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M Katharina Grauel, Marta Maglione, Suneel Reddy-Alla, Claudia G Willmes, Marisa M Brockmann, Thorsten Trimbuch, Tanja Rosenmund, Maria Pangalos, Gülçin Vardar, Alexander Stumpf, Alexander M Walter, Benjamin R Rost, Britta J Eickholt, Volker Haucke, Dietmar Schmitz, Stephan J Sigrist, Christian Rosenmund
The tight spatial coupling of synaptic vesicles and voltage-gated Ca(2+) channels (CaVs) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca(2+) channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2-deficient murine hippocampal neurons in cultures and slices...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
Fikru Nigussie, Pei-San Huang, Kris Lukauskis, Bhupinder Bawa, Eid Moussa, Louise C Abbott
Tottering mutant mice carry a mutation in the pore-forming subunit (α1A) of CaV2.1 (P/Q-type) voltage-gated calcium ion (Ca(2+)) channels resulting in reduced neuronal Ca(2+) current density. We assessed male tottering mice for spatial learning using the Morris water maze. Tottering mice performed worse than wild type mice, suggesting abnormal hippocampal function. Because Ca(2+) influx via voltage-dependent Ca(2+) channels regulates neuronal survival and function, we assessed hippocampus volume and cell density using hematoxylin and eosin stained serial sections...
November 1, 2016: Brain Research
Katalin Kerti-Szigeti, Zoltan Nusser
Hippocampal pyramidal cells (PCs) express many GABAAR subunit types and receive GABAergic inputs from distinct interneurons. Previous experiments revealed input-specific differences in α1 and α2 subunit densities in perisomatic synapses, suggesting distinct IPSC decay kinetics. However, IPSC decays evoked by axo-axonic, parvalbumin- or cholecystokinin-expressing basket cells were found to be similar. Using replica immunogold labeling, here we show that all CA1 PC somatic and AIS synapses contain the α1, α2, β1, β2, β3 and γ2 subunits...
2016: ELife
Karen M Page, Simon W Rothwell, Annette C Dolphin
CaVβ subunits interact with the voltage-gated calcium channel CaV2.2 on a site in the intracellular loop between domains I and II (the I-II loop). This interaction influences the biophysical properties of the channel and leads to an increase in its trafficking to the plasma membrane. We have shown previously that a mutant CaV2.2 channel that is unable to bind CaVβ subunits (CaV2.2 W391A) was rapidly degraded (Waithe, D., Ferron, L., Page, K. M., Chaggar, K., and Dolphin, A. C. (2011) J. Biol. Chem. 286, 9598-9611)...
September 23, 2016: Journal of Biological Chemistry
Chiung-Hui Liu, Hung-Ming Chang, To-Jung Tseng, Chyn-Tair Lan, Li-You Chen, Su-Chung Youn, Jian-Jr Lee, Fu-Der Mai, Jui-Feng Chou, Wen-Chieh Liao
The P/Q-type voltage-dependent calcium channel (Cav2.1) in the presynaptic membranes of motor nerve terminals plays an important role in regulating Ca(2+) transport, resulting in transmitter release within the nervous system. The recovery of Ca(2+)-dependent signal transduction on motor end plates (MEPs) and innervated muscle may directly reflect nerve regeneration following peripheral nerve injury. Although the functional significance of calcium channels and the levels of Ca(2+) signalling in nerve regeneration are well documented, little is known about calcium channel expression and its relation with the dynamic Ca(2+) ion distribution at regenerating MEPs...
November 2016: Histochemistry and Cell Biology
Yi Chang, Cheng Wei Lu, Tzu Yu Lin, Shu Kuei Huang, Su Jane Wang
Interest in the health benefits of flavonoids, particularly their effects on neurodegenerative disease, is increasing. This study evaluated the role of baicalein, a flavonoid compound isolated from the traditional Chinese medicine Scutellaria baicalensis, in glutamate release and glutamate neurotoxicity in the rat hippocampus. In the rat hippocampal nerve terminals (synaptosomes), baicalein inhibits depolarization-induced glutamate release, and this phenomenon is prevented by chelating the extracellular Ca[Formula: see text] ions and blocking presynaptic Cav2...
2016: American Journal of Chinese Medicine
Willcyn Tang, Jervis Vermal Thevathasan, Qingshu Lin, Kim Buay Lim, Keisuke Kuroda, Kozo Kaibuchi, Marcel Bilger, Tuck Wah Soong, Marc Fivaz
Lesions and mutations of the DISC1 (Disrupted-in-schizophrenia-1) gene have been linked to major depression, schizophrenia, bipolar disorder and autism, but the influence of DISC1 on synaptic transmission remains poorly understood. Using two independent genetic approaches-RNAi and a DISC1 KO mouse-we examined the impact of DISC1 on the synaptic vesicle (SV) cycle by population imaging of the synaptic tracer vGpH in hippocampal neurons. DISC1 loss-of-function resulted in a marked decrease in SV exocytic rates during neuronal stimulation and was associated with reduced Ca(2+) transients at nerve terminals...
2016: Frontiers in Synaptic Neuroscience
Sabiha R Gardezi, Arup R Nath, Qi Li, Elise F Stanley
Neurotransmitter is released from synaptic vesicles (SVs) that are gated to fuse with the presynaptic membrane by calcium ions that enter through voltage-gated calcium channels (CaVs). There is compelling evidence that SVs associate closely with the CaVs but the molecular linking mechanisms remain poorly understood. Using a cell-free, synaptic vesicle-pull-down assay method (SV-PD) we have recently demonstrated that SVs can bind both to the intact CaV2.2 channel and also to a fusion protein comprising the distal third, C3 segment, of its long C-terminal...
2016: Frontiers in Cellular Neuroscience
Cheng Wei Lu, Tzu Yu Lin, Shu Kuei Huang, Su Jane Wang
The glutamatergic system may be involved in the effects of neuroprotectant therapies. Echinacoside, a phenylethanoid glycoside extracted from the medicinal Chinese herb Herba Cistanche, has neuroprotective effects. This study investigated the effects of echinacoside on 4-aminopyridine-evoked glutamate release in rat cerebrocortical nerve terminals (synaptosomes). Echinacoside inhibited Ca(2+)-dependent, but not Ca(2+)-independent, 4-aminopyridine-evoked glutamate release in a concentration-dependent manner...
2016: International Journal of Molecular Sciences
Anna Marchenkova, Arn M J M van den Maagdenberg, Andrea Nistri
Purinergic P2X3 receptors (P2X3Rs) play an important role in pain pathologies, including migraine. In trigeminal neurons, P2X3Rs are constitutively downregulated by endogenous brain natriuretic peptide (BNP). In a mouse knock-in (KI) model of familial hemiplegic migraine type-1 with upregulated calcium CaV2.1 channel function, trigeminal neurons exhibit hyperexcitability with gain-of-function of P2X3Rs and their deficient BNP-mediated inhibition. We studied whether the absent BNP-induced control over P2X3Rs activity in KI cultures may be functionally expressed in altered firing activity of KI trigeminal neurons...
September 7, 2016: Neuroscience
Shi Song Rong, Li Jia Chen, Christopher K S Leung, Kenji Matsushita, Liyun Jia, Atsuya Miki, Sylvia W Y Chiang, Pancy O S Tam, Noriyasu Hashida, Alvin L Young, Motokazu Tsujikawa, Mingzhi Zhang, Ningli Wang, Kohji Nishida, Chi Pui Pang
A single-nucleotide polymorphism (SNP) rs4236601 at the CAV1/CAV2 locus is associated with primary open-angle glaucoma (POAG). Rs4236601 is common in Caucasians but rare in East Asians. Here we conducted a haplotype-tagging SNP analysis followed by replication in a total of 848 POAG cases and 1574 controls drawn from 3 cities in China and 1 city in Japan. Two SNPs, rs4236601 (odds ratio [OR] = 6.25; P = 0.0086) and a tagging-SNP rs3801994 (OR = 1.32; P = 0.042), were associated with POAG in the Hong Kong Chinese cohort after age and gender adjustments...
2016: Scientific Reports
Shehrazade Dahimene, Karen M Page, Manuela Nieto-Rostro, Wendy S Pratt, Marianna D'Arco, Annette C Dolphin
Episodic ataxia 2 (EA2) is an autosomal dominant disorder caused by mutations in the gene CACNA1A that encodes the pore-forming CaV2.1 calcium channel subunit. The majority of EA2 mutations reported so far are nonsense or deletion/insertion mutations predicted to form truncated proteins. Heterologous expression of wild-type CaV2.1, together with truncated constructs that mimic EA2 mutants, significantly suppressed wild-type calcium channel function, indicating that the truncated protein produces a dominant-negative effect (Jouvenceau et al...
September 2016: Neurobiology of Disease
Géza Berecki, Leonid Motin, David J Adams
U50488H is a benzeneacetamide κ-opioid receptor (κ-OR) agonist analgesic, widely used for investigating the pharmacology of G protein-coupled κ-ORs. However, U50488H is also known to directly block various voltage-gated ion channels in a G protein-independent manner. We investigated the direct actions of U50488H on various high voltage-activated (HVA) and low voltage-activated (LVA) neuronal Ca(2+) channels heterologously expressed in human embryonic kidney (HEK293) cells. U50488H inhibited HVA rat Cav1...
October 2016: Neuropharmacology
Cade Bedford, Catherine Sears, Maria Perez-Carrion, Giovanni Piccoli, Steven B Condliffe
Voltage-gated Ca(2+) (CaV) channels enable Ca(2+) influx in response to membrane depolarization. CaV2.1 channels are localized to the presynaptic membrane of many types of neurons where they are involved in triggering neurotransmitter release. Several signaling proteins have been identified as important CaV2.1 regulators including protein kinases, G-proteins and Ca(2+) binding proteins. Recently, we discovered that leucine rich repeat kinase 2 (LRRK2), a protein associated with inherited Parkinson's disease, interacts with specific synaptic proteins and influences synaptic transmission...
2016: Frontiers in Molecular Neuroscience
Yuan Lei, Maomao Song, Jihong Wu, Chao Xing, Xinghuai Sun
PURPOSE: To investigate endothelial nitric oxide synthase (eNOS) activity and the response of conventional outflow facility to nitric oxide donors and a nitric oxide synthase (NOS) inhibitor in caveolin-1 (CAV1) knockout (KO) mice. METHODS: Intraocular pressure (IOP) was measured in both CAV1 KO and wild-type (WT) mice by rebound tonometry. The expressions of caveolin-2 (CAV2), eNOS, eNOS-phospho Ser1177, eNOS-phospho Thr495, Akt, Akt-phospho Ser473, and nitrotyrosin were measured by Western blot analysis...
May 1, 2016: Investigative Ophthalmology & Visual Science
Anna Marchenkova, Sandra Vilotti, Niels Ntamati, Arn Mjm van den Maagdenberg, Andrea Nistri
BACKGROUND: On trigeminal ganglion neurons, pain-sensing P2X3 receptors are constitutively inhibited by brain natriuretic peptide via its natriuretic peptide receptor-A. This inhibition is associated with increased P2X3 serine phosphorylation and receptor redistribution to non-lipid raft membrane compartments. The natriuretic peptide receptor-A antagonist anantin reverses these effects. We studied whether P2X3 inhibition is dysfunctional in a genetic familial hemiplegic migraine type-1 model produced by introduction of the human pathogenic R192Q missense mutation into the mouse CACNA1A gene (knock-in phenotype)...
2016: Molecular Pain
Zhen Liu, Fei Wang, Gregory Fischer, Quinn H Hogan, Hongwei Yu
BACKGROUND: Gαi-interacting protein (GINIP) is expressed specifically in dorsal root ganglion (DRG) neurons and functions in modulation of peripheral gamma-aminobutyric acid B receptor (GBR). Genetic deletion of GINIP leads to impaired responsiveness to GBR agonist-mediated analgesia in rodent. It is, however, not defined whether nerve injury changes GINIP expression. RESULTS: Immunolabeling with validated antibody revealed GINIP expression in ~40% of total lumbar DRG neurons in normal adult rats...
2016: Molecular Pain
Richard Cheng, Babak Azarbal, Aaron Yung, Jignesh K Patel, David H Chang, Frank Liou, Raj Makkar, Jon A Kobashigawa
BACKGROUND: Elevated immune monitoring (IM), as measured by adenosine triphosphate (ATP) release from activated lymphocytes, has been suggested to represent an under-immunosuppressed state. Its association with the development of angiographic cardiac allograft vasculopathy (CAV) is unknown. METHODS: Patients transplanted between January 2007 and December 2011 with annual angiograms and at least 1 IM assay were included in the analysis. Peak IM scores were determined for each patient...
August 2016: Journal of Heart and Lung Transplantation
Akil A Puckerin, Donald D Chang, Prakash Subramanyam, Henry M Colecraft
Rad/Rem/Rem2/Gem (RGK) proteins are Ras-like GTPases that potently inhibit all high-voltage-gated calcium (CaV1/CaV2) channels and are, thus, well-positioned to tune diverse physiological processes. Understanding how RGK proteins inhibit CaV channels is important for perspectives on their (patho)physiological roles and could advance their development and use as genetically-encoded CaV channel blockers. We previously reported that Rem can block surface CaV1.2 channels in two independent ways that engage distinct components of the channel complex: (1) by binding auxiliary β subunits (β-binding-dependent inhibition, or BBD); and (2) by binding the pore-forming α1C subunit N-terminus (α1C-binding-dependent inhibition, or ABD)...
April 26, 2016: Channels
Hue Yu Wang, Cheng Wei Lu, Tzu Yu Lin, Jinn Rung Kuo, Su Jane Wang
Evidence suggests that the glutamatergic system plays a crucial role in the pathophysiology and treatment of depression. This study investigates the effect of WAY208466, a 5-HT6 receptor agonist exhibiting an antidepressant effect, on glutamate release from rat hippocampal nerve terminals (synaptosomes). WAY208466 inhibited the Ca(2+)-dependent release of glutamate that was evoked by exposing the synaptosomes to the potassium channel blocker 4-aminopyridine, and the selective 5-HT6 receptor antagonist SB258585 blocked this phenomenon...
June 15, 2016: European Journal of Pharmacology
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