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Overview of Ion Channels, Antiepileptic Drugs, and Seizures
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Potassium channels are ubiquitous in eukaryotic cells and exhibit more diverse characteristics than channels for other ions.22 Over a dozen types of K+ channels have already been identified using variations on the patch clamp technique.2 Selective toxins also have been discovered that potently block particular types of K+ channels, which allow examination of the role of the particular current type in controlling the excitability pattern of specific cell types.23 These agents include apamin, a toxin from the honey bee, that inhibits Ca2+-activated K+ channels. Two scorpion toxins, charybdotoxin and noxioustoxin, and a toxin from mamba snake venom, dendrotoxin, also selectively affect different K+ channels.23 G-proteins act to couple many types of K+ channel to neurotransmitters.24
BK channels and a cGMP-dependent protein kinase (PKG) function through independent mechanisms to regulate the tolerance of synaptic transmission to acute oxidative stress at the Drosophila larval neuromuscular junction
Published in Journal of Neurogenetics, 2018
Wesley L. Bollinger, Nadia Sial, Ken Dawson-Scully
Iberiotoxin has been used to inhibit BK channel conductance in mammalian systems (McKay et al., 1994). BK channels expressed in Xenopus oocytes have been shown to be insensitive to iberiotoxin up to 100 nM (Meera, Wallner, Song, & Toro, 1997). Thus, there is no direct evidence of low doses of iberiotoxin inhibiting Drosophila BK channels; however, 200 nM charybdotoxin has been shown to inhibit the BK channel encoded K+ current (ICF current) at the Drosophila NMJ (Kadas et al., 2015). Despite its highly similar amino acid sequence and mechanism of action, iberiotoxin has been shown to be approximately ten times more effective at inhibiting rat BK channels compared to charybdotoxin (Candia, Garcia, & Latorre, 1992). If low doses of iberiotoxin also inhibited non-BK K+ channels, we might expect to observe an increase in time to synaptic failure in Slo4 mutants using our assay; contrarily, our results demonstrate that application of 0.5 nM iberiotoxin to the Drosophila NMJ does not significantly modify time to synaptic failure in Slo4 mutants. Thus, 0.5 nM iberiotoxin may specifically act on BK channels as opposed to other K+ channels at the Drosophila NMJ. Iberiotoxin was used in this study because of its structural similarity to charybdotoxin; unlike charybdotoxin, however, iberiotoxin has not demonstrated any off-target effects at the larval NMJ (Candia et al., 1992; Kadas et al., 2015).
Dihydromyricetin improves vascular hyporesponsiveness in experimental sepsis via attenuating the over-excited MaxiK and KATP channels
Published in Pharmaceutical Biology, 2018
Jin Peng, Jian Zhang, Li Zhang, Yonggang Tian, Yahong Li, Lujun Qiao
Thoracic aortas were isolated and prepared for vascular function studies (Spradley et al. 2012). On the 8th day, rats were anesthetized using 300 mg/kg chloral hydrate and decapitated. The thoracic aorta was carefully excised and placed in a Petri dish filled with cold Kerbs solution (KHS) containing (in mM) NaCl 118.5, KCl 4.7, KH2PO4 1.2, MgSO4 1.2, NaHCO3 25.0, CaCl2 2.5 and glucose 5.5 at 37 °C continuously bubbled with a 95% O2 to 5% CO2 mixture (pH 7.4). The aorta was cleaned of excess connective tissue and cut into rings of approximately 3 mm in length. Thoracic aorta segments were mounted on two parallel stainless-steel pins for arterial isometric tension recording through a MAP2000 isometric force transducer (Alcott Biotech Co. Ltd., Shanghai, China) connected to a computer. Segments were suspended in an organ bath containing 20 mL of KHS and subjected to a tension of 2 g which was readjusted every 30 min during a 120 min equilibration period before drug administration. The vessels were then exposed to KCl (60 mM) to check their functional integrity. After washing out the thoracic aorta rings with KHS solution, we recorded the basal vascular tone prior to evaluating the contractile response by measuring the maximal peak height which is expressed as the maximal tension % achieved in response to 140 mM K+ (Kmax). Dose-response curves for NE (doses from 10−9 to 10−6 M) were obtained in aortic rings in a cumulative manner. To explore the role of K+ channels in vascular tension, the contractility was quantitated after administration of 3 × 10−3 M TEA (tetraethylammounium, a nonselective potassium channel blocker), 3 × 10−8 M charybdotoxin (ChTX, a potent MaxiK channel blocker), 3 × 10−8 M glibenclamide (Glib, KATP channel blocker) and 3 × 10−3 M 4-AP (4-aminopyridine, a potent Kv channel blocker) and 3 × 10−3 M BaCl2 (a potent Kir channel blocker).