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César Mattei
Tetrodotoxin (TTX), the mode of action of which has been known since the 1960s, is widely used in pharmacology as a specific inhibitor of voltage-gated sodium channels (Nav channels). This toxin has contributed to the characterization of the allosteric model of the Nav channel, and to discriminating TTX-sensitive and TTX-resistant subtypes. In addition to its role as a pharmacological tool, TTX is now considered a therapeutic molecule, and its development should lead to its use in certain pathologies involving Nav channels, particularly in the field of pain...
February 22, 2018: Marine Drugs
Rhîannan H Williams, Sarah W Black, Alexia M Thomas, Juliette Piquet, Bruno Cauli, Thomas S Kilduff
We have proposed that cortical nNOS/NK1R interneurons have a role in sleep homeostasis. The hypocretins (orexins) are wake-promoting neuropeptides and hypocretin/orexin (Hcrt) neurons project to the cortex. Hcrt peptides affect deep layer cortical neurons, and Hcrt receptor 1 (Hcrtr1; Ox1r) mRNA is expressed in cortical nNOS/NK1R cells. Therefore, we investigated whether Hcrt neuron stimulation affects cingulate cortex nNOS/NK1R neurons. Bath application of HCRT1/orexin-A evoked an inward current and membrane depolarization in most nNOS/NK1R cells which persisted in tetrodotoxin; optogenetic stimulation of Hcrt terminals expressing channelrhodopsin-2 confirmed these results, and pharmacological studies determined that HCRTR1 mediated these responses...
February 16, 2018: Cerebral Cortex
Kazuki Noma, Hironari Akaike, Yuki Kurauchi, Hiroshi Katsuki, Yasuo Oyama, Norio Akaike
Glycine is a fast inhibitory transmitter like γ-aminobutyric acid in the mammalian spinal cord and brainstem, and it is involved in motor reflex, nociception, and neuronal development. Triphenyltin (TPT) is an organometallic compound causing environmental hazard to many wild creatures. Our previous findings show that TPT ultimately induces a drain and/or exhaustion of glutamate in excitatory presynaptic nerve terminals, resulted in blockage of neurotransmission as well as methylmercury. Therefore, we have investigated the neurotoxic mechanism how TPT modulates inhibitory glycinergic transmission in the synaptic bouton preparation of rat isolated spinal neurons using a patch clamp technique...
February 13, 2018: Environmental Research
Vladimir Rancic, Bijal Rawal, Bogdan Panaitescu, Araya Ruangkittisakul, Klaus Ballanyi
The brainstem locus coeruleus (LC) controling behaviors like arousal, sleep, breathing, pain or opioid withdrawal is an established model for spontaneous action potential synchronization. Such synchronous 'spiking' might produce an extracellular field potential (FP) which is a crucial tool for neural network analyses. We found using ≥10 μm tip diameter suction electrodes in newborn rat brainstem slices that the LC generates at ∼1 Hz a robust rhythmic FP (rFP). During distinct rFP phases, LC neurons discharge with a jitter of ±33 ms single spikes that summate to a ∼200 ms-lasting population burst...
February 12, 2018: Neuroscience Letters
M Kollarik, H Sun, R A Herbstsomer, F Ru, M Kocmalova, S N Meeker, B J Undem
The action potential (AP) initiation in the nerve terminals and AP conduction along the axons do not necessarily depend on the same subtypes of Na V 1s. We evaluated the role of tetrodotoxin(TTX)-sensitive and TTX-resistant Na V 1s in vagal afferent nociceptor nerves derived from jugular and nodose ganglia innervating the respiratory system. Single cell RT-PCR was performed on vagal afferent neurons retrogradely labelled from the guinea pig trachea. Virtually all the jugular neurons expressed the TTX-sensitive channel Na V 1...
February 12, 2018: Journal of Physiology
Chong Chen, Songhua Wang, Qingjuan Hu, Lvming Zeng, Hailong Peng, Chao Liu, Li-Ping Huang, Hao Song, Yuping Li, Li-Hua Yao, Wei Meng
BACKGROUND/AIMS: Islet beta cells (β-cells) are unique cells that play a critical role in glucose homeostasis by secreting insulin in response to increased glucose levels. Voltage-gated ion channels in β-cells, such as K+ and Ca2+ channels, contribute to insulin secretion. The response of voltage-gated Na+ channels (VGSCs) in β-cells to the changes in glucose levels remains unknown. This work aims to determine the role of extracellular glucose on the regulation of VGSC. METHODS: The effect of glucose on VGSC currents (INa) was investigated in insulin-secreting β-cell line (INS-1) cells of rats using whole-cell patch clamp techniques, and the effects of glucose on insulin content and cell viability were determined using Enzyme-Linked Immunosorbent Assay (ELISA) and Methylthiazolyldiphenyl-tetrazolium Bromide (MTT) assay methods respectively...
January 24, 2018: Cellular Physiology and Biochemistry
Xiongzhi Zeng, Pengpeng Li, Bo Chen, Juan Huang, Ren Lai, Jingze Liu, Mingqiang Rong
Jingzhaotoxin-34 (JZTX-34) is a selective inhibitor of tetrodotoxin-sensitive (TTX-S) sodium channels. In this study, we found that JZTX-34 selectively acted on Nav1.7 with little effect on other sodium channel subtypes including Nav1.5. If the DIIS3-S4 linker of Nav1.5 is substituted by the correspond linker of Nav1.7, the sensitivity of Nav1.5 to JZTX-34 extremely increases to 1.05 µM. Meanwhile, a mutant D816R in the DIIS3-S4 linker of Nav1.7 decreases binding affinity of Nav1.7 to JZTX-34 about 32-fold...
February 2, 2018: Toxins
Rachel Feldman-Goriachnik, Bing Wu, Menachem Hanani
Satellite glial cells (SGCs) surround the neurons in sympathetic ganglia and are believed to make important contributions to the function of the ganglia under normal and pathological conditions. It has been proposed that SGCs communicate chemically with the neurons, but little is known about their pharmacological properties and there is no information on whether they respond to acetylcholine (ACh), which is the major neurotransmitter in these ganglia. We used calcium imaging to examine responses of SGCs in the mouse superior cervical ganglion to ACh...
January 30, 2018: Neuroscience Letters
Ao Ri-Ge-le, Zhuang-Li Guo, Qi Wang, Bao-Jian Zhang, Da-Wei Kong, Wen-Qiang Yang, Yan-Bing Yu, Li Zhang
Painful diabetic neuropathy (PDN) is one of the intractable complications of diabetes mellitus, which manifest as exaggerated pain perception. Previous studies showed that Tanshinone IIA (TIIA), one of the major bioactive extracts of Salvia miltiorrhiza Bunge, have obvious analgesic effect on different types of pain process, and the underlying analgesic mechanisms are not fully understood. The present study combined the behavioral, electrophysiological and biochemical methods to elucidate the analgesic mechanism of TIIA, using streptozotocin (STZ)-induced PDN rat models...
January 31, 2018: Experimental and Clinical Endocrinology & Diabetes
Cesar C Ceballos, Rodrigo F O Pena, Antônio C Roque, Ricardo M Leão
The negative slope conductance created by the persistent sodium current (INaP) prolongs the decay phase of excitatory postsynaptic potentials (EPSPs). In a recent study, we demonstrated that this effect was due to an increase of the membrane time constant. When the negative slope conductance opposes completely the positive slope conductances of the other currents it creates a zero slope conductance region. In this region the membrane time constant is infinite and the decay phase of the EPSPs is virtually absent...
January 30, 2018: Channels
Xiaopeng Bai, Eikichi Ihara, Katsuya Hirano, Yoshimasa Tanaka, Kayoko Nakano, Satomi Kita, Takahiro Iwamoto, Haruei Ogino, Mayumi Hirano, Yoshinao Oda, Kazuhiko Nakamura, Yoshihiro Ogawa
Background and Aims: Hydrogen sulfide (H2S) is a major physiologic gastrotransmitter. Its role in the regulation of the lower esophageal sphincter (LES) function remains unknown. The present study addresses this question. Methods: Isometric contraction was monitored in circular smooth muscle strips of porcine LES. Changes in cytosolic Ca2+ concentration ([Ca2+]i) and force were simultaneously monitored in fura-2-loaded strips with front-surface fluorometry. The contribution of endogenous H2S to LES contractility was investigated by examining the effects of inhibitors of H2S-generating enzymes, including cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, on the LES function...
March 2018: Cellular and Molecular Gastroenterology and Hepatology
K Beck, A Friebe, B Voussen
BACKGROUND: Regulation of gastrointestinal motility involves excitatory and inhibitory neurotransmission. Nitric oxide (NO), the major inhibitory neurotransmitter, acts via its receptor NO-sensitive guanylyl cyclase (NO-GC). In the GI tract, NO-GC is expressed in several cell types such as smooth muscle cells (SMC) and interstitial cells of Cajal (ICC). Using cell-specific knockout mice, we have previously shown that NO-GC modulates spontaneous contractions in colonic longitudinal smooth muscle...
January 29, 2018: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Yejia Song, Luiz Belardinelli
Aging hearts have prolonged QT interval and are vulnerable to oxidative stress. Because the QT interval indirectly reflects the action potential duration (APD), we examined the hypotheses that 1) the APD of ventricular myocytes increases with age; 2) the age-related prolongation of APD is due to an enhancement of basal late Na+ current (INaL); 3) inhibition of INaL may protect aging hearts from arrhythmogenic effects of hydrogen peroxide (H2O2). Experiments were performed on ventricular myocytes isolated from one-month (young) and one-year (old) guinea pigs (GPs)...
December 14, 2017: Journal of Applied Physiology
Naoki Adachi, Shingo Suzuki, Hidetada Matsuoka, Satoko Fushimi, Junichiro Ono, Ken-Ichi Ohta, Yohei Hirai, Takanori Miki, Hisatsugu Koshimizu
A recent study revealed that corticotropin-releasing hormone (CRH) in the cerebral cortex (CTX) plays a regulatory role in emotional behaviors in rodents. Given the functional interaction between brain-derived neurotrophic factor (BDNF) and the CRH-signaling pathway in the hypothalamic-pituitary-adrenal (HPA) axis, we hypothesized that BDNF may regulate gene expression of CRH and its related molecules in the CTX. Findings of real-time quantitative PCR (RT-qPCR) indicated that stimulation of cultured rat cortical neurons with BDNF led to marked elevations in the mRNA levels of CRH and CRH-binding protein (CRH-BP)...
January 22, 2018: Journal of Neurochemistry
Hiroyuki Ueda, Shiro Itoi, Haruo Sugita
Polyclad flatworms comprise a highly diverse and cosmopolitan group of marine turbellarians. Although some species of the genera Planocera and Stylochoplana are known to be tetrodotoxin (TTX)-bearing, there are few new reports. In this study, planocerid-like flatworm specimens were found in the sea bottom off the waters around the Ryukyu Islands, Japan. The bodies were translucent with brown reticulate mottle, contained two conical tentacles with eye spots clustered at the base, and had a slightly frilled-body margin...
January 19, 2018: Marine Drugs
A Lütt, K Michel, D Krüger, M S Volz, M Nassir, E Schulz, L Poralla, P Tangermann, C Bojarski, M Höltje, B Teegen, W Stöcker, M Schemann, B Siegmund, H Prüss
BACKGROUND: Antineuronal antibodies can be associated with both gastrointestinal (GI) and brain disorders. For example, antibodies against the potassium channel subunit dipeptidyl-peptidase-like protein-6 (DPPX) bind to neurons in the central nervous system (CNS) and myenteric plexus and cause encephalitis, commonly preceded by severe unspecific GI symptoms. We therefore investigated the prevalence of antineuronal antibodies indicative of treatable autoimmune CNS etiologies in GI patients...
January 18, 2018: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Yuji Nagashima, Akira Ohta, Xianzhe Yin, Shoichiro Ishizaki, Takuya Matsumoto, Hiroyuki Doi, Toshiaki Ishibashi
Although pufferfish of the family Tetraodontidae contain high levels of tetrodotoxin (TTX) mainly in the liver, some species of pufferfish, boxfish of the family Ostraciidae, and porcupinefish of the family Diodontidae do not. To clarify the mechanisms, uptake of TTX and saxitoxins (STXs) into liver tissue slices of pufferfish, boxfish and porcupinefish was examined. Liver tissue slices of the pufferfish (toxic species Takifugu rubripes and non-toxic species Lagocephalus spadiceus, L. cheesemanii and Sphoeroides pachygaster) incubated with 50 µM TTX accumulated TTX (0...
January 8, 2018: Marine Drugs
Loris L Ferrari, Daniel Park, Lin Zhu, Matthew R Palmer, Rebecca Y Broadhurst, Elda Arrigoni
Orexin (also known as hypocretin) neurons are considered a key component of the ascending arousal system. They are active during wakefulness, at which time they drive and maintain arousal, and are silent during sleep. Their activity is controlled by long-range inputs from many sources, as well as by more short-range inputs, including from presumptive GABAergic neurons in the lateral hypothalamus/perifornical region (LH/PF). To characterize local GABAergic input to orexin neurons we employed channelrhodopsin-2 (ChR2)-assisted-circuit-mapping in brain slices...
January 8, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
L Candenas, F M Pinto, A Cejudo-Román, C González-Ravina, M Fernández-Sánchez, N Pérez-Hernández, J Irazusta, N Subirán
AIMS: The sperm plasma membrane contains specific ion channels and transporters that initiate changes in Ca2+, Na+, K+ and H+ ions in the sperm cytoplasm. Ion channels are key regulators of the sperm membrane potential, cytoplasmic Ca2+ and intracellular pH (pHi), which leads to regulate motility, capacitation, acrosome reaction and other physiological processes crucial for successful fertilization. Expression of epithelial sodium channels (ENaC) and voltage-gated sodium channels (Nav) in human spermatozoa has been reported, but the role of Na+ fluxes sodium channels in the regulation of sperm cell function remains poorly understood...
January 4, 2018: Life Sciences
Poojan Pyakurel, Mimi Shin, B Jill Venton
Acetylcholine is an excitatory neurotransmitter in the central nervous system of insects and the nicotinic acetylcholine receptor (nAChR) is a target for neonicotinoid insecticides. Functional insect nAChRs are difficult to express in host cells, and hence difficult to study. In mammals, acetylcholine and nicotine evoke dopamine release, but the extent to which this mechanism is conserved in insects is unknown. In intact larval ventral nerve cords (VNCs), we studied dopamine evoked by acetylcholine, nicotine, or neonicotinoids...
January 3, 2018: Neurochemistry International
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