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Harry Z E Greenberg, Kazi S Jahan, Jian Shi, W-S Vanessa Ho, Anthony P Albert
The present study investigates the effect of commonly used negative and positive allosteric modulators of the calcium-sensing receptor (CaSR) on vascular reactivity. In wire myography studies, increasing [Ca(2+)]o from 1mM to 6mM induced concentration-dependent relaxations of methoxamine-induced pre-contracted rabbit mesenteric arteries, with 6mM [Ca(2+)]o producing almost complete relaxation. [Ca(2+)]o-induced relaxations were attenuated in the presence of the calcilytics Calhex-231 and NPS 2143, and abolished by the removal of the endothelium...
October 8, 2016: European Journal of Pharmacology
Deepika Sharma, Brijendra Kumar Tiwari, Subhash Mehto, Cecil Antony, Gunjan Kak, Yogendra Singh, Krishnamurthy Natarajan
The prevalence of Mycobacterium tuberculosis (M. tb) strains eliciting drug resistance has necessitated the need for understanding the complexities of host pathogen interactions. The regulation of calcium homeostasis by Voltage Gated Calcium Channel (VGCCs) upon M. tb infection has recently assumed importance in this area. We previously showed a suppressor role of VGCC during M. tb infections and recently reported the mechanisms of its regulation by M. tb. Here in this report, we further characterize the role of VGCC in mediating defence responses of macrophages during mycobacterial infection...
2016: PloS One
Yan-Yan Jin, Meng-Zao He, Zhen-Yong Wu, Ke Huang, Ying Shen, Li Liang, Jian-Hua Mao
OBJECTIVE: To investigate the role of intrauterine malnourishment in the development and function of pancreatic islet β-cells. METHODS: Whole-cell patch clamping was used to record voltage-gated calcium channel (VGCC)-mediated currents. Insulin secretion was detected by measuring capacitance using a sequence of sine wave stimuli. VGCC currents and insulin secretion were measured in the small for gestational age (SGA) group treated with human recombinant growth hormone (hGH)...
September 29, 2016: Growth Factors
Agnieszka Michalak, Grazyna Biala
Long-term potentiation (LTP) and long-term depression (LTD) depend on specific postsynaptic Ca(2+)/calmodulin concentration. LTP results from Ca(2+) influx through the activated NMDA receptors or voltage-gated calcium channels (VGCCs) and is linked with activation of protein kinases including mitogen-activated protein kinase (MAPK). Weaker synaptic stimulation, as a result of low Ca(2+) influx, leads to activation of Ca(2+)/calmodulin-dependent phosphatase (calcineurin - CaN) and triggers LTD. Interestingly, both memory formation and drug addiction share similar neuroplastic changes...
September 12, 2016: Behavioural Brain Research
Nese Sinmaz, Tina Nguyen, Fiona Tea, Russell C Dale, Fabienne Brilot
BACKGROUND: Our knowledge of autoantibody-associated diseases of the central (CNS) and peripheral (PNS) nervous systems has expanded greatly over the recent years. A number of extracellular and intracellular autoantigens have been identified, and there is no doubt that this field will continue to expand as more autoantigens are discovered as a result of improved clinical awareness and methodological practice. In recent years, interest has shifted to uncover the target epitopes of these autoantibodies...
2016: Journal of Neuroinflammation
Divpreet Kaur, Divisha Raheja
The presence of P/Q type voltage gated calcium channel (VGCC) antibodies has been strongly correlated with Lambert Eaton Syndrome (LES), present in 90% of non-immunocompromised patients with LES. However, there have been case reports which have shown its association between paraneoplastic syndrome affecting both central nervous system and the peripheral nervous system causing encephalomyelitis and sensory neuronopathy/neuropathy. We present a case of a young man, who presented with encephalomyelitis, and was further noted to have superimposed cervical polyradiculopathy associated with P/Q type VGCC antibodies...
November 2016: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Beatrice M Pigott, John Garthwaite
Nitric oxide (NO) has long been implicated in the generation of long-term potentiation (LTP) and other types of synaptic plasticity, a role for which the intimate coupling between NMDA receptors (NMDARs) and the neuronal isoform of NO synthase (nNOS) is likely to be instrumental in many instances. While several types of synaptic plasticity depend on NMDARs, others do not, an example of which is LTP triggered by opening of L-type voltage-gated Ca(2+) channels (L-VGCCs) in postsynaptic neurons. In CA3-CA1 synapses in the hippocampus, NMDAR-dependent LTP (LTPNMDAR) appears to be primarily expressed postsynaptically whereas L-VGCC-dependent LTP (LTPL-VGCC), which often coexists with LTPNMDAR, appears mainly to reflect enhanced presynaptic transmitter release...
2016: Frontiers in Synaptic Neuroscience
Peter Koch, Stefan Herzig, Jan Matthes
INTRODUCTION: Pore-forming subunits of voltage gated calcium channels (VGCC) are large membrane proteins (260kDa) containing 24 transmembrane domains. Despite transfection with viral promoter driven vectors, biochemical analysis of VGCC is often hampered by rather low expression levels in heterologous systems rendering VGCC challenging targets. Especially in immunofluorescent detection, calcium channels are demanding proteins. METHODS: We provide an expert step-by-step protocol with adapted conditions for handling procedures (tsA-201 cell culture, transient transfection, incubation time and temperature at 28°C or 37°C and immunostaining) to address the L-type calcium-channel pore Cav1...
July 12, 2016: Journal of Pharmacological and Toxicological Methods
Fernanda B Morrone, Marina P Gehring, Natália F Nicoletti
Malignant brain tumors are highly lethal and aggressive. Despite recent advances in the current therapies, which include the combination of surgery and radio/chemotherapy, the average survival rate remains poor. Altered regulation of ion channels is part of the neoplastic transformation, which suggests that ion channels are involved in cancer. Distinct classes of calcium-permeable channels are abnormally expressed in cancer and are likely involved in the alterations underlying malignant growth. Specifically, cytosolic Ca(2+) activity plays an important role in the regulation of cell proliferation, and Ca(2+) signaling is altered in proliferating tumor cells...
September 2016: Molecular Pharmacology
David Weise, Jakob Mann, Jost-Julian Rumpf, Stefan Hallermann, Joseph Classen
Activity-dependent changes of postsynaptic Ca(2+)-concentration are influenced by a variety of different Ca(2+)-channels and play an important role in synaptic plasticity. Paired associative stimulation (PAS) and theta-burst stimulation (TBS) are noninvasive magnetic stimulation protocols used in human subjects to induce lasting corticospinal excitability changes that have been likened to synaptic long-term potentiation and long-term depression. To better characterize the Ca(2+)-related physiological mechanisms underlying PAS- and TBS-induced plasticity, we examined the impact of different Ca(2+)-sources...
July 11, 2016: Cerebral Cortex
Jun Chen, Michael J Sanderson
Asthma is characterized by airway hyper-responsiveness - the excessive contraction of airway smooth muscle. The extent of this airway contraction is proportional to the frequency of Ca(2+) oscillations within airway smooth muscle cells (ASMCs). Sustained Ca(2+) oscillations require a Ca(2+) influx to replenish Ca(2+) losses across the plasma membrane. Our previous studies implied store-operated calcium entry (SOCE) as the major pathway for this Ca(2+) influx. Here, we explore this hypothesis, by examining the effects of SOCE inhibitors (GSK7975A and GSK5498A) as well as L-type voltage-gated Ca(2+) channel (VGCC) inhibitors (nifedipine and nimodipine) on airway contraction and Ca(2+) oscillations and SOCE-mediated Ca(2+) influx in ASMCs within mouse precision-cut lung slices (PCLS)...
July 11, 2016: Journal of Physiology
Mohamad Rima, Marwa Daghsni, Ziad Fajloun, Ridha M'rad, Juan L Brusés, Michel Ronjat, Michel De Waard
Calcium plays a key role in cell signalling by its intervention in a wide range of physiological processes. Its entry into cells occurs mainly via voltage-gated calcium channels (VGCC), which are found not only in the plasma membrane of excitable cells but also in cells insensitive to electrical signals. VGCC are composed of different subunits, α1, β, α2δ and γ, among which the cytosolic β subunit (Cavβ) controls the trafficking of the channel to the plasma membrane, its regulation and its gating properties...
July 1, 2016: Biochemical Journal
Payal Gupta, Reshmi Chanda, Nishant Rai, Vijay K Kataria, Navin Kumar
Candida albicans and Candida glabrata are two important human pathogens associated with high mortality. The anti-Candida potential of an antihypertensive drug, amlodipine besilate (AB), was studied against 10 strains of Candida, including 8 clinical isolates. AB is an inhibitor of voltage-gated Ca(2+) channel (VGCC) of mammals. CCH1 expresses in a part of Ca(2+) channel of Candida, which is a homologue of α subunit of mammalian VGCC. In plate assays, all strains of Candida showed sensitivity to AB on agar media at 256 μg/mL concentration, AB caused lethality at concentrations of 16 and 64 μg/mL in clinical isolates of C...
June 23, 2016: Assay and Drug Development Technologies
Hiroshi Nishimune, Yomna Badawi, Shuuichi Mori, Kazuhiro Shigemoto
Presynaptic active zones play a pivotal role as synaptic vesicle release sites for synaptic transmission, but the molecular architecture of active zones in mammalian neuromuscular junctions (NMJs) at sub-diffraction limited resolution remains unknown. Bassoon and Piccolo are active zone specific cytosolic proteins essential for active zone assembly in NMJs, ribbon synapses, and brain synapses. These proteins are thought to colocalize and share some functions at active zones. Here, we report an unexpected finding of non-overlapping localization of these two proteins in mouse NMJs revealed using dual-color stimulated emission depletion (STED) super resolution microscopy...
2016: Scientific Reports
Alberto di Silvio, JeanFrancois Rolland, Michela Stucchi
The FLIPR (Fluorescent Imaging Plate Reader) system has been extensively used in the early stages of drug discovery for the identification of small molecules as a starting point for drug development, and for the pharmacological characterization of compounds. The main application of the system has been the measurement of intracellular Ca(2+) signals using fluorescent calcium indicators.This chapter describes the application of a protocol for the study and characterization of state-dependent blockers of Voltage-Gated Calcium Channels (VGCC) on the FLIPR(TETRA)...
2016: Methods in Molecular Biology
Rocío Lajarín-Cuesta, Carmen Nanclares, Juan-Alberto Arranz-Tagarro, Laura González-Lafuente, Raquel L Arribas, Monique Araujo de Brito, Luis Gandía, Cristóbal de Los Ríos
We describe the synthesis of gramine derivatives and their pharmacological evaluation as multipotent drugs for the treatment of Alzheimer's disease. An innovative multitarget approach is presented, targeting both voltage-gated Ca(2+) channels, classically studied for neurodegenerative diseases, and Ser/Thr phosphatases, which have been marginally aimed, even despite their key role in protein τ dephosphorylation. Twenty-five compounds were synthesized, and mostly their neuroprotective profile exceeded that offered by the head compound gramine...
July 14, 2016: Journal of Medicinal Chemistry
Christian Schön, François Paquet-Durand, Stylianos Michalakis
Retinitis pigmentosa is an inherited blinding disorder characterized by progressive degeneration and loss of photoreceptors. The exact mechanism of degeneration and cell death of photoreceptors is not known, but is thought to involve disturbed Ca2+-signaling. Ca2+ can enter the photoreceptor cell via outer segment cyclic nucleotide-gated (CNG) channels or synaptic Cav1.4 L-type voltage-gated calcium channels (VGCC). Previously, we have shown that genetic ablation of the Cngb1 gene encoding the B subunit of the rod CNG channel delays the fast progressing degeneration in the rd1 mutant mouse model of retinitis pigmentosa...
2016: PloS One
Thom Griffith, Krasimira Tsaneva-Atanasova, Jack R Mellor
The key trigger for Hebbian synaptic plasticity is influx of Ca2+ into postsynaptic dendritic spines. The magnitude of [Ca2+] increase caused by NMDA-receptor (NMDAR) and voltage-gated Ca2+ -channel (VGCC) activation is thought to determine both the amplitude and direction of synaptic plasticity by differential activation of Ca2+ -sensitive enzymes such as calmodulin. Ca2+ influx is negatively regulated by Ca2+ -activated K+ channels (SK-channels) which are in turn inhibited by neuromodulators such as acetylcholine...
May 2016: PLoS Computational Biology
Marilyn McKasson, Stacey L Clardy, Susan A Clawson, Kenneth E Hill, Blair Wood, Noel Carlson, Mark Bromberg, John E Greenlee
OBJECTIVES: To describe response to treatment in a patient with autoantibodies against voltage-gated calcium channels (VGCCs) who presented with autoimmune cerebellar degeneration and subsequently developed Lambert-Eaton myasthenic syndrome (LEMS), and to study the effect of the patient's autoantibodies on Purkinje cells in rat cerebellar slice cultures. METHODS: Case report and study of rat cerebellar slice cultures incubated with patient VGCC autoantibodies. RESULTS: A 53-year-old man developed progressive incoordination with ataxic speech...
June 2016: Neurology® Neuroimmunology & Neuroinflammation
Stepan Kortus, Chinnapaiyan Srinivasan, Oksana Forostyak, Martin Zapotocky, Yoichi Ueta, Eva Sykova, Alexandr Chvatal, Alexei Verkhratsky, Govindan Dayanithi
Isolated supraoptic neurones generate spontaneous [Ca(2+)]i oscillations in isolated conditions. Here we report in depth analysis of the contribution of plasmalemmal ion channels (Ca(2+), Na(+)), Na(+)/Ca(2+) exchanger (NCX), intracellular Ca(2+) release channels (InsP3Rs and RyRs), Ca(2+) storage organelles, plasma membrane Ca(2+) pump and intracellular signal transduction cascades into spontaneous Ca(2+) activity. While removal of extracellular Ca(2+) or incubation with non-specific voltage-gated Ca(2+) channel (VGCC) blocker Cd(2+) suppressed the oscillations, neither Ni(2+) nor TTA-P2, the T-type VGCC blockers, had an effect...
June 2016: Cell Calcium
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