1,721,030 research outputs found
Octopus. vulgaris (MOLLUSCA CEPHALOPODA) as a model in behavioral pharmacology: a test of handling effects.
No full textHistidines 578 and 587 in the S5-S6 linker of the human Ether-a-gogo Related Gene-1 K+ channels confer sensitivity to reactive oxygen species
No full textThe K(+) channels encoded by the human Ether-a-gogo Related Gene-1 (hERG1) are crucially involved in controlling heart and brain excitability and are selectively influenced by reactive oxygen species (ROS). To localize the molecular regions involved in ROS-induced modulation of hERG1, segmental exchanges between the ROS-sensitive hERG1 and the ROS-insensitive bovine ether-a-gogo gene (bEAG) K(+) channels were generated, and the sensitivity of these chimeric channels to ROS was studied with the two-microelectrode voltage-clamp technique upon their expression in Xenopus oocytes. Substitution of the S(5)-S(6) linker of hERG1 with the corresponding bEAG region removed channel sensitivity to ROS, whereas the reverse chimeric exchange introduced ROS sensitivity into bEAG. Mutation of each of the two hERG1 histidines at positions 578 and 587 within the S(5)-S(6) linker generated K(+) channels insensitive to modulation by ROS. In addition, the two iron chelators desferrioxamine (1 mm) and o-phenanthroline (0.2 mm) significantly inhibited hERG1 outward K(+) currents and prevented hERG1 inhibition induced by the ROS-scavenging enzyme catalase (1000 units/ml). Finally, the hERG1-inhibitory effect exerted by the iron chelators was prevented by the hERG1 H578D/H587Y double mutation. Collectively, the results obtained suggest that histidines at positions 578 and 587 in the S(5)-S(6) linker region of hERG1 K(+) channels are crucial players in ROS-induced modulation of hERG1 K(+) channels
Histidines 578 and 587 in the S5-S6 linker of the human Ether-a-gogo Related Gene-1 K+ channels confer sensitivity to reactive oxygen species
Full text linkHuman ether-a-gogo related gene (HERG) K+ channels as pharmacological targets: present and future implications
No full textElectrophysiological and molecular biology techniques have widely expanded our knowledge of the diverse functions where K+ channels are implicated as potential and proven pharmacological targets. The aim of the present commentary is to review the recent progress in the understanding of the functional role of the K+ channels encoded by the human ether-a-gogo related gene (HERG), with particular emphasis on their direct pharmacological modulation by drugs, or on their regulation by pharmacologically relevant phenomena. About 3 years have passed since the cloning, expression, and description of the pathophysiological role of HERG K+ channels in human cardiac repolarization. Despite this short lapse of time, these K+ channels have already gained considerable attention as pharmacological targets. In fact, interference with HERG K+ channels seems to be the main mechanism explaining both the therapeutic actions of the class III antiarrhythmics and the potential cardiotoxicity of second-generation H1 receptor antagonists such as terfenadine and astemizole, as well as of psychotropic drugs such as some antidepressants and neuroleptics. It seems possible to anticipate that the main tasks for future investigation will be, on the one side, the better understanding of the intimate mechanism of action of HERG K+ channel-blocking drugs in order to elucidate the conditions regulating the delicate balance between antiarrhythmic and proarrhythmic potential and, on the other, to unravel the pathophysiological role of this K+ channel in the function of the brain and of other excitable tissues
Modulation of the K(+) channels encoded by the human ether-a-gogo-related gene-1 (hERG1) by nitric oxide
Full text linkInhibition of HERG1 K(+) channels by the novel second-generation antihistamine mizolastine
Full text linkRetention in the endoplasmic reticulum as a mechanism of dominant-negative current suppression in human long QT syndrome
Full text linkM Channels Containing KCNQ2 Subunits Modulate Norepinephrine, Aspartate, and GABA Release from Hippocampal Nerve Terminals
No full textKCNQ subunits encode for the M current (I(KM)), a neuron-specific voltage-dependent K+ current with a well established role in the control of neuronal excitability. In this study, by means of a combined biochemical, pharmacological, and electrophysiological approach, the role of presynaptic I(KM) in the release of previously taken up tritiated norepineprine (NE), GABA, and d-aspartate (d-ASP) from hippocampal nerve terminals (synaptosomes) has been evaluated. Retigabine (RT) (0.01-30 microm), a specific activator of I(KM), inhibited [3H]NE, [3H]d-ASP, and [3H]GABA release evoked by 9 mm extracellular K+ ([K+]e). RT-induced inhibition of [3H]NE release was prevented by synaptosomal entrapment of polyclonal antibodies directed against KCNQ2 subunits, an effect that was abolished by antibody preabsorption with the KCNQ2 immunizing peptide; antibodies against KCNQ3 subunits were ineffective. Flupirtine (FP), a structural analog of RT, also inhibited 9 mm [K+]e-induced [3H]NE release, although its maximal inhibition was lower than that of RT. Electrophysiological studies in KCNQ2-transfected Chinese hamster ovary cells revealed that RT and FP (10 microm) caused a -19 and -9 mV hyperpolarizing shift, respectively, in the voltage dependence of activation of KCNQ2 K+ channels. In the same cells, the cognition enhancer 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991) (10 microm) blocked KCNQ2 channels and prevented their activation by RT (1-10 microm). Finally, both XE-991 (10-100 microm) and tetraethylammonium ions (100 microm) abolished the inhibitory effect of RT (1 microm) on [3H]NE release. These findings provide novel evidence for a major regulatory role of KCNQ2 K+ channel subunits in neurotransmitter release from rat hippocampal nerve endings
Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels
No full textThe muscarinic-regulated potassium current (M-current), formed by the heteromeric assembly of subunits encoded by the KCNQ2 and KCNQ3 genes, is a primary regulator of neuronal excitability; this regulation is accomplished by impeding repetitive firing and causing spike-frequency adaptation. Mutations in KCNQ2 or KCNQ3 cause benign familial neonatal convulsions (BFNC), a rare autosomal-dominant generalized epilepsy of newborns, by reducing the maximal current carried by the M-channels without affecting ion selectivity or gating properties. Here we show that KCNQ2/KCNQ3 channels carrying a novel BFNC-causing mutation leading to an arginine to tryptophan substitution in the voltage-sensing S4 domain of KCNQ2 subunits (R214W) displayed slower opening and faster closing kinetics and a decreased voltage sensitivity with no concomitant changes in maximal current or plasma membrane expression. These results suggest that mutation-induced gating alterations of the M-current may cause epilepsy in neonates
New challenges in clinical and forensic toxicology
No full textAnalytical toxicology plays a critical role in clinical biochemistry and laboratory medicine, primarily by identifying pharmacologically active substances and xenobiotics in biological and non-biological samples. Clinical toxicology uses these results to diagnose and treat patients, while forensic toxicology applies them for legal purposes, such as drug-related deaths or criminal cases. However, clinical data can sometimes have forensic implications, necessitating adherence to strict procedures to ensure the reliability of results in legal contexts. Recent advancements in analytical toxicology have posed new challenges and opportunities, especially in detecting new psychoactive substances (NPS). These substances are difficult to detect due to their varied chemical structures and complex biological matrices. Laboratories are developing new extraction methods and use advanced technologies such as high-resolution mass spectrometry to detect a broader range of substances, including NPS. In addition to detection, metabolite profiling is key for identifying biomarkers of NPS abuse, as the pharmacokinetics of these substances are poorly understood when they first appear on the market. In silico and in vitro models are used to predict NPS metabolism, aiding in finding reliable biomarkers for consumption. NPS can have serious toxic effects on the central nervous system, including agitation, euphoria, and hypertension, with few studies addressing their pharmacological impacts. Research suggests that NPS may interfere with neuronal excitability and alter ion channel activity, potentially leading to neurological damage. Overall, the continuous advancement of analytical techniques and growing understanding of NPS metabolism are crucial for addressing the public health and legal challenges posed by these substances
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