Sulfide Analogues of Flupirtine and Retigabine with Nanomolar KV7.2/KV7.3 Channel Opening Activity

The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which structural features can be altered to avoid the detrimental oxidation of the aromatic ring and shift oxidation toward the formation of more benign metabolites. Structure–activity relationship studies were performed to evaluate the K_V7.2/3 channel opening activity of 45 derivatives. Sulfide analogues were identified that are devoid of the risk of quinone formation, but possess potent K_V7.2/3 opening activity. For example, flupirtine analogue 3-(3,5-difluorophenyl)-N-(6-(isobutylthio)-2-(pyrrolidin-1-yl)pyridin-3-yl)propanamide ( 48 ) has 100-fold enhanced activity (EC₅₀=1.4 nm ), a vastly improved toxicity/activity ratio, and the same efficacy as retigabine in vitro.     

The Role of KV7.3 in Regulating Osteoblast Maturation and Mineralization

KCNQ (K_V7) channels are voltage-gated potassium (K_V) channels, and the function of K_V7 channels in muscles, neurons, and sensory cells is well established. We confirmed that overall blockade of K_V channels with tetraethylammonium augmented the mineralization of bone-marrow-derived human mesenchymal stem cells during osteogenic differentiation, and we determined that K_V7.3 was expressed in MG-63 and Saos-2 cells at the mRNA and protein levels. In addition, functional K_V7 currents were detected in MG-63 cells. Inhibition of K_V7.3 by linopirdine or XE991 increased the matrix mineralization during osteoblast differentiation. This was confirmed by alkaline phosphatase, osteocalcin, and osterix in MG-63 cells, whereas the expression of Runx2 showed no significant change. The extracellular glutamate secreted by osteoblasts was also measured to investigate its effect on MG-63 osteoblast differentiation. Blockade of K_V7.3 promoted the release of glutamate via the phosphorylation of extracellular signal-regulated kinase 1/2-mediated upregulation of synapsin, and induced the deposition of type 1 collagen. However, activation of K_V7.3 by flupirtine did not produce notable changes in matrix mineralization during osteoblast differentiation. These results suggest that K_V7.3 could be a novel regulator in osteoblast differentiation.     

Murine K2P5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K2P3.1- and KV1.3-Dependent Mechanisms

Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K_2P5.1 (TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K_2P5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K_2P5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K_2P5.1 knockout (K_2P5.1^−/−) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K_2P5.1^−/− mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K_2P3.1 and K_V1.3 seems to counterbalance the deletion of K_2P5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K_2P5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K_2P5.1-targeting drugs.     

Roles of Voltage-Gated Tetrodotoxin-Sensitive Sodium Channels NaV1.3 and NaV1.7 in Diabetes and Painful Diabetic Neuropathy

Diabetes mellitus (DM) is a common chronic medical problem worldwide; one of its complications is painful peripheral neuropathy, which can substantially erode quality of life and increase the cost of management. Despite its clinical importance, the pathogenesis of painful diabetic neuropathy (PDN) is complex and incompletely understood. Voltage-gated sodium channels (VGSCs) link many physiological processes to electrical activity by controlling action potentials in all types of excitable cells. Two isoforms of VGSCs, Na_V1.3 and Na_V1.7, which are encoded by the sodium voltage-gated channel alpha subunit 3 and 9 (Scn3A and Scn9A) genes, respectively, have been identified in both peripheral nociceptive neurons of dorsal root ganglion (DRG) and pancreatic islet cells. Recent advances in our understanding of tetrodotoxin-sensitive (TTX-S) sodium channels Na_V1.3 and Na_V1.7 lead to the rational doubt about the cause–effect relation between diabetes and painful neuropathy. In this review, we summarize the roles of Na_V1.3 and Na_V1.7 in islet cells and DRG neurons, discuss the link between DM and painful neuropathy, and present a model, which may provide a starting point for further studies aimed at identifying the mechanisms underlying diabetes and painful neuropathy.     

Molecular Dynamics-Derived Pharmacophore Model Explaining the Nonselective Aspect of KV10.1 Pore Blockers

The K_V10.1 voltage-gated potassium channel is highly expressed in 70% of tumors, and thus represents a promising target for anticancer drug discovery. However, only a few ligands are known to inhibit K_V10.1, and almost all also inhibit the very similar cardiac hERG channel, which can lead to undesirable side-effects. In the absence of the structure of the K_V10.1–inhibitor complex, there remains the need for new strategies to identify selective K_V10.1 inhibitors and to understand the binding modes of the known K_V10.1 inhibitors. To investigate these binding modes in the central cavity of K_V10.1, a unique approach was used that allows derivation and analysis of ligand–protein interactions from molecular dynamics trajectories through pharmacophore modeling. The final molecular dynamics-derived structure-based pharmacophore model for the simulated K_V10.1–ligand complexes describes the necessary pharmacophore features for K_V10.1 inhibition and is highly similar to the previously reported ligand-based hERG pharmacophore model used to explain the nonselectivity of K_V10.1 pore blockers. Moreover, analysis of the molecular dynamics trajectories revealed disruption of the π–π network of aromatic residues F359, Y464, and F468 of K_V10.1, which has been reported to be important for binding of various ligands for both K_V10.1 and hERG channels. These data indicate that targeting the K_V10.1 channel pore is also likely to result in undesired hERG inhibition, and other potential binding sites should be explored to develop true K_V10.1-selective inhibitors as new anticancer agents.     

Chemical and Biological Tools for the Study of Voltage-Gated Sodium Channels in Electrogenesis and Nociception

The malfunction and misregulation of voltage-gated sodium channels (Na_Vs) underlie in large part the electrical hyperexcitability characteristic of chronic inflammatory and neuropathic pain. Na_Vs are responsible for the initiation and propagation of electrical impulses (action potentials) in cells. Tissue and nerve injury alter the expression and localization of multiple Na_V isoforms, including Na_V1.1, 1.3, and 1.6–1.9, resulting in aberrant action potential firing patterns. To better understand the role of Na_V regulation, localization, and trafficking in electrogenesis and pain pathogenesis, a number of chemical and biological reagents for interrogating Na_V function have been advanced. The development and application of such tools for understanding Na_V physiology are the focus of this review.     

Negative Influence by the Force: Mechanically Induced Hyperpolarization via K2P Background Potassium Channels

The two-pore domain K_2P subunits form background (leak) potassium channels, which are characterized by constitutive, although not necessarily constant activity, at all membrane potential values. Among the fifteen pore-forming K_2P subunits encoded by the KCNK genes, the three members of the TREK subfamily, TREK-1, TREK-2, and TRAAK are mechanosensitive ion channels. Mechanically induced opening of these channels generally results in outward K⁺ current under physiological conditions, with consequent hyperpolarization and inhibition of membrane potential-dependent cellular functions. In the past decade, great advances have been made in the investigation of the molecular determinants of mechanosensation, and members of the TREK subfamily have emerged among the best-understood examples of mammalian ion channels directly influenced by the tension of the phospholipid bilayer. In parallel, the crucial contribution of mechano-gated TREK channels to the regulation of membrane potential in several cell types has been reported. In this review, we summarize the general principles underlying the mechanical activation of K_2P channels, and focus on the physiological roles of mechanically induced hyperpolarization.     

Combustion of carbon particulate catalysed by mixed potassium vanadates and KI

A K–V–I‐containing catalyst for low‐temperature combustion of carbonaceous materials was studied so as to check its potential in diesel particulate removal. X‐ray diffraction (XRD) and scanning electron microscopy (SEM‐EDS) showed that its main constituting compounds are KVO₃, KI and K₄V₂O₇. Differential scanning calorimetry (DSC) and temperature‐programmed oxidation (TPO) tests enlightened that the catalyst is active well below 400 °C (peak combustion temperature: T_p= 380 °C). Thermal treatments carried out at this temperature with dry or humid air did not entail detrimental effects on the catalyst performance. Similar treatments at higher temperatures (600 and 750 °C) resulted in a modification of the catalyst composition and in a slight decrease of its activity (T_p increases of about 60 °C). These last treatments caused the progressive loss of active components due to either evaporation of eutectic liquid formed at about 450 °C or production of gaseous iodine through a reaction between KI and KVO₃, which also gave rise to the formation of K₄V₂O₇. However, the consequent deactivation was moderate owing to the high intrinsic activity displayed by the formed potassium pyrovanadate. This revised version was published online in July 2006 with corrections to the Cover Date.     

Empagliflozin Relaxes Resistance Mesenteric Arteries by Stimulating Multiple Smooth Muscle Cell Voltage-Gated K+ (KV) Channels

The antidiabetic drug empagliflozin is reported to produce a range of cardiovascular effects, including a reduction in systemic blood pressure. However, whether empagliflozin directly modulates the contractility of resistance-size mesenteric arteries remains unclear. Here, we sought to investigate if empagliflozin could relax resistance-size rat mesenteric arteries and the associated underlying molecular mechanisms. We found that acute empagliflozin application produces a concentration-dependent vasodilation in myogenic, depolarized and phenylephrine (PE)-preconstricted mesenteric arteries. Selective inhibition of smooth muscle cell voltage-gated K⁺ channels K_V1.5 and K_V7 abolished empagliflozin-induced vasodilation. In contrast, pharmacological inhibition of large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels and ATP-sensitive (K_ATP) channels did not abolish vasodilation. Inhibition of the vasodilatory signaling axis involving endothelial nitric oxide (NO), smooth muscle cell soluble guanylyl cyclase (sGC) and protein kinase G (PKG) did not abolish empagliflozin-evoked vasodilation. Inhibition of the endothelium-derived vasodilatory molecule prostacyclin (PGI₂) had no effect on the vasodilation. Consistently, empagliflozin-evoked vasodilation remained unaltered by endothelium denudation. Overall, our data suggest that empagliflozin stimulates smooth muscle cell K_V channels K_V1.5 and K_V7, resulting in vasodilation in resistance-size mesenteric arteries. This study demonstrates for the first time a novel mechanism whereby empagliflozin regulates arterial contractility, resulting in vasodilation. Due to known antihypertensive properties, treatment with empagliflozin may complement conventional antihypertensive therapy.     

Polyamines Influence Mouse Sperm Channels Activity

Polyamines are ubiquitous polycationic compounds that are highly charged at physiological pH. While passing through the epididymis, sperm lose their capacity to synthesize the polyamines and, upon ejaculation, again come into contact with the polyamines contained in the seminal fluid, unleashing physiological events that improve sperm motility and capacitation. In the present work, we hypothesize about the influence of polyamines, namely, spermine, spermidine, and putrescine, on the activity of sperm channels, evaluating the intracellular concentrations of chloride [Cl⁻]i, calcium [Ca²⁺]i, sodium [Na⁺]i, potassium [K⁺]i, the membrane V_m, and pHi. The aim of this is to identify the possible regulatory mechanisms mediated by the polyamines on sperm-specific channels under capacitation and non-capacitation conditions. The results showed that the presence of polyamines did not directly influence the activity of calcium and chloride channels. However, the results suggested an interaction of polyamines with sodium and potassium channels, which may contribute to the membrane V_m during capacitation. In addition, alkalization of the pHi revealed the possible activation of sperm-specific Na⁺/H⁺ exchangers (NHEs) by the increased levels of cyclic AMP (cAMP), which were produced by soluble adenylate cyclase (sAC) and interact with the polyamines, evidence that is supported by in silico analysis.     

The electrochemical oxidation of sulphur dioxide at porous catalysed carbon electrodes in sulphuric acid

The electrochemical oxidation of sulphur dioxide has been studied in sulphuric acid solution at porous carbon electrodes coated with catalysts consisting of aluminum-vanadium mixed oxides with traces of platinum.Catalyst activity and stability in acid electrolytes are determined by the preparation conditions and the V₂O₅: Al₂O₃ ratio.Potentiodynamic measurements were made for investigating the mechanism of the anodic oxidation of sulphur dioxide. When catalysts are present, sulphur dioxide is anodically oxidized at the porous carbon electrodes. Direct electron transfer from the sulphur dioxide to the anode takes place at low potentials, whereas at more positive potentials reaction takes place between the sulphur dioxide and the electrolytically produced surface oxides on the platinum.     

Augmented KCa2.3 Channel Feedback Regulation of Oxytocin Stimulated Uterine Strips from Nonpregnant Mice

Uterine contractions prior to 37 weeks gestation can result in preterm labor with significant risk to the infant. Current tocolytic therapies aimed at suppressing premature uterine contractions are largely ineffective and cause serious side effects. Calcium (Ca²⁺) dependent contractions of uterine smooth muscle are physiologically limited by the opening of membrane potassium (K⁺) channels. Exploiting such inherent negative feedback mechanisms may offer new strategies to delay labor and reduce risk. Positive modulation of small conductance Ca²⁺-activated K⁺ (K_Ca2.3) channels with cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), effectively decreases uterine contractions. This study investigates whether the receptor agonist oxytocin might solicit K_Ca2.3 channel feedback that facilitates CyPPA suppression of uterine contractions. Using isometric force myography, we found that spontaneous phasic contractions of myometrial tissue from nonpregnant mice were suppressed by CyPPA and, in the presence of CyPPA, oxytocin failed to augment contractions. In tissues exposed to oxytocin, depletion of internal Ca²⁺ stores with cyclopiazonic acid (CPA) impaired CyPPA relaxation, whereas blockade of nonselective cation channels (NSCC) using gadolinium (Gd³⁺) had no significant effect. Immunofluorescence revealed close proximity of K_Ca2.3 channels and ER inositol trisphosphate receptors (IP₃Rs) within myometrial smooth muscle cells. The findings suggest internal Ca²⁺ stores play a role in K_Ca2.3-dependent feedback control of uterine contraction and offer new insights for tocolytic therapies.     

Evidence for Dual Activation of IK(M) and IK(Ca) Caused by QO-58 (5-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one)

QO-58 (5-(2,6-dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one) has been regarded to be an activator of K_V7 channels with analgesic properties. However, whether and how the presence of this compound can result in any modifications of other types of membrane ion channels in native cells are not thoroughly investigated. In this study, we investigated its perturbations on M-type K⁺ current (I_K(M)), Ca²⁺-activated K⁺ current (I_K(Ca)), large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels, and erg-mediated K⁺ current (I_K(erg)) identified from pituitary tumor (GH₃) cells. Addition of QO-58 can increase the amplitude of I_K(M) and I_K(Ca) in a concentration-dependent fashion, with effective EC₅₀ of 3.1 and 4.2 μM, respectively. This compound could shift the activation curve of I_K(M) toward a leftward direction with being void of changes in the gating charge. The strength in voltage-dependent hysteresis (V_hys) of I_K(M) evoked by upright triangular ramp pulse (V_ramp) was enhanced by adding QO-58. The probabilities of M-type K⁺ (K_M) channels that will be open increased upon the exposure to QO-58, although no modification in single-channel conductance was seen. Furthermore, GH₃-cell exposure to QO-58 effectively increased the amplitude of I_K(Ca) as well as enhanced the activity of BK_Ca channels. Under inside-out configuration, QO-58, applied at the cytosolic leaflet of the channel, activated BK_Ca-channel activity, and its increase could be attenuated by further addition of verruculogen, but not by linopirdine (10 μM). The application of QO-58 could lead to a leftward shift in the activation curve of BK_Ca channels with neither change in the gating charge nor in single-channel conductance. Moreover, cell exposure of QO-58 (10 μM) resulted in a minor suppression of I_K(erg) amplitude in response to membrane hyperpolarization. The docking results also revealed that there are possible interactions of the QO-58 molecule with the KCNQ or K_Ca1.1 channel. Overall, dual activation of I_K(M) and I_K(Ca) caused by the presence of QO-58 eventually may have high impacts on the functional activity (e.g., anti-nociceptive effect) residing in electrically excitable cells. Care must be exercised when interpreting data generated with QO-58 as it is not entirely KCNQ/K_V7 selective.     

A Study on the Mechanism of the Thermal Decomposition of Ammonium Perchlorate

The thermal decomposition of ammonium perchlorate in the presence of potassium chloride and chromium (III) oxide was investigated using K³⁶ Cl and⁵¹ Cr₂ O₃ to elucidate the reaction mechanism. Two simultaneous routes are suggested for the decomposition. It was found that double decomposition in vacuo between potassium chloride and ammonium perchlorate does not result in the formation of potassium perchlorate. Chromium (III) oxide was not oxidized by ammonium perchlorate, but oxidation to the hexavalent state took place when potassium chloride was present.     

Oxidation of SO2over Supported Metal Oxide Catalysts

A systematic catalytic investigation of the sulfur dioxide oxidation reactivity of several binary (M_xO_y/TiO₂) and ternary (V₂O₅/M_xO_y/TiO₂) supported metal oxide catalysts was conducted. Raman spectroscopy characterization of the supported metal oxide catalysts revealed that the metal oxide components were essentially 100% dispersed as surface metal oxide species. Isolated fourfold coordinated metal oxide surface species are present for most oxides tested at low coverages, whereas at surface coverages approaching monolayer polymerized surface metal oxide species with sixfold coordination are present for some of the oxides. The sulfur dioxide oxidation turnover frequencies (SO₂molecules converted per surface redox site per second) of the binary catalysts were all within an order of magnitude (V₂O₅/TiO₂>Fe₂O₃/TiO₂>Re₂O₇/TiO₂∼CrO₃/TiO₂∼Nb₂O₅/TiO₂>MoO₃/TiO₂∼WO₃/TiO₂). An exception was the K₂O/TiO₂catalyst system, which is inactive for sulfur dioxide oxidation under the chosen reaction conditions. With the exception of K₂O, all of the surface metal oxide species present in the ternary catalysts (i.e., oxides of V, Fe, Re, Cr, Nb, Mo, and W) can undergo redox cycles and oxidize sulfur dioxide to sulfur trioxide. The turnover frequency for SO₂oxidation over all of these catalysts is approximately the same at both low and high surface coverages, despite structural differences in the surface metal oxide overlayers. This indicates that the mechanism of sulfur dioxide oxidation is not sensitive to the coordination of the surface metal oxide species. A comparison of the activities of the ternary catalysts with the corresponding binary catalysts suggests that the surface vanadium oxide and the additive surface oxide redox sites act independently without synergistic interactions: the sum of the individual activities of the binary catalysts quantitatively correspond to the activity of the corresponding ternary catalyst. The V₂O₅/K₂O/TiO₂catalyst showed a dramatic reduction in catalytic activity in comparison to the unpromoted V₂O₅/TiO₂catalyst. The ability of potassium oxide to significantly retard the redox potential of the surface vanadia species is primarily responsible for the lower catalytic reactivity.     

Mass transfer at horizontal gas-evolving electrodes

The effect of H₂ and O₂ evolution on the mass transfer coefficient of the reduction of K₃Fe(CN)₆ and the oxidation of K₄Fe(CN)₆ at nickel electrodes was studied up to 105 mA/cm². The relation between the rate gas evolution and the mass transfer coefficient was found to be: log K = a + 0·25 log V for a H₂-evolving horizontal electrode and log K = a + 0·4 log V for an O₂-evolving horizontal electrode.Comparison was made between mass transfer coefficients at horizontal and vertical gas-evolving electrodes. Mass transfer coefficients at horizontal electrodes are much higher than at vertical electrodes.     

A Comparison of the Effect of Lead (Pb) on the Slow Vacuolar (SV) and Fast Vacuolar (FV) Channels in Red Beet (Beta vulgaris L.) Taproot Vacuoles

Little is known about the effect of lead on the activity of the vacuolar K⁺ channels. Here, the patch-clamp technique was used to compare the impact of lead (PbCl₂) on the slow-activating (SV) and fast-activating (FV) vacuolar channels. It was revealed that, under symmetrical 100-mM K⁺, the macroscopic currents of the SV channels exhibited a typical slow activation and a strong outward rectification of the steady-state currents, while the macroscopic currents of the FV channels displayed instantaneous currents, which, at the positive potentials, were about three-fold greater compared to the one at the negative potentials. When PbCl₂ was added to the bath solution at a final concentration of 100 µM, it decreased the macroscopic outward currents of both channels but did not change the inward currents. The single-channel recordings demonstrated that cytosolic lead causes this macroscopic effect by a decrease of the single-channel conductance and decreases the channel open probability. We propose that cytosolic lead reduces the current flowing through the SV and FV channels, which causes a decrease of the K⁺ fluxes from the cytosol to the vacuole. This finding may, at least in part, explain the mechanism by which cytosolic Pb²⁺ reduces the growth of plant cells.     

Remodeling of Arterial Tone Regulation in Postnatal Development: Focus on Smooth Muscle Cell Potassium Channels

Maturation of the cardiovascular system is associated with crucial structural and functional remodeling. Thickening of the arterial wall, maturation of the sympathetic innervation, and switching of the mechanisms of arterial contraction from calcium-independent to calcium-dependent occur during postnatal development. All these processes promote an almost doubling of blood pressure from the moment of birth to reaching adulthood. This review focuses on the developmental alterations of potassium channels functioning as key smooth muscle membrane potential determinants and, consequently, vascular tone regulators. We present evidence that the pattern of potassium channel contribution to vascular control changes from K_ir2, K_v1, K_v7 and TASK-1 channels to BK_Ca channels with maturation. The differences in the contribution of potassium channels to vasomotor tone at different stages of postnatal life should be considered in treatment strategies of cardiovascular diseases associated with potassium channel malfunction.     

The Effectiveness in Activating M-Type K+ Current Produced by Solifenacin ([(3R)-1-azabicyclo[2.2.2]octan-3-yl] (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate): Independent of Its Antimuscarinic Action

Solifenacin (Vesicare^®, SOL), known to be a member of isoquinolines, is a muscarinic antagonist that has anticholinergic effect, and it has been beneficial in treating urinary incontinence and neurogenic detrusor overactivity. However, the information regarding the effects of SOL on membrane ionic currents is largely uncertain, despite its clinically wide use in patients with those disorders. In this study, the whole-cell current recordings revealed that upon membrane depolarization in pituitary GH₃ cells, the exposure to SOL concentration-dependently increased the amplitude of M-type K⁺ current (I_K(M)) with effective EC₅₀ value of 0.34 μM. The activation time constant of I_K(M) was concurrently shortened in the SOL presence, hence yielding the K_D value of 0.55 μM based on minimal reaction scheme. As cells were exposed to SOL, the steady-state activation curve of I_K(M) was shifted along the voltage axis to the left with no change in the gating charge of the current. Upon an isosceles-triangular ramp pulse, the hysteretic area of I_K(M) was increased by adding SOL. As cells were continually exposed to SOL, further application of acetylcholine (1 μM) failed to modify SOL-stimulated I_K(M); however, subsequent addition of thyrotropin releasing hormone (TRH, 1 μM) was able to counteract SOL-induced increase in I_K(M) amplitude. In cell-attached single-channel current recordings, bath addition of SOL led to an increase in the activity of M-type K⁺ (K_M) channels with no change in the single channel conductance; the mean open time of the channel became lengthened. In whole-cell current-clamp recordings, the SOL application reduced the firing of action potentials (APs) in GH₃ cells; however, either subsequent addition of TRH or linopirdine was able to reverse SOL-mediated decrease in AP firing. In hippocampal mHippoE-14 neurons, the I_K(M) was also stimulated by adding SOL. Altogether, findings from this study disclosed for the first time the effectiveness of SOL in interacting with K_M channels and hence in stimulating I_K(M) in electrically excitable cells, and this noticeable action appears to be independent of its antagonistic activity on the canonical binding to muscarinic receptors expressed in GH₃ or mHippoE-14 cells.     

Electrochemistry of vanadium-doped ZrSiO4: Site-selective electrocatalytic effect on nitrite oxidation

The electrochemistry of vanadium-doped zircon (V_xZrSiO₄, 0 < x < 0.10) has been studied using abrasive-conditioned paraffin-impregnated graphite electrodes. It is compared with that of ZrSiO₄, ZrO₂, and vanadium-doped tetragonal and monoclinic zirconias. In contact with acetic/acetate and HCl + NaCl electrolytes, zirconium materials are reduced to Zr(III) at potentials near to −0.5 versus AgCl/Ag and to Zr metal at potentials more negative than −1.2 V, via proton-assisted reductive processes, influenced by the complexing action of chloride ions. Vanadium-centred oxidation processes appear at potentials from +0.2 to +0.7 V enabling for a distinction between different coordinative arrangements. ZrSiO₄ exerts a significant electrocatalytic effect on nitrite oxidation in acetic/acetate buffers, slightly enhanced in the presence of increasing vanadium loadings. Electrocatalytic data are indicative that only V centres substituting Zr are catalytically active, whereas V substituting Si are catalytically silent.