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Cav2.1

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https://www.readbyqxmd.com/read/28809766/crispr-cas9-editing-of-nf1-gene-identifies-crmp2-as-a-therapeutic-target-in-neurofibromatosis-type-1-related-pain-that-is-reversed-by-s-lacosamide
#1
Aubin Moutal, Xiaofang Yang, Wennan Li, Kerry B Gilbraith, Shizhen Luo, Song Cai, Liberty François-Moutal, Lindsey A Chew, Seul Ki Yeon, Shreya S Bellampalli, Chaoling Qu, Jennifer Y Xie, Mohab M Ibrahim, May Khanna, Ki Duk Park, Frank Porreca, Rajesh Khanna
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease linked to mutations of the Nf1 gene. Patients with NF1 commonly experience severe pain. Studies on mice with Nf1 haploinsufficiency have been instructive in identifying sensitization of ion channels as a possible cause underlying the heightened pain suffered by patients with NF1. However, behavioral assessments of Nf1 mice have led to uncertain conclusions about the potential causal role of Nf1 in pain. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) genome editing system to create and mechanistically characterize a novel rat model of NF1-related pain...
July 3, 2017: Pain
https://www.readbyqxmd.com/read/28767512/dissecting-the-role-of-the-crmp2-neurofibromin-complex-on-pain-behaviors
#2
Aubin Moutal, Yue Wang, Xiaofang Yang, Yingshi Ji, Shizhen Luo, Angie Dorame, Shreya S Bellampalli, Lindsey A Chew, Song Cai, Erik T Dustrude, James E Keener, Michael T Marty, Todd W Vanderah, Rajesh Khanna
Neurofibromatosis type 1 (NF1), a genetic disorder linked to inactivating mutations or homozygous deletion of the Nf1 gene, is characterized by tumorigenesis, cognitive dysfunction, seizures, migraine, and pain. Omic studies on human NF1 tissues identified an increase in expression of collapsin response mediator protein 2 (CRMP2), a cytosolic protein reported to regulate the trafficking and activity of presynaptic N-type voltage-gated calcium (Cav2.2) channels. Since neurofibromin, the protein product of the Nf1 gene, binds to and inhibits CRMP2, the neurofibromin-CRMP2 signaling cascade will likely affect Ca2+ channel activity and regulate nociceptive neurotransmission and in vivo responses to noxious stimulation...
July 31, 2017: Pain
https://www.readbyqxmd.com/read/28710481/the-lrrk2-g2385r-variant-is-a-partial-loss-of-function-mutation-that-affects-synaptic-vesicle-trafficking-through-altered-protein-interactions
#3
Maria Dolores Perez Carrion, Silvia Marsicano, Federica Daniele, Antonella Marte, Francesca Pischedda, Eliana Di Cairano, Ester Piovesana, Felix von Zweydorf, Elisabeth Kremmer, Christian Johannes Gloeckner, Franco Onofri, Carla Perego, Giovanni Piccoli
Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson's disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28700936/alternative-splicing-of-p-q-type-ca-2-channels-shapes-presynaptic-plasticity
#4
Agnes Thalhammer, Andrea Contestabile, Yaroslav S Ermolyuk, Teclise Ng, Kirill E Volynski, Tuck Wah Soong, Yukiko Goda, Lorenzo A Cingolani
Alternative splicing of pre-mRNAs is prominent in the mammalian brain, where it is thought to expand proteome diversity. For example, alternative splicing of voltage-gated Ca(2+) channel (VGCC) α1 subunits can generate thousands of isoforms with differential properties and expression patterns. However, the impact of this molecular diversity on brain function, particularly on synaptic transmission, which crucially depends on VGCCs, is unclear. Here, we investigate how two major splice isoforms of P/Q-type VGCCs (Cav2...
July 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28688851/characterization-of-the-dominant-inheritance-mechanism-of-episodic-ataxia-type-2
#5
Kevin Dorgans, Julie Salvi, Federica Bertaso, Ludivine Bernard, Philippe Lory, Frederic Doussau, Alexandre Mezghrani
Episodic Ataxia type 2 (EA2) is an autosomal dominant neuronal disorder linked to mutations in the Cav2.1 subunit of P/Q-type calcium channels. In vitro studies have established that EA2 mutations induce loss of channel activity and that EA2 mutants can exert a dominant negative effect, suppressing normal Cav2.1 activity through protein misfolding and trafficking defects. To date, the role of this mechanism in the disease pathogenesis is unknown because no animal model exists. To address this issue, we have generated a mouse bearing the R1497X nonsense mutation in Cav2...
July 5, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28669545/retrograde-synaptic-inhibition-is-mediated-by-%C3%AE-neurexin-binding-to-the-%C3%AE-2%C3%AE-subunits-of-n-type-calcium-channels
#6
Xia-Jing Tong, Eduardo Javier López-Soto, Lei Li, Haowen Liu, Daniel Nedelcu, Diane Lipscombe, Zhitao Hu, Joshua M Kaplan
The synaptic adhesion molecules Neurexin and Neuroligin alter the development and function of synapses and are linked to autism in humans. In C. elegans, post-synaptic Neurexin (NRX-1) and pre-synaptic Neuroligin (NLG-1) mediate a retrograde synaptic signal that inhibits acetylcholine (ACh) release at neuromuscular junctions. Here, we show that the retrograde signal decreases ACh release by inhibiting the function of pre-synaptic UNC-2/CaV2 calcium channels. Post-synaptic NRX-1 binds to an auxiliary subunit of pre-synaptic UNC-2/CaV2 channels (UNC-36/α2δ), decreasing UNC-36 abundance at pre-synaptic elements...
July 19, 2017: Neuron
https://www.readbyqxmd.com/read/28645621/two-delta-opioid-receptor-subtypes-are-functional-in-single-ventral-tegmental-area-neurons-and-can-interact-with-the-mu-opioid-receptor
#7
Elyssa B Margolis, Wakako Fujita, Lakshmi A Devi, Howard L Fields
The mu and delta opioid receptors (MOR and DOR) are highly homologous members of the opioid family of GPCRs. There is evidence that MOR and DOR interact, however the extent to which these interactions occur in vivo and affect synaptic function is unknown. There are two stable DOR subtypes: DPDPE sensitive (DOR1) and deltorphin II sensitive (DOR2); both agonists are blocked by DOR selective antagonists. Robust motivational effects are produced by local actions of both MOR and DOR ligands in the ventral tegmental area (VTA)...
June 21, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28607047/numbers-of-presynaptic-ca-2-channel-clusters-match-those-of-functionally-defined-vesicular-docking-sites-in-single-central-synapses
#8
Takafumi Miki, Walter A Kaufmann, Gerardo Malagon, Laura Gomez, Katsuhiko Tabuchi, Masahiko Watanabe, Ryuichi Shigemoto, Alain Marty
Many central synapses contain a single presynaptic active zone and a single postsynaptic density. Vesicular release statistics at such "simple synapses" indicate that they contain a small complement of docking sites where vesicles repetitively dock and fuse. In this work, we investigate functional and morphological aspects of docking sites at simple synapses made between cerebellar parallel fibers and molecular layer interneurons. Using immunogold labeling of SDS-treated freeze-fracture replicas, we find that Cav2...
June 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28566750/mutation-spectrum-in-the-cacna1a-gene-in-49-patients-with-episodic-ataxia
#9
Cèlia Sintas, Oriel Carreño, Noèlia Fernàndez-Castillo, Roser Corominas, Marta Vila-Pueyo, Claudio Toma, Ester Cuenca-León, Isabel Barroeta, Carles Roig, Víctor Volpini, Alfons Macaya, Bru Cormand
Episodic ataxia is an autosomal dominant ion channel disorder characterized by episodes of imbalance and incoordination. The disease is genetically heterogeneous and is classified as episodic ataxia type 2 (EA2) when it is caused by a mutation in the CACNA1A gene, encoding the α1A subunit of the P/Q-type voltage-gated calcium channel Cav2.1. The vast majority of EA2 disease-causing variants are loss-of-function (LoF) point changes leading to decreased channel currents. CACNA1A exonic deletions have also been reported in EA2 using quantitative approaches...
May 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28510727/alternative-splicing-in-the-c-terminal-tail-of-cav2-1-is-essential-for-preventing-a-neurological-disease-in-mice
#10
Tomonori Aikawa, Takaki Watanabe, Taisuke Miyazaki, Takayasu Mikuni, Minoru Wakamori, Miyano Sakurai, Hidenori Aizawa, Nobutaka Ishizu, Masahiko Watanabe, Masanobu Kano, Hidehiro Mizusawa, Kei Watase
Alternative splicing (AS) that occurs at the final coding exon (exon 47) of the Cav2.1 voltage-gated calcium channel (VGCC) gene produces two major isoforms in the brain, MPI and MPc. These isoforms differ in their splice acceptor sites; human MPI is translated into a polyglutamine tract associated with spinocerebellar ataxia type 6 (SCA6), whereas MPc splices to an immediate stop codon, resulting in a shorter cytoplasmic tail.To gain insight into the functional role of the AS in vivo and whether modulating the splice patterns at this locus can be a potential therapeutic strategy for SCA6, here we created knockin mice that exclusively express MPc by inserting the splice-site mutation...
May 16, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28498149/inhibition-of-glutamate-release-by-cilnidipine-in-rat-cerebrocortical-nerve-terminals-synaptosomes
#11
Cheng Wei Lu, Tzu Yu Lin, Shu Kuei Huang, Su Jane Wang
Cilnidipine is an antihypertensive drug that was reported to have a neuroprotective profile. The present study aimed to investigate the effect of cilnidipine on the 4-aminopyridine (4-AP)-induced glutamate release in the rat cerebral cortex using isolated nerve terminals (synaptosomes). Cilnidipine reduced the release of glutamate release induced by 4-AP in a concentration-dependent manner. This inhibitory effect was associated with a reduction in the 4-AP-induced intrasynaptosomal Ca concentration elevation and was not because of an alteration of the synaptosomal membrane potential...
June 14, 2017: Neuroreport
https://www.readbyqxmd.com/read/28472212/association-of-glaucoma-susceptible-genes-to-regional-circumpapillary-retinal-nerve-fiber-layer-thickness-and-visual-field-defects
#12
Munemitsu Yoshikawa, Hideo Nakanishi, Kenji Yamashiro, Masahiro Miyake, Tadamichi Akagi, Norimoto Gotoh, Hanako O Ikeda, Kenji Suda, Hiroshi Yamada, Tomoko Hasegawa, Yuto Iida, Ryo Yamada, Fumihiko Matsuda, Nagahisa Yoshimura
Purpose: To examine the associations of the earlier reported glaucoma-related genes to the regional circumpapillary retinal nerve fiber layer thicknesses (cpRNFLTs) and corresponding visual field defects. Methods: We studied 756 patients with primary open-angle glaucoma (POAG) and 3094 normal controls. Each participant was genotyped for nine single nucleotide polymorphisms (SNPs) of four glaucoma-susceptible genes: the CDKN2B(AS1), TMCO1, CAV1/CAV2, and SIX1/SIX6 genes...
May 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28424589/the-calcium-channel-c-terminal-and-synaptic-vesicle-tethering-analysis-by-immuno-nanogold-localization
#13
Robert H C Chen, Qi Li, Christine A Snidal, Sabiha R Gardezi, Elise F Stanley
At chemical synapses the incoming action potential triggers the influx of Ca(2+) through voltage-sensitive calcium channels (CaVs, typically CaV2.1 and 2.2) and the ions binds to sensors associated with docked, transmitter filled synaptic vesicles (SVs), triggering their fusion and discharge. The CaVs and docked SVs are located within the active zone (AZ) region of the synapse which faces a corresponding neurotransmitter receptor-rich region on the post-synaptic cell. Evidence that the fusion of a SV can be gated by Ca(2+) influx through a single CaV suggests that the channel and docked vesicle are linked by one or more molecular tethers (Stanley, 1993)...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28418433/capsaicin-presynaptically-inhibits-glutamate-release-through-the-activation-of-trpv1-and-calcineurin-in-the-hippocampus-of-rats
#14
Cheng Wei Lu, Tzu Yu Lin, Ting Yang Hsie, Shu Kuei Huang, Su Jane Wang
Capsaicin is the major ingredient in hot peppers of the plant Capsicum genus with neuroprotective effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus using isolated nerve terminals (synaptosomes) and brain slices. In a synaptosomal preparation, capsaicin dose-dependently reduced 4-aminopyridine-evoked Ca(2+)-dependent glutamate release, with an IC50 of approximately 11 μM. This inhibition was blocked by capsazepin, an antagonist of TRPV1, which was found to be colocalized with the vesicle marker protein synaptophysin in synaptosomes using double immunostaining...
May 24, 2017: Food & Function
https://www.readbyqxmd.com/read/28393090/gender-specific-hippocampal-whole-genome-transcriptome-data-from-mice-lacking-the-cav2-3-r-type-or-cav3-2-t-type-voltage-gated-calcium-channel
#15
Anna Papazoglou, Christina Henseler, Andreas Lundt, Carola Wormuth, Julien Soos, Karl Broich, Dan Ehninger, Marco Weiergräber
Voltage-gated Ca(2+) channels are of central relevance in mediating numerous intracellular and transcellular processes including excitation-contraction coupling, excitation secretion-coupling, hormone and neurotransmitter release and gene expression. The Cav2.3 R-type Ca(2+) channel is a high-voltage activated channel which plays a crucial role in neurotransmitter release, long-term potentiation and hormone release. Furthermore, Cav2.3 R-type channels were reported to be involved in ictogenesis, epileptogenesis, fear behavior, sleep, pre-and postsynaptic integration and rhythmicity within the hippocampus...
June 2017: Data in Brief
https://www.readbyqxmd.com/read/28377503/c-terminal-splice-variants-of-p-q-type-ca-2-channel-cav2-1-%C3%AE-1-subunits-are-differentially-regulated-by-rab3-interacting-molecule-proteins
#16
Mitsuru Hirano, Yoshinori Takada, Chee Fah Wong, Kazuma Yamaguchi, Hiroshi Kotani, Tatsuki Kurokawa, Masayuki X Mori, Terrance P Snutch, Michel Ronjat, Michel De Waard, Yasuo Mori
Voltage-dependent Ca(2+) channels (VDCCs) mediate neurotransmitter release controlled by presynaptic proteins such as the scaffolding proteins Rab3-interacting molecules (RIMs). RIMs confer sustained activity and anchoring of synaptic vesicles to the VDCCs. Multiple sites on the VDCC α1 and β subunits have been reported to mediate the RIMs-VDCC interaction, but their significance is unclear. Because alternative splicing of exons 44 and 47 in the P/Q-type VDCC α1 subunit CaV2.1 gene generates major variants of the CaV2...
June 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28363781/hyperpolarization-activated-current-ih-in-mouse-trigeminal-sensory-neurons-in-a-transgenic-mouse-model-of-familial-hemiplegic-migraine-type-1
#17
Francesca Eroli, Sandra Vilotti, Arn M J M van den Maagdenberg, Andrea Nistri
Transgenic knock-in (KI) mice that express CaV2.1 channels containing an R192Q gain-of-function mutation in the α1A subunit known to cause familial hemiplegic migraine type-1 in patients, exhibit key disease characteristics and provide a useful tool to investigate pathophysiological mechanisms of pain transduction. Previously, KI trigeminal sensory neurons were shown to exhibit constitutive hyperexcitability due to up-regulation of ATP-gated P2X3 receptors that trigger spike activity at a more negative threshold...
March 29, 2017: Neuroscience
https://www.readbyqxmd.com/read/28330839/evolutionary-insights-into-t-type-ca-2-channel-structure-function-and-ion-selectivity-from-the-trichoplax-adhaerens-homologue
#18
Carolyn L Smith, Salsabil Abdallah, Yuen Yan Wong, Phuong Le, Alicia N Harracksingh, Liana Artinian, Arianna N Tamvacakis, Vincent Rehder, Thomas S Reese, Adriano Senatore
Four-domain voltage-gated Ca(2+) (Cav) channels play fundamental roles in the nervous system, but little is known about when or how their unique properties and cellular roles evolved. Of the three types of metazoan Cav channels, Cav1 (L-type), Cav2 (P/Q-, N- and R-type) and Cav3 (T-type), Cav3 channels are optimized for regulating cellular excitability because of their fast kinetics and low activation voltages. These same properties permit Cav3 channels to drive low-threshold exocytosis in select neurons and neurosecretory cells...
April 3, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28330759/amiodarone-reduces-depolarization-evoked-glutamate-release-from-hippocampual-synaptosomes
#19
Chia Yu Chang, Chi Feng Hung, Shu Kuei Huang, Jinn Rung Kuo, Su Jane Wang
Decreased brain glutamate level has emerged as a new therapeutic approach for epilepsy. This study investigated the effect and mechanism of amiodarone, an anti-arrhythmic drug with antiepileptic activity, on glutamate release in the rat hippocampus. In a synaptosomal preparation, amiodarone reduced 4-aminopyridine-evoked Ca(2+)-dependent glutamate release and cytosolic Ca(2+) concentration elevation. Amiodarone did not affect the 4-aminopyridine-evoked depolarization of the synaptosomal membrane potential or the Na(+) channel activator veratridine-evoked glutamate release, indicating that the amiodarone-mediated inhibition of glutamate release is not caused by a decrease in synaptosomal excitability...
March 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28256585/lrp1-influences-trafficking-of-n-type-calcium-channels-via-interaction-with-the-auxiliary-%C3%AE-2%C3%AE-1-subunit
#20
Ivan Kadurin, Simon W Rothwell, Beatrice Lana, Manuela Nieto-Rostro, Annette C Dolphin
Voltage-gated Ca(2+) (CaV) channels consist of a pore-forming α1 subunit, which determines the main functional and pharmacological attributes of the channel. The CaV1 and CaV2 channels are associated with auxiliary β- and α2δ-subunits. The molecular mechanisms involved in α2δ subunit trafficking, and the effect of α2δ subunits on trafficking calcium channel complexes remain poorly understood. Here we show that α2δ-1 is a ligand for the Low Density Lipoprotein (LDL) Receptor-related Protein-1 (LRP1), a multifunctional receptor which mediates trafficking of cargoes...
March 3, 2017: Scientific Reports
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