elucidate the molecular mechanism underlying calmodulin (CaM)-mediated Ca2+-dependent inactivation (CDI) of TRPC6. To address the pathophysiologic contribution of CDI, we assessed the actin filament organization in cultured mouse podocytes.
RESULTS: Both lobes of CaM helped induce CDI. Moreover, CaM binding to the TRPC6 CaM-binding domain (CBD) was Ca2+-dependent and exhibited a 1:2 (CaM/CBD) stoichiometry. The TRPC6 coiled-coil assembly, which brought two CBDs into adequate proximity, was essential for CDI. Deletion of the coiled-coil slowed CDI of TRPC6, indicating that the coiled-coil assembly configures both lobes of CaM binding on two CBDs to induce normal CDI. The FSGS-associated TRPC6 mutations within the coiled-coil severely delayed CDI and often increased TRPC6 current amplitudes. In cultured mouse podocytes, FSGS-associated channels and CaM mutations led to sustained Ca2+ elevations and a disorganized cytoskeleton.
CONCLUSIONS: The gain-of-function mechanism found in FSGS-causing mutations in TRPC6 can be explained by impairments of the CDI, caused by disruptions of TRPC's coiled-coil assembly which is essential for CaM binding. The resulting excess Ca2+ may contribute to structural damage in the podocytes.

Matched MeSH terms: Cytoskeleton/ultrastructure*
Effects of Nicotine and Tocotrienol-Rich Fraction Supplementation on Cytoskeletal Structures of Murine Pre-Implantation Embryos

Hamirah NK, Kamsani YS, Mohamed Nor Khan NA, Ab Rahim S, Rajikin MH

Med Sci Monit Basic Res, 2017 Dec 08;23:373-379.
PMID: 29217815

BACKGROUND Cytoskeletal structures, in particular actin and tubulin, provide a fundamental framework in all cells, including embryos. The objective of this study was to evaluate the effects of nicotine, which is a source of oxidative stress, and subsequent supplementation with Tocotrienol-rich fraction (TRF) on actin and tubulin of 2- and 8-cell murine embryos. MATERIAL AND METHODS Thirty female Balb/C mice were divided into 4 groups: Group 1 received: subcutaneous (sc) injection of 0.9% NaCl; Group 2 received sc injection of 3.0 nicotine mg/kg bw/day; Group 3 received 3.0 sc injection of nicotine mg/kg bw/day +60 mg/kg bw/day TRF; and Group 4 received 60 sc injection of TRF mg/kg bw/day for 7 consecutive days. The animals were superovulated with 5 IU PMSG followed by 5 IU hCG 48 h later. Animals were cohabited with fertile males overnight and euthanized through cervical dislocation at 24 h post coitum. Embryos at the 2- and 8-cell stages were harvested, fixed, and stained to visualize actin and tubulin distributions by using CLSM. RESULTS Results showed that at 2-cell stage, actin intensities were significantly reduced in the nicotine group compared to that of the control group (p<0.001). In Group 3, the intensity of actin significantly increased compared to that of the nicotine group (p<0.001). At 8-cell stage, actin intensity of the nicotine group was significantly lower than that of the control group (p<0.001). The intensities of actin in Group 3 were increased compared to that of nicotine treatment alone (p<0.001). The same trend was seen in tubulin at 2- and 8-cell stages. Interestingly, both actin and tubulin structures in the TRF-treated groups were enhanced compared to the control. CONCLUSIONS This study suggests that TRF prevents the deleterious effects of nicotine on the cytoskeletal structures of 2- and 8-cell stages of pre-implantation mice embryos in vitro.

Matched MeSH terms: Cytoskeleton/drug effects*

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