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Hisanao Izumi, Yasuharu Shinoda, Takashi Saito, Takaomi Saido, Keita Sato, Yasushi Yabuki, Yotaro Matsumoto, Yoshitomi Kanemitsu, Yoshihisa Tomioka, Nona Abolhassani, Yusaku Nakabeppu, Kohji Fukunaga
Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of elderly dementia in the world. At present, acetylcholine inhibitors, such as donepezil, galantamine and rivastigmine, are used for AD therapy, but the therapeutic efficacy is limited. We recently proposed T-type voltage gated Ca2+ channels (T-VGCCs) enhancer as a new therapeutic candidate for AD. In the current study, we confirmed the pharmacokinetics of SAK3 in the plasma and brain of mice using ultra performance liquid chromatography-tandem mass spectrometry...
March 3, 2018: Neuroscience
Aleksi Suo, Allison Childers, Adrijana D'Silva, Lars F Petersen, Shannon Otsuka, Michelle Dean, Haocheng Li, Emeka K Enwere, Brant Pohorelic, Alexander Klimowicz, Ivana A Souza, Jawed Hamid, Gerald W Zamponi, DGwyn Bebb
Introduction: Voltage-gated calcium channels (VGCC) have been found to be differentially expressed in several different tumor types, but their role in tumor growth, malignant invasion, metastases and impact on clinical outcomes has not been clarified. Materials and Methods: From a cohort database of 193 patients with early-stage NSCLC, 163 formalin-fixed paraffin-embedded specimens were available for analysis to construct tissue microarrays. Cav3.1 protein expression was detected using fluorescence immunohistochemistry, and quantified using automated image acquisition and analysis...
February 2, 2018: Oncotarget
Jens Ingwersen, Lorenzo De Santi, Britta Wingerath, Jonas Graf, Barbara Koop, Reiner Schneider, Christina Hecker, Friederike Schröter, Mary Bayer, Anna Dorothee Engelke, Michael Dietrich, Philipp Albrecht, Hans-Peter Hartung, Pasquale Annunziata, Orhan Aktas, Tim Prozorovski
Multiple sclerosis (MS) is characterized by inflammatory neurodegeneration, with axonal injury and neuronal cell death occurring in parallel to demyelination. Regarding the molecular mechanisms responsible for demyelination and axonopathy, energy failure, aberrant expression of ion channels and excitotoxicity have been suggested to lead to Ca2+ overload and subsequent activation of calcium-dependent damage pathways. Thus, the inhibition of Ca2+ influx by pharmacological modulation of Ca2+ channels may represent a novel neuroprotective strategy in the treatment of secondary axonopathy...
February 23, 2018: Journal of Neurochemistry
David von der Ahe, Petra Huehnchen, Mustafa Balkaya, Sarah Peruzzaro, Matthias Endres, Wolfgang Boehmerle
Suramin is a trypan blue analogon originally developed to treat protozoan infections, which was found to have diverse antitumor effects. One of the most severe side effects in clinical trials was the development of a peripheral sensory-motor polyneuropathy. In this study, we aimed to investigate suramin-induced neuropathy with a focus on calcium (Ca2+) homeostasis as a potential pathomechanism. Adult C57Bl/6 mice treated with a single injection of 250 mg/kg bodyweight suramin developed locomotor and sensory deficits, which were confirmed by electrophysiological measurements showing a predominantly sensory axonal-demyelinating polyneuropathy...
February 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Parviz Daniel Hejazi Pastor, Xiaofei Du, Sarah Fazal, Andre N Davies, Christopher M Gomez
We have discovered that the P/Q-type voltage-gated Ca2+ channel (VGCC) gene, CACNA1A, encodes both the α1A (Cav2.1) subunit and a newly recognized transcription factor, α1ACT, by means of a novel internal ribosomal entry site (IRES) within the α1A C-terminal coding region. α1ACT, when mutated with an expansion of the polyglutamine tract in the C-terminus, gives rise to spinocerebellar ataxia type 6 (SCA6). Because silencing of the entire CACNA1A gene would result in the loss of the essential Cav2.1 channel, the IRES controlling α1ACT expression is an excellent target for selective silencing of α1ACT as a therapeutic intervention for SCA6...
January 26, 2018: Cerebellum
Chen Kang, Litao Xie, Susheel K Gunasekar, Anil Mishra, Yanhui Zhang, Saachi Pai, Yiwen Gao, Ashutosh Kumar, Andrew W Norris, Samuel B Stephens, Rajan Sah
Insulin secretion is initiated by activation of voltage-gated Ca2+ channels (VGCC) to trigger Ca2+-mediated insulin vesicle fusion with the β-cell plasma membrane. The firing of VGCC requires β-cell membrane depolarization, which is regulated by a balance of depolarizing and hyperpolarizing ionic currents. Here, we show that SWELL1 mediates a swell-activated, depolarizing chloride current (ICl,SWELL) in both murine and human β-cells. Hypotonic and glucose-stimulated β-cell swelling activates SWELL1-mediated ICl,SWELL and this contributes to membrane depolarization and activation of VGCC-dependent intracellular calcium signaling...
January 25, 2018: Nature Communications
Man Wu, Hayley V White, Blake Boehm, Christopher J Meriney, Kaylan Kerrigan, Michael Frasso, Mary Liang, Erika M Gotway, Madeleine Wilcox, Jon W Johnson, Peter Wipf, Stephen D Meriney
Voltage-gated calcium channels (VGCCs) are critical regulators of many cellular functions, including the activity-dependent release of chemical neurotransmitter from nerve terminals. At nerve terminals, the Cav2 family of VGCCs are closely positioned with neurotransmitter-containing synaptic vesicles. The relationship between calcium ions and transmitter release is such that even subtle changes in calcium flux through VGCCs have a strong influence on the magnitude of transmitter released. Therefore, modulators of the calcium influx at nerve terminals have the potential to strongly affect transmitter release at synapses...
December 12, 2017: Neuropharmacology
Joshua P Whitt, Beth A McNally, Andrea L Meredith
Large conductance K+ (BK) channels are expressed widely in neurons, where their activation is regulated by membrane depolarization and intracellular Ca2+ (Ca2+i). To enable this regulation, BK channels functionally couple to both voltage-gated Ca2+ channels (VGCCs) and channels mediating Ca2+ release from intracellular stores. However, the relationship between BK channels and their specific Ca2+ source for particular patterns of excitability is not well understood. In neurons within the suprachiasmatic nucleus (SCN)-the brain's circadian clock-BK current, VGCC current, and Ca2+i are diurnally regulated, but paradoxically, BK current is greatest at night when VGCC current and Ca2+i are reduced...
December 13, 2017: Journal of General Physiology
Jonathan J Cho, James P Wymer
OBJECTIVE: To characterize Lambert-Eaton myasthenic syndrome and limbic encephalitis with coexistent voltage-gated calcium channel (VGCC) antibody and γ-aminobutyric acid (GABA) B receptor antibody. METHODS: Case study. RESULTS: A 57-year-old man presented with 6 months of weakness, unsteadiness, and vision difficulties. Examination revealed proximal weakness and diminished reflexes. Electrodiagnostic study revealed low-amplitude motor potentials and facilitation on high-frequency stimulation...
December 2017: Journal of Clinical Neuromuscular Disease
Brian G Hiester, Ashley M Bourke, Brooke L Sinnen, Sarah G Cook, Emily S Gibson, Katharine R Smith, Matthew J Kennedy
The repertoire and abundance of proteins displayed on the surface of neuronal dendrites are tuned by regulated fusion of recycling endosomes (REs) with the dendritic plasma membrane. While this process is critical for neuronal function and plasticity, how synaptic activity drives RE fusion remains unexplored. We demonstrate a multistep fusion mechanism that requires Ca2+ from distinct sources. NMDA receptor Ca2+ initiates RE fusion with the plasma membrane, while L-type voltage-gated Ca2+ channels (L-VGCCs) regulate whether fused REs collapse into the membrane or reform without transferring their cargo to the cell surface...
November 21, 2017: Cell Reports
Phillip H Beske, Katie M Hoffman, James B Machamer, Margaret R Eisen, Patrick M McNutt
Botulinum neurotoxins (BoNTs) are highly potent toxins that cleave neuronal SNARE proteins required for neurotransmission, causing flaccid paralysis and death by asphyxiation. Currently, there are no clinical treatments to delay or reverse BoNT-induced blockade of neuromuscular transmission. While aminopyridines have demonstrated varying efficacy in transiently reducing paralysis following BoNT poisoning, the precise mechanisms by which aminopyridines symptomatically treat botulism are not understood. Here we found that activity-dependent potentiation of presynaptic voltage-gated calcium channels (VGCCs) underlies 3,4-diaminopyridine (3,4-DAP)-mediated rescue of neurotransmission in central nervous system synapses and mouse diaphragm neuromuscular junctions fully intoxicated by BoNT serotype A...
November 20, 2017: Scientific Reports
Hengyong Lv, Zhen Li, Tiantian Hu, Yuexiang Wang, Jinpeng Wu, Yingxin Li
We aimed to elucidate the increased inflammatory cytokines expression such as nuclear factor kappa B (NF-kB/p65), cyclooxygenase-2 (COX-2), and voltage-gated calcium channels (VGCC) in the area of activated myofascial trigger points (MTrPs) in a rat model by blunt trauma to the vastus medialis and to evaluate the feasibility of a quantitative analysis of muscle elastic modulus using shear wave elastography (SWE). Twelve 7-week-old male SD rats were divided into normal (NM, n = 6) and model groups (MO, n = 6)...
November 6, 2017: Journal of Biomechanics
Wenxu Wang, Donghuo Zhong, Yu Lin, Rong Fan, Zhengjun Hou, Xiumei Cao, Yubin Ren
In this study, poly-L-lactic acid micropillar substrates were fabricated to evaluate the influence of topographic substrates on cell morphological and functional characteristics, such as spreading area, voltage-gated calcium channels (VGCCs) and membrane potential. The proliferation, spreading area, perimeter and circularity of SH-SY5Y cells interfaced with different substrates were first investigated. In addition, the cytoskeleton and focal adhesion of a cell as important manifestations of cell morphology were analyzed by immunofluorescence...
February 2018: Journal of Biomaterials Science. Polymer Edition
Andrea K Pinto-Martinez, Jessica Rodriguez-Durán, Xenon Serrano-Martin, Vanessa Hernandez-Rodriguez, Gustavo Benaim
Leishmania donovani is the causing agent of visceral leishmaniasis, a common infection that affects millions of people from the most underdeveloped countries. Miltefosine is the only oral drug to treat infections caused by L. donovani. Nevertheless, its mechanism of action is not well understood. While miltefosine inhibits the synthesis of phosphatidylcholine, and also affects the parasite mitochondrion inhibiting the cytochrome C oxidase, it is to be expected that this potent drug also produces its effect through other targets...
October 23, 2017: Antimicrobial Agents and Chemotherapy
Phillip H Beske, Aaron B Bradford, Katie M Hoffman, Sydney Mason, Patrick M McNutt
Botulinum neurotoxins (BoNTs) are exceedingly potent neurological poisons that block cholinergic release in the peripheral nervous system and cause death by asphyxiation. While post-exposure prophylaxis can effectively eliminate toxin in the bloodstream, there are no clinically effective treatments to prevent or reverse disease once BoNT has entered the neuron. To address the need for post-symptomatic countermeasures, we designed and developed an in vitro assay based on whole-cell, patch-clamp electrophysiological monitoring of miniature excitatory post-synaptic currents in synaptically active murine embryonic stem cell-derived neurons...
October 17, 2017: Toxicon: Official Journal of the International Society on Toxinology
Kazuko Iida, Jinfeng Teng, Toshihiko Cho, Sato Yoshikawa-Kimura, Hidetoshi Iida
Saccharomyces cerevisiae Mid1 is composed of 548 amino acids and a regulatory subunit of Cch1, a member of the eukaryotic pore-forming, four-domain cation channel family. The amino acid sequence and voltage insensitivity of Cch1 are more similar to those of Na+ leak channel non-selective (NALCN) than to the α1 subunit of voltage-gated Ca2+ channels (VGCCs). Despite a lack in overall primary sequence similarity, Mid1 resembles in some aspects VGCC α2/δ regulatory subunits and NALCN-associated proteins. Unlike animal α2/δ subunits, Mid1 and NALCN-associated proteins are essential for the function of the pore-forming subunit...
October 17, 2017: Journal of Biological Chemistry
Alexander F Jeans, Fran C van Heusden, Bashayer Al-Mubarak, Zahid Padamsey, Nigel J Emptage
Voltage-dependent Ca(2+) channels (VGCC) represent the principal source of Ca(2+) ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca(2+) influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity. However, whether this represents a functional motif also present in other forms of activity-dependent regulation is unknown. Here, we study the role of VGCC in homeostatic plasticity (HSP) in mammalian hippocampal neurons using optical techniques...
October 10, 2017: Cell Reports
Ellen Strijbos, Maartje G Huijbers, Inge E van Es, Iris Alleman, Monique M van Ostaijen-Ten Dam, Jaap Bakker, Erik W van Zwet, Cornelia M Jol-van der Zijde, Maarten D van Tol, Jan J Verschuuren
OBJECTIVE: To investigate the humoral immune response to and safety of a tetanus revaccination in patients with myasthenia gravis or Lambert-Eaton myasthenic syndrome. METHODS: A tetanus revaccination was administered to 66 patients. Before and 4weeks after revaccination a blood sample and clinical outcome scores were obtained. Anti-tetanus IgG total, IgG1 and IgG4 titres were measured with an ELISA and disease-specific antibody titres (AChR, MuSK or VGCC) with a radio-immunoprecipitation assay...
October 6, 2017: Vaccine
Dong Li, Shu-Zhuo Zhang, Yu-Hong Yao, Yun Xiang, Xiao-Yun Ma, Xiao-Li Wei, Hai-Tao Yan, Xiao-Yan Liu
INTRODUCTION: Sigma-1 receptors (Sig-1Rs) are unique endoplasmic reticulum proteins that have been implicated in both neurodegenerative and ischemic diseases, such as Alzheimer's disease and stroke. Accumulating evidence has suggested that Sig-1R plays a role in neuroprotection and axon outgrowth. The underlying mechanisms of Sig-1R-mediated neuroprotection have been well elucidated. However, the mechanisms underlying the effects of Sig-1R on axon outgrowth are not fully understood. METHODS: To clarify this issue, we utilized immunofluorescence to compare the axon lengths of cultured naïve hippocampal neurons before and after the application of the Sig-1R agonist, SA4503...
October 8, 2017: CNS Neuroscience & Therapeutics
Andre Greiner, Simon Kelterborn, Heide Evers, Georg Kreimer, Irina Sizova, Peter Hegemann
The fast-growing biflagellated single celled chlorophyte Chlamydomonas reinhardtii is the most widely used alga in basic research. The physiological functions of the 18 sensory photoreceptors are of particular interest with respect to C. reinhardtii development and behavior. Despite the demonstration of gene editing in C. reinhardtii in 1995, the isolation of mutants lacking easily ascertained newly acquired phenotypes remains problematic due to low DNA recombination efficiency. We optimized gene-editing protocols for several Chlamydomonas strains (including wild-type CC-125) using zinc-finger nucleases (ZFNs), genetically encoded CRISPR/associated protein 9 (Cas9) from Staphylococcus aureus and Streptococcus pyogenes, and recombinant Cas9 and developed protocols for rapidly isolating non-selectable gene mutants...
October 4, 2017: Plant Cell
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