Noncanonical pharmacological inhibition of the hERG K channel by a synthetic cannabinoid.

Synthetic cannabinoid receptor agonists (SCRAs) are illicit 'street' drugs (colloquially known as "K2", "Spice" or "Mamba"), the use of which has been linked to QT interval prolongation and changes in T wave morphology. Machine learning models have predicted that SCRAs have some propensity to interact with hERG potassium channels. This study was conducted to evaluate effects of the SCRA 5F-AKB48 on hERG channel electrophysiology.

Palmitoylation regulates the magnitude of HCN4-mediated currents in mammalian cells.

The sinoatrial node (SAN) and subsidiary pacemakers in the cardiac conduction system generate spontaneous electrical activity which is indispensable for electrical and therefore contractile function of the heart. The hyperpolarisation-activated cyclic nucleotide-gated channel HCN4 is responsible for genesis of the pacemaker "funny" current during diastolic depolarisation. S-palmitoylation, the reversible conjugation of the fatty acid palmitate to protein cysteine sulfhydryls, regulates the activity of key cardiac Na and Ca handling proteins, influencing their membrane microdomain localisation and function.

Investigation of the Effects of the Short QT Syndrome D172N Kir2.1 Mutation on Ventricular Action Potential Profile Using Dynamic Clamp.

The congenital short QT syndrome (SQTS) is a cardiac condition that leads to abbreviated ventricular repolarization and an increased susceptibility to arrhythmia and sudden death. The SQT3 form of the syndrome is due to mutations to the gene that encodes Kir2.1, a critical component of channels underlying cardiac inwardly rectifying K current, I.

Identification through action potential clamp of proarrhythmic consequences of the short QT syndrome T618I hERG 'hotspot' mutation.

The T618I KCNH2-encoded hERG mutation is the most frequently observed mutation in genotyped cases of the congenital short QT syndrome (SQTS), a cardiac condition associated with ventricular fibrillation and sudden death. Most T618I hERG carriers exhibit a pronounced U wave on the electrocardiogram and appear vulnerable to ventricular, but not atrial fibrillation (AF). The basis for these effects is unclear.

Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant.

The lipophilic polycyclic aromatic hydrocarbon (PAH) phenanthrene is relatively abundant in polluted air and water and can access and accumulate in human tissue. Phenanthrene has been reported to interact with cardiac ion channels in several fish species. This study was undertaken to investigate the ability of phenanthrene to interact with hERG (human Ether-à-go-go-Related Gene) encoded Kv11.

Impact of ambient relative humidity and acidity on chemical composition evolution for malonic acid/calcium nitrate mixed particles.

The chemical compositions in atmospheric aerosols, which often evolve with environmental factors, have significant impact on climate and human health, while our fundamental understanding of chemical process is limited owing to their sensitive to atmospheric conditions. pH and RH are critical chemical factors of aerosols, impacting reaction pathways and kinetics that ultimately govern final components in particles. Herein, we monitored the chemical composition in internally mixed malonic acid/calcium nitrate with the mole ratio of 1:1 as a function of pH and relative humidity (RH).

Hygroscopicity measurement of sodium carbonate, β-alanine and internally mixed β-alanine/NaCO particles by ATR-FTIR.

Water-uptakes of pure sodium carbonate (NaCO), pure β-alanine and internally mixed β-alanine/NaCO aerosol particles with different mole ratios are first monitored using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) technique. For pure NaCO aerosol particles, combining the absorptions at 877 and 1422 cm with abrupt water loss shows the efflorescence relative humidity (ERH) of 62.9%-51.

Potent hERG channel inhibition by sarizotan, an investigative treatment for Rett Syndrome.

Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder associated with respiratory abnormalities and, in up to ~40% of patients, with prolongation of the cardiac QT interval. QT prolongation calls for cautious use of drugs with a propensity to inhibit hERG channels. The STARS trial has been undertaken to investigate the efficacy of sarizotan, a 5-HT receptor agonist, at correcting RTT respiratory abnormalities.

Emerging therapeutic targets in the short QT syndrome.

Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable. Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed.

Structural implications of hERG K channel block by a high-affinity minimally structured blocker.

Cardiac potassium channels encoded by human ether-à-go-go-related gene () are major targets for structurally diverse drugs associated with acquired long QT syndrome. This study characterized hERG channel inhibition by a minimally structured high-affinity hERG inhibitor, Cavalli-2, composed of three phenyl groups linked by polymethylene spacers around a central amino group, chosen to probe the spatial arrangement of side chain groups in the high-affinity drug-binding site of the hERG pore. hERG current () recorded at physiological temperature from HEK293 cells was inhibited with an IC of 35.

Development of Potent, Selective SRPK1 Inhibitors as Potential Topical Therapeutics for Neovascular Eye Disease.

Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance of pro/antiangiogenic isoforms to normal physiological levels. The lack of potency and selectivity of available compounds has limited development of SRPK1 inhibitors, with the control of alternative splicing by splicing factor-specific kinases yet to be translated. We present here compounds that occupy a binding pocket created by the unique helical insert of SRPK1, and trigger a backbone flip in the hinge region, that results in potent (<10 nM) and selective inhibition of SRPK1 kinase activity.

Suppression of the hERG potassium channel response to premature stimulation by reduction in extracellular potassium concentration.

Potassium channels encoded by human ether-à-go-go-related gene (hERG) mediate the cardiac rapid delayed rectifier K(+) current (IKr), which participates in ventricular repolarization and has a protective role against unwanted premature stimuli late in repolarization and early in diastole. Ionic current carried by hERG channels (IhERG) is known to exhibit a paradoxical dependence on external potassium concentration ([K(+)]e), but effects of acute [K(+)]e changes on the response of IhERG to premature stimulation have not been characterized. Whole-cell patch-clamp measurements of hERG current were made at 37°C from hERG channels expressed in HEK293 cells.

Ranolazine inhibition of hERG potassium channels: drug-pore interactions and reduced potency against inactivation mutants.

The antianginal drug ranolazine, which combines inhibitory actions on rapid and sustained sodium currents with inhibition of the hERG/IKr potassium channel, shows promise as an antiarrhythmic agent. This study investigated the structural basis of hERG block by ranolazine, with lidocaine used as a low potency, structurally similar comparator. Recordings of hERG current (IhERG) were made from cell lines expressing wild-type (WT) or mutant hERG channels.

Modification by KCNE1 variants of the hERG potassium channel response to premature stimulation and to pharmacological inhibition.

human Ether-à-go-go-Related Gene (hERG) encodes the pore-forming subunit of cardiac rapid delayed rectifier K(+) current (I Kr) channels, which play important roles in ventricular repolarization, in protecting the myocardium from unwanted premature stimuli, and in drug-induced Long QT Syndrome (LQTS). KCNE1, a small transmembrane protein, can coassemble with hERG. However, it is not known how KCNE1 variants influence the channel's response to premature stimuli or if they influence the sensitivity of hERG to pharmacological inhibition.

Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD.

Purpose: Exudative AMD (wet AMD) is treated by monthly injection into the eye of anti-VEGF proteins. VEGF is alternatively spliced to produce numerous isoforms that differ in angiogenic activity. Serine-rich protein kinase-1 (SRPK1) has been identified as a regulator of pro-angiogenic VEGF splicing by phosphorylating serine-rich splicing factor-1 (SRSF1), which binds to VEGF pre-mRNA.

High potency inhibition of hERG potassium channels by the sodium-calcium exchange inhibitor KB-R7943.

Background And Purpose: KB-R7943 is an isothiourea derivative that is used widely as a pharmacological inhibitor of sodium-calcium exchange (NCX) in experiments on cardiac and other tissue types. This study investigated KB-R7943 inhibition of hERG (human ether-à-go-go-related gene) K(+) channels that underpin the cardiac rapid delayed rectifier potassium current, I(Kr) .

Experimental Approach: Whole-cell patch-clamp measurements were made of hERG current (I(hERG) ) carried by wild-type or mutant hERG channels and of native rabbit ventricular I(Kr) .

[Effects of beta-cypermethrin on voltage-gated potassium channels in rat hippocampal CA3 neurons].

The effects of beta-cypermethrin (consisting of alpha-cypermethrin and theta-cypermethrin) on the transient outward potassium current (I(A)) and delayed rectifier potassium current (I(K)) in freshly dissociated hippocampal CA3 neurons of rats were studied using whole-cell patch-clamp technique. The results indicated that alpha-cypermethrin increased the value of I(A) and theta-cypermethrin decreased the value of I(A), though both of them shifted steady activation curve of I(A) towards negative potential. theta-cypermethrin contributed to the inactivation of I(A).

[Changes of heart rate variability and impairment of learning and memory induced by cerebral ischemia/reperfusion in rats].

The present study was designed to observe the influence of cerebral ischemia/reperfusion injury on learning and memory in hyperlipidemic rats and estimate the changes of activity of autonomic nervous system. Twenty-three male Wistar rats were randomly divided into three groups, named control group (C group, n=10), hyperlipidemia group (H group, n=6) and hyperlipidemia-ischemia group (HI group, n=7), respectively. The rats in H and HI group were fed a high-fat diet for 2 weeks and the rats in all groups were examined through Morris water maze (MWM) task.