Correction to: Dynamic expression of homeostatic ion channels in differentiated cortical astrocytes in vitro

Ovarian cancer (OC) is the deadliest gynecologic cancer, due to late diagnosis, development of platinum resistance, and inadequate alternative therapy. It has been demonstrated that membrane ion channels play important roles in cancer processes, including cell proliferation, apoptosis, motility, and invasion. Here, we review the contribution of ion channels in the development and progression of OC, evaluating their potential in clinical management. Increased expression of voltage-gated and epithelial sodium channels has been detected in OC cells and tissues and shown to be involved in cancer proliferation and invasion. Potassium and calcium channels have been found to play a critical role in the control of cell cycle and in the resistance to apoptosis, promoting tumor growth and recurrence. Overexpression of chloride and transient receptor potential channels was found both in vitro and in vivo, supporting their contribution to OC. Furthermore, ion channels have been shown to influence the sensitivity of OC cells to neoplastic drugs, suggesting a critical role in chemotherapy resistance. The study of ion channels expression and function in OC can improve our understanding of pathophysiology and pave the way for identifying ion channels as potential targets for tumor diagnosis and treatment.

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Synthesis and Evaluation of Novel α-Aminoamides Containing Benzoheterocyclic Moiety for the Treatment of Pain

Molecules ◽

10.3390/molecules26061716 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1716

Author(s):

Kun Tong ◽

Ruotian Zhang ◽

Fengzhi Ren ◽

Tao Zhang ◽

Junlin He ◽

...

Keyword(s):

Ion Channels ◽

Patch Clamp ◽

Formalin Test ◽

Sodium Ion ◽

Inhibitory Potency ◽

Voltage Gated ◽

Patch Clamp Electrophysiology ◽

Sodium Ion Channels

Novel α-aminoamide derivatives containing different benzoheterocyclics moiety were synthesized and evaluated as voltage-gated sodium ion channels blocks the treatment of pain. Compounds 6a, 6e, and 6f containing the benzofuran group displayed more potent in vivo analgesic activity than ralfinamide in both the formalin test and the writhing assay. Interestingly, they also exhibited potent in vitro anti-Nav1.7 and anti-Nav1.8 activity in the patch-clamp electrophysiology assay. Therefore, compounds 6a, 6e, and 6f, which have inhibitory potency for two pain-related Nav targets, could serve as new leads for the development of analgesic medicines.

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The transient receptor potential, TRP4, cation channel is a novel member of the family of calmodulin binding proteins

Biochemical Journal ◽

10.1042/bj3550663 ◽

2001 ◽

Vol 355 (3) ◽

pp. 663-670 ◽

Cited By ~ 62

Author(s):

Claudia TROST ◽

Christiane BERGS ◽

Nina HIMMERKUS ◽

Veit FLOCKERZI

Keyword(s):

Amino Acid ◽

Ion Channels ◽

Transient Receptor Potential ◽

Direct Interaction ◽

Receptor Potential ◽

Amino Acid Residues ◽

Glutathione S Transferase ◽

Calmodulin Binding ◽

Transient Receptor

The mammalian gene products, transient receptor potential (trp)1 to trp7, are related to the Drosophila TRP and TRP-like ion channels, and are candidate proteins underlying agonist-activated Ca2+-permeable ion channels. Recently, the TRP4 protein has been shown to be part of native store-operated Ca2+-permeable channels. These channels, most likely, are composed of other proteins in addition to TRP4. In the present paper we report the direct interaction of TRP4 and calmodulin (CaM) by: (1) retention of in vitro translated TRP4 and of TRP4 protein solubilized from bovine adrenal cortex by CaM–Sepharose in the presence of Ca2+, and (2) TRP4–glutathione S-transferase pull-down experiments. Two domains of TRP4, amino acid residues 688–759 and 786–848, were identified as being able to interact with CaM. The binding of CaM to both domains occurred only in the presence of Ca2+ concentrations above 10µM, with half maximal binding occurring at 16.6µM (domain 1) and 27.9µM Ca2+ (domain 2). Synthetic peptides, encompassing the two putative CaM binding sites within these domains and covering amino acid residues 694–728 and 829–853, interacted directly with dansyl–CaM with apparent Kd values of 94–189nM. These results indicate that TRP4/Ca2+-CaM are parts of a signalling complex involved in agonist-induced Ca2+ entry.

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Dynamic expression of srGAP2 in cell nuclei and cytoplasm during the differentiation of rat neural stem cells in vitro

Molecular Medicine Reports ◽

10.3892/mmr.2016.5795 ◽

2016 ◽

Vol 14 (5) ◽

pp. 4599-4605 ◽

Cited By ~ 2

Author(s):

Qian Jiao ◽

Li Wang ◽

Zhichao Zhang ◽

Yuanyuan Wang ◽

Hanqi Yan ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Nuclei ◽

Dynamic Expression

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Notch1 and Galectin-3 Modulate Cortical Reactive Astrocyte Response After Brain Injury

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.649854 ◽

2021 ◽

Vol 9 ◽

Author(s):

Tais Novaki Ribeiro ◽

Lina Maria Delgado-García ◽

Marimelia A. Porcionatto

Keyword(s):

Brain Injury ◽

Notch Signaling ◽

Nuclear Translocation ◽

Reactive Astrocytes ◽

Reactive Astrocyte ◽

Notch1 Signaling ◽

Cortical Astrocytes ◽

Lesion Core ◽

Galectin 3

After a brain lesion, highly specialized cortical astrocytes react, supporting the closure or replacement of the damaged tissue, but fail to regulate neural plasticity. Growing evidence indicates that repair response leads astrocytes to reprogram, acquiring a partially restricted regenerative phenotype in vivo and neural stem cells (NSC) hallmarks in vitro. However, the molecular factors involved in astrocyte reactivity, the reparative response, and their relation to adult neurogenesis are poorly understood and remain an area of intense investigation in regenerative medicine. In this context, we addressed the role of Notch1 signaling and the effect of Galectin-3 (Gal3) as underlying molecular candidates involved in cortical astrocyte response to injury. Notch signaling is part of a specific neurogenic microenvironment that maintains NSC and neural progenitors, and Gal3 has a preferential spatial distribution across the cortex and has a central role in the proliferative capacity of reactive astrocytes. We report that in vitro scratch-reactivated cortical astrocytes from C57Bl/6J neonatal mice present nuclear Notch1 intracellular domain (NICD1), indicating Notch1 activation. Colocalization analysis revealed a subpopulation of reactive astrocytes at the lesion border with colocalized NICD1/Jagged1 complexes compared with astrocytes located far from the border. Moreover, we found that Gal3 increased intracellularly, in contrast to its extracellular localization in non-reactive astrocytes, and NICD1/Gal3 pattern distribution shifted from diffuse to vesicular upon astrocyte reactivation. In vitro, Gal3–/– reactive astrocytes showed abolished Notch1 signaling at the lesion core. Notch1 receptor, its ligands (Jagged1 and Delta-like1), and Hes5 target gene were upregulated in C57Bl/6J reactive astrocytes, but not in Gal3–/– reactive astrocytes. Finally, we report that Gal3–/– mice submitted to a traumatic brain injury model in the somatosensory cortex presented a disrupted response characterized by the reduced number of GFAP reactive astrocytes, with smaller cell body perimeter and decreased NICD1 presence at the lesion core. These results suggest that Gal3 might be essential to the proper activation of Notch signaling, facilitating the cleavage of Notch1 and nuclear translocation of NICD1 into the nucleus of reactive cortical astrocytes. Additionally, we hypothesize that reactive astrocyte response could be dependent on Notch1/Jagged1-Hes5 signaling activation following brain injury.

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Smooth muscle cell-specific TMEM16A deletion does not alter Ca2+ signaling, uterine contraction, gestation length, or litter size in mice†

Biology of Reproduction ◽

10.1093/biolre/ioz096 ◽

2019 ◽

Vol 101 (2) ◽

pp. 318-327 ◽

Cited By ~ 1

Author(s):

Mingzi Qu ◽

Ping Lu ◽

Karl Bellve ◽

Kevin Fogarty ◽

Lawrence Lifshitz ◽

...

Keyword(s):

Smooth Muscle ◽

Ion Channels ◽

Smooth Muscle Cell ◽

Litter Size ◽

Muscle Cell ◽

Uterine Contraction ◽

Gestation Length ◽

Specific Marker ◽

Myometrial Cells

Abstract Ion channels in myometrial cells play critical roles in spontaneous and agonist-induced uterine contraction during the menstrual cycle, pregnancy maintenance, and parturition; thus, identifying the genes of ion channels in these cells and determining their roles are essential to understanding the biology of reproduction. Previous studies with in vitro functional and pharmacological approaches have produced controversial results regarding the presence and role of TMEM16A Ca2+-activated Cl− channels in myometrial cells. To unambiguously determine the function of this channel in these cells, we employed a genetic approach by using smooth muscle cell-specific TMEM16A deletion (i.e. TMEM16ASMKO) mice. We found that myometrial cells from TMEM16ASMKO mice generated the same pattern and magnitude in Ca2+ signals upon stimulation with KCl, oxytocin, and PGF2α compared to the isogenic control myometrial cells. At the uterine tissue level, TMEM16A deletion also did not cause detectable changes in either spontaneous or agonist (i.e. KCl, oxytocin, and PGF2α)-induced contractions. Moreover, in vivo the TMEM16ASMKO mice gave birth at full term with the same litter size as genetically identical control mice. Finally, TMEM16A immunostaining in both control and TMEM16ASMKO mice revealed that this protein was highly expressed in the endometrial stroma, but did not co-localize with a smooth muscle specific marker MYH11. Collectively, these results unequivocally demonstrate that TMEM16A does not serve as a pacemaking channel for spontaneous uterine contraction, neither does it function as a depolarizing channel for agonist-evoked uterine contraction. Yet these two functions could underlie the normal gestation length and litter size in the TMEM16ASMKO mice.

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Sensing through Non-Sensing Ocular Ion Channels

International Journal of Molecular Sciences ◽

10.3390/ijms21186925 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6925

Author(s):

Meha Kabra ◽

Bikash Ranjan Pattnaik

Keyword(s):

Ion Channels ◽

Visual Processing ◽

Signal Transmission ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Cone Dystrophy ◽

Wide Range ◽

The Impact

Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. In the eye, ion channels are involved in various physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to an array of blindness, termed ocular channelopathies. These mutations result in either a loss- or gain-of channel functions affecting the structure, assembly, trafficking, and localization of channel proteins. A dominant-negative effect is caused in a few channels formed by the assembly of several subunits that exist as homo- or heteromeric proteins. Here, we review the role of different mutations in switching a “sensing” ion channel to “non-sensing,” leading to ocular channelopathies like Leber’s congenital amaurosis 16 (LCA16), cone dystrophy, congenital stationary night blindness (CSNB), achromatopsia, bestrophinopathies, retinitis pigmentosa, etc. We also discuss the various in vitro and in vivo disease models available to investigate the impact of mutations on channel properties, to dissect the disease mechanism, and understand the pathophysiology. Innovating the potential pharmacological and therapeutic approaches and their efficient delivery to the eye for reversing a “non-sensing” channel to “sensing” would be life-changing.

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Developmental axon regrowth and primary neuron sprouting utilize distinct actin elongation factors

The Journal of Cell Biology ◽

10.1083/jcb.201903181 ◽

2020 ◽

Vol 219 (5) ◽

Cited By ~ 2

Author(s):

Shiri P. Yaniv ◽

Hagar Meltzer ◽

Idan Alyagor ◽

Oren Schuldiner

Keyword(s):

Neurite Growth ◽

Growth Potential ◽

Neuronal Regeneration ◽

Cell Type ◽

Elongation Factors ◽

Dynamic Expression ◽

Unique System

Intrinsic neurite growth potential is a key determinant of neuronal regeneration efficiency following injury. The stereotypical remodeling of Drosophila γ-neurons includes developmental regrowth of pruned axons to form adult specific connections, thereby offering a unique system to uncover growth potential regulators. Motivated by the dynamic expression in remodeling γ-neurons, we focus here on the role of actin elongation factors as potential regulators of developmental axon regrowth. We found that regrowth in vivo requires the actin elongation factors Ena and profilin, but not the formins that are expressed in γ-neurons. In contrast, primary γ-neuron sprouting in vitro requires profilin and the formin DAAM, but not Ena. Furthermore, we demonstrate that DAAM can compensate for the loss of Ena in vivo. Similarly, DAAM mutants express invariably high levels of Ena in vitro. Thus, we show that different linear actin elongation factors function in distinct contexts even within the same cell type and that they can partially compensate for each other.

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Gadolinium and mechanotransduction of rat aortic baroreceptors

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.262.5.h1415 ◽

1992 ◽

Vol 262 (5) ◽

pp. H1415-H1421 ◽

Cited By ~ 6

Author(s):

M. C. Andresen ◽

M. Yang

Keyword(s):

Ion Channels ◽

Direct Effects ◽

Cellular Mechanisms ◽

Pressure Discharge ◽

Ethanesulfonic Acid ◽

Discharge Pressure ◽

Aortic Baroreceptors ◽

Stretch Activated Channels ◽

Stretch Activated Ion Channels

The cellular mechanisms enabling baroreceptors to transduce wall distortion into axonal discharge are unknown but might involve stretch-activated ion channels. Gadolinium (Gd3+, 10 microM) blocks stretch-activated channels in several preparations. Here we tested Gd3+ effects on discharge responses of 15 single-fiber baroreceptors in vitro. We simultaneously measured discharge, pressure, and aortic diameter at Gd3+ concentrations from 0.001 to 400 microM. High levels of Gd3+ added to a bicarbonate-buffered perfusate (Krebs) slightly shifted the pressure-discharge relation (less than 4 mmHg, n = 3, P = 0.01) without affecting slope or discharge frequency at threshold. Gd3+ in Krebs variably altered the pressure-diameter relation. Because 500 microM Gd3+ produced visible precipitate in Krebs, we tested Gd3+ in a simpler perfusate using N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). Gd3+ in HEPES (n = 10) induced minor, but statistically significant, average increases in threshold (less than +5-7%) and no changes in gain. However, prolonged HEPES exposure alone (n = 2) produced similar shifts. Electron microscopy verified that Gd3+ diffused from the lumen to reach extracellular locations near baroreceptor endings. We conclude that 1) HEPES perfusate alone reversibly depresses baroreceptor discharge and 2) Gd3+ has no direct effects on baroreceptors. Thus it appears that aortic baroreceptor mechanotransduction must utilize a different class of stretch-activated ion channels.

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Monocarboxylic acid transporters, MCT1 and MCT2, in cortical astrocytes in vitro and in vivo

AJP Cell Physiology ◽

10.1152/ajpcell.2000.278.5.c921 ◽

2000 ◽

Vol 278 (5) ◽

pp. C921-C930 ◽

Cited By ~ 82

Author(s):

Rekha Hanu ◽

Mary McKenna ◽

Andrea O'Neill ◽

Wendy G. Resneck ◽

Robert J. Bloch

Keyword(s):

Monocarboxylic Acid ◽

Primary Cultures ◽

Cortical Astrocytes ◽

Immunofluorescence Studies ◽

Double Label ◽

Low Levels ◽

The Brain ◽

Astrocytic Endfeet

We used sequence-specific antibodies to characterize two monocarboxylic acid transporters, MCT1 and MCT2, in astrocytes. Both proteins are expressed in primary cultures of cortical astrocytes, as indicated by immunoblotting and immunofluorescence. Both MCT1 and MCT2 are present in small, punctate structures in the cytoplasm and at the cell membrane. Cells showing very low levels of labeling for glial fibrillary acidic protein (GFAP) also label more dimly for MCT2, but not for MCT1. In vivo, double-label immunofluorescence studies coupled with confocal microscopy indicate that MCT1 and MCT2 are rare in astrocytes in the cortex. However, they are specifically labeled in astrocytes of the glial limiting membrane and in white matter tracts. Both transporters are also present in the microvasculature. Comparison of labeling for MCT1 and MCT2 with markers of the blood-brain barrier shows that the transporters are not always limited to the astrocytic endfeet in vivo. Our results suggest that the level of expression of monocarboxylic acid transporters MCT1 and MCT2 by cortical astrocytes in vivo is significantly lower than in vitro but that astrocytes in some other regions of the brain can express one or both proteins in significant amounts.

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