bk channel inhibitor

In neocortical layer-5 pyramidal neurons, the action potential (AP) is generated in the axon initial segment (AIS) when the membrane potential (Vm ) reaches the threshold for activation of the voltage-gated Na+ channels (VGNCs) Nav 1.2 and Nav 1.6. Yet, whereas it is known that these VGNCs differ in spatial distribution along the AIS and in biophysical properties, the understanding of the functional differences between the two channels remains elusive. Here, using ultrafast Na+ , Vm and Ca2+ imaging in combination with the partial block of Nav 1...

Tutin, an established toxic natural product that causes epilepsy in rodents, is often used as a tool to develop animal model of acute epileptic seizures. However, the molecular target and toxic mechanism of tutin were unclear. In this study, for the first time, we conducted experiments to clarify the targets in tutin-induced epilepsy using thermal proteome profiling. Our studies showed that calcineurin (CN) was a target of tutin, and that tutin activated CN, leading to seizures. Binding site studies further established that tutin bound within the active site of CN catalytic subunit...

Previous our study found that improvement of skin blood flow associated with neuropathic pain using vasodilators is useful for alleviation of neuropathic pain. In this study, we aimed to elucidate the mechanism underlying enhanced vasorelaxation induced by vasodilators, which increase cAMP and cyclic guanosine monophosphate (cGMP), in chronic constriction injury model rat. We assessed vasorelaxation effect of vasodilators by measurement of isometric contraction in isolated plantar artery from chronic constriction injury of sciatic nerve model rats...

Exposure of human lung epithelial cells (A549 cell line) to the oxidant pollutant ozone (O3 ) alters cell membrane currents inducing its decrease, when the cell undergoes to a voltage-clamp protocol ranging from -90 to +70mV. The membrane potential of these cells is mainly maintained by the interplay of potassium and chloride currents. Our previous studies indicated the ability of O3 to activate ORCC and consequently increases the chloride current (Outward Rectifier Chloride Channel). In this paper our aim was to understand the response of potassium current to oxidative stress challenge and to identify the kind potassium channel involved in O3 induced current changes...

A number of mutations to members of several CNS potassium (K) channel families have been identified which result in rare forms of neonatal onset epilepsy, or syndromes of which one prominent characteristic is a form of epilepsy. Benign Familial Neonatal Convulsions or Seizures (BFNC or BFNS), also referred to as Self-Limited Familial Neonatal Epilepsy (SeLNE), results from mutations in 2 members of the KV 7 family (KCNQ) of K channels; while generally self-resolving by about 15 weeks of age, these mutations significantly increase the probability of generalized seizure disorders in the adult, in some cases they result in more severe developmental syndromes...

Barbados has a rich traditional use of medicinal plants, especially among the older population who may have a chronic noncommunicable disease. This study aims to identify possible drug-herb interactions between popular herbal remedies used to manage elevated blood pressure and conventional antihypertensive drugs. In this study, in silico molecular docking experiments with AutoDock Vina (Scripps Research Institute, La Jolla, CA), a part of Yasara Structure software, version 20.12.24, were used to screen 30 potential phytochemicals for drug interactions from 11 popular plants in Barbados that are used for high blood pressure and could influence the pharmacology of the most prescribed antihypertensive drugs in Barbados...

Sensory neuron hyperexcitability is a critical driver of pathological pain and can result from axon damage, inflammation, or neuronal stress. G-protein coupled receptor (GPCR) signaling can induce pain amplification by modulating the activation of Trp-family ionotropic receptors and voltage-gated ion channels. Here, we sought to use calcium imaging to identify novel inhibitors of the intracellular pathways that mediate sensory neuron sensitization and lead to hyperexcitability. We identified a novel stimulus cocktail consisting of L-054,264, a SST2R agonist, and CYM5541, a S1PR3 agonist, that elicits calcium responses in mouse primary sensory neurons in vitro as well as pain and thermal hypersensitivity in mice in vivo...

Epilepsy is the results from the imbalance between inhibition and excitation in neural circuits, which is mainly treated by some chemical drugs with side effects. Gain-of-function of BK channels or knockout of its β4 subunit associates with spontaneous epilepsy. Currently, few reports were published about the efficacy of BK(α+β4) channel modulators in epilepsy prevention. Charybdotoxin is a non-specific inhibitor of BK and other K+ channels. Here, by nuclear magnetic resonance (NMR) and other biochemical techniques, we found that charybdotoxin might interact with the extracellular loop of human β4 subunit (i...

Acetylcholine can excite neurons by suppressing M-type (KCNQ) potassium channels. This effect is mediated by M1 muscarinic receptors coupled to the Gq protein. Although PIP2 depletion and PKC activation have been strongly suggested to contribute to muscarinic inhibition of M currents (IM ), direct evidence is lacking. We investigated the mechanism involved in muscarinic inhibition of IM with Ca2+ measurement and electrophysiological studies in both neuronal (rat sympathetic neurons) and heterologous (HEK cells expressing KCNQ2/KCNQ3) preparations...

AIM: The kaliuretic action of the renin-angiotensin-aldosterone system (RAAS) is well established as highlighted by hyperkalemia side effect of RAAS inhibitors but such action is usually ascribed to systemic RAAS. The present study addresses the involvement of intrarenal RAAS in K+ homeostasis with emphasis on locally generated renin within the collecting duct (CD). METHODS: Wild-type (Floxed) and CD-specific deletion of renin (CD renin KO) mice were treated for 7 days with high K+ (HK) diet to investigate the role of CD renin in kaliuresis regulation and further to define the underlying mechanism with emphasis on analysis of intrarenal aldosterone biosynthesis...

H2 S is a gaseous signaling molecule enzymatically produced in mammals and H2 S-producing enzymes are expressed throughout the vascular wall. We previously reported that H2 S-induced vasodilation is mediated through transient receptor potential cation channel subfamily V member 4 (TRPV4) and large conductance (BKCa ) potassium channels; however, regulators of this pathway have not been defined. Previous reports have shown that membrane cholesterol limits activity of TRPV4 and BKCa potassium channels. The current study examined the ability of endothelial cell (EC) plasma membrane (PM) cholesterol to regulate H2 S-induced vasodilation...

Atrial fibrillation is the most common sustained cardiac arrhythmia in humans. Current atrial fibrillation antiarrhythmic drugs have limited efficacy and carry the risk of ventricular proarrhythmia. GsMTx4, a mechanosensitive channel-selective inhibitor, has been shown to suppress arrhythmias through the inhibition of stretch-activated channels (SACs) in the heart. The cost of synthesizing this peptide is a major obstacle to clinical use. Here, we studied two types of short peptides derived from GsMTx4 for their effects on a stretch-activated big potassium channel (SAKcaC) from the heart...

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in adult central nervous system (CNS) synapses, but it excites immature CNS neurons as well as neurons in the myenteric plexus. The present work aimed to determine whether GABA-induced nonadrenergic, noncholinergic (NANC) neuronal-mediated relaxation of the rat duodenum is dependent on the activity of Na+ K+ Cl- cotransporters (NKCC) and requires calcium influx. In the presence of guanethidine (3 µmol/L), atropine (3 µmol/L), and indomethacin (1 µmol/L), relaxations induced by GABA (100 µmol/L), KCl (5-10 mmol/L) and electrical field stimulation (1-8 Hz, 2 ms, 60 V), but not those induced by bradykinin (10-100 nmol/L) were abolished by lidocaine (300 µmol/L)...

INTRODUCTION: Accumulating evidence demonstrates the importance of the galectin protein Placental Protein 13 (PP13) in predicting Preeclampsia (PE), a gestational disorder that has no cure and is associated with a compromised uterine vascular adaptation to pregnancy. Uterine vasculature undergoes significant remodeling (growth in length and in circumference) during normal pregnancy to accommodate the increased blood volume to the feto-placental unit. The aim of this study was to demonstrate the role of PP13 on the uterine veins (UVs)...

Voltage-gated KV 1.3 channel has been reported to be a drug target for the treatment of autoimmune diseases, and specific inhibitors of Kv1.3 are potential therapeutic drugs for multiple diseases. The scorpions could produce various bioactive peptides which could inhibit KV 1.3 channel. Here we identified a new scorpion toxin polypeptide gene ImKTX58 from the venom gland cDNA library of the Chinese scorpion Isometrus maculatus Sequence alignment revealed high similarities between ImKTX58 mature peptide and previously reported KV 1...

Tick-borne encephalitis virus (TBEV), the most medically relevant tick-transmitted flavivirus in Eurasia, targets the host central nervous system and frequently causes severe encephalitis. The severity of TBEV-induced neuropathogenesis is highly cell-type specific and the exact mechanism responsible for such differences has not been fully described yet. Thus, we performed a comprehensive analysis of alterations in host poly-(A)/miRNA/lncRNA expression upon TBEV infection in vitro in human primary neurons (high cytopathic effect) and astrocytes (low cytopathic effect)...

BK potassium channels are are activated by intracellular Ca+ and depolarization, opening during action potential firing and speeding repolarization. Because of this, they are key regulators of fast spiking activity and important determinants of neuronal excitability. Due to their role in regulating excitability as well as their broad expression in both excitable and non-excitable tissues, BK channels are implicated in many pathological states including epilepsy. The BK channel antagonist, paxilline, has been shown to delay seizure induction in adult rodents that have had prior seizures, but not in seizure naïve rodents...

We recently demonstrated that endothelial inwardly rectifying potassium (Kir) channels play a key role in flow-induced vasodilation (FIV) of resistance arteries via regulating nitric oxide (NO) production with Akt/eNOS pathway. However, the role of endothelial Kir channels in receptor-mediated vasodilation remains unknown. Therefore, we tested the role of Kir channels in receptor-mediated vasodilation of mesenteric arteries. A significant reduction in the vasodilation to bradykinin was observed in mesenteric arteries from Kir2...

The corticosteroid hormone, aldosterone, markedly enhances K+ secretion throughout the colon - a mechanism critical to its role in maintaining overall K+ balance. Previous studies from our lab have demonstrated that basolateral Na+ -K+ -2Cl- cotransporter 1 (NKCC1) is transcriptionally up-regulated by aldosterone in the distal colon specifically to support large conductance K+ (BK) channel-mediated K+ secretion. This function is distinct from the more well-established role of NKCC1 in supporting luminal Cl- secretion throughout the gastrointestinal tract...

TRPM3 is a calcium-permeable cation channel expressed in a range of sensory neurons that can be activated by heat and the endogenous steroid pregnenolone sulfate (PS). During inflammation, the expression and function of TRPM3 are both augmented in somatosensory nociceptors. However, in isolated dorsal root ganglion (DRG) neurons application of inflammatory mediators like prostaglandins and bradykinin (BK) inhibit TRPM3. Therefore, the aim of this study was to examine the effect of preceding activation of cultured 1 day old mouse DRG neurons by the inflammatory mediator BK on TRPM3-mediated calcium responses...