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BACKGROUND: This study investigated the behavioral responses and toxicity of three basic amines: 1‐methylpiperazine, 1‐methylpyrrolidine, and triethylamine (TEA), compounds suggested previously to be anosmic in vapor exposures to caged mosquitoes. RESULTS: These compounds showed repellency of Aedes aegypti mosquitoes, followed by flightlessness, knockdown, and paralysis, all increasing with exposure time and dosage. Electrophysiological experiments showed a blocking effect on nerve discharge of the Drosophila melanogaster larval central nervous system (CNS) with little evidence of hyperexcitation. Blockage of voltage‐gated (Kv2) potassium channel currents under patch clamp occurred at similar concentrations. Involvement of K+ channels in the action of basic amines was supported by behavior and CNS recordings of a Shaker Kv1 mutant exposed to TEA, where instead of blockage, a hyperexcitation of nerve firing was observed. Experiments on cockroach leg mechanoreceptors demonstrated neuronal excitation and on mosquito antennae strong electroantennogram (EAG) signals with an augmentation of blank air responses after a single puff of basic amine. CONCLUSIONS: The neurophysiological effects of basic amines are consistent with K+ channel block, whereas the antennal EAG response was not obviously associated with anosmia. The low‐dose effects of basic amines appear to be repellency and bradykinesia. Overall, the findings provide key insights into the mechanisms underlying the biological activity of basic amines. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background and Purposes Experimental Approach Key Results Conclusion and Implications Reduced inward rectifier potassium channel (Kir2.1) functioning is associated with heart failure and may cause Andersen‐Tawil Syndrome, among others characterized by ventricular arrhythmias. Most heart failure or Andersen–Tawil Syndrome patients are treated with β‐adrenoceptor antagonists (β‐blockers) or sodium channel blockers; however, these do not specifically address the inward rectifier current (IK1) nor aim to improve resting membrane potential stability. Consequently, additional pharmacotherapy for heart failure and Andersen–Tawil Syndrome treatment would be highly desirable. Acute propafenone treatment at low concentrations enhances IK1 current, but it also exerts many off‐target effects. Therefore, discovering and exploring new IK1‐channel openers is necessary.Effects of propafenone and 10 additional propafenone analogues were analysed. Currents were measured by single‐cell patch‐clamp electrophysiology. Kir2.1 protein expression levels were determined by western blot analysis and action potential characteristics were further validated in human‐induced pluripotent stem cells–derived cardiomyocytes (hiPSC‐CMCs). Molecular docking was performed to obtain detailed information on drug‐channel interactions.Analogues GPV0019, GPV0057 and GPV0576 strongly increased the outward component of IK1 while not affecting the Kir2.1 channel expression levels. GPV0057 did not block IKr at concentrations below 0.5 μmol L−1 nor NaV1.5 current below 1 μmol L−1. Moreover, hiPSC‐CMC action potential duration was also not affected by GPV0057 at 0.5 and 1 μmol L−1. Structure analysis indicates a mechanism by which GPV0057 might enhance Kir2.1 channel activation.GPV0057 has a strong efficiency towards increasing IK1, which makes it a good candidate to address IK1 deficiency‐associated diseases. [ABSTRACT FROM AUTHOR]

The essential role of the inwardly rectifying potassium channel Kir5.1 (KCNJ16) in controlling electrolyte homeostasis and blood pressure has been demonstrated in human and animal studies. Previous studies have identified several bi‐allelic mutations of KCNJ16 in humans, causing severe hypokalemia, renal salt wasting, and disturbed acid–base homeostasis. Here, we identified a novel homozygous variant of KCNJ16, I26T, in an Amish patient affected with polydipsia, developmental delay, and chronic metabolic acidosis with low serum bicarbonate concentration. Subsequently, we generated the rat model with I26T mutation using Dahl salt‐sensitive rat (I26T rat) to characterize this variant. The male mutant rats displayed similar blood pressure and electrolyte homeostasis under baseline and with a high salt (4% NaCl) challenge. Blood pH, HCO3− and renal damage also remained similar between WT and I26T rats after high salt challenge. Additionally, single‐channel patch clamp analysis revealed similar channel activity in CHO cells overexpressed with WT and I26T mutant Kir4.1/5.1 channels. In summary, this study reported a novel variant in KCNJ16, namely I26T, which is likely a benign variant and not associated with pathologic phenotype in either human or Dahl salt‐sensitive rats, indicating that the type/location of variant should be considered when diagnosing and treating patients with KCNJ16 mutations. [ABSTRACT FROM AUTHOR]

Key points Patients with myotonia congenita suffer from slowed muscle relaxation caused by hyperexcitability. The diaphragm is only mildly affected in myotonia congenita; discovery of the mechanism underlying its resistance to myotonia could identify novel therapeutic targets. Intracellular recordings from two mouse models of myotonia congenita revealed the diaphragm had less myotonia than either the extensor digitorum longus (EDL) or the soleus muscles. A mechanism contributing to resistance of the diaphragm to myotonia was reduced depolarization of the interspike membrane potential during repetitive firing of action potentials, a process driven by build‐up of K+ in small invaginations of muscle membrane known as t‐tubules. We explored differences between diaphragm and EDL that might underlie reduction of K+ build‐up in diaphragm t‐tubules. Smaller size of diaphragm fibres, which promotes diffusion of K+ out of t‐tubules, was identified as a contributor. Intracellular recording revealed slower repolarization of action potentials in diaphragm suggesting reduced Kv conductance. Higher resting membrane conductance was identified suggesting increased Kir conductance. Computer simulation found that a reduction of Kv conductance had little effect on K+ build‐up whereas increased Kir conductance lessened build‐up, although the effect was modest. Our data and computer simulation suggest opening of K+ channels during action potentials has little effect on K+ build‐up whereas opening of K+ channels during the interspike interval slightly lessens K+ build‐up. We conclude that activation of K+ channels may lessen myotonia by opposing depolarization to action potential threshold without worsening K+ build‐up in t‐tubules. In mouse models of the muscle disease myotonia congenita, the diaphragm has much less myotonia (muscle stiffness) than the extensor digitorum longus or soleus muscles. Identifying why the diaphragm is resistant to myotonia may help in developing novel therapy. We found the reason the diaphragm has less myotonia is that it is less prone to depolarization caused by K+ build‐up in t‐tubules during repetitive firing of action potentials. Smaller fibre size contributes to resistance to K+ build‐up with differences in K+ currents playing little role. Our data suggest drugs that open K+ channels may be effective in treating myotonia as they may lessen excitability without worsening K+ build‐up in t‐tubules. [ABSTRACT FROM AUTHOR]

Diamondback terrapins (Malaclemys terrapin centrata) exhibit strong environmental adaptability and live in both freshwater and saltwater. However, the genetic basis of this adaptability has not been the focus of research. In this study, we successfully constructed a ∼2.21‐Gb chromosome‐level genome assembly for M. t. centrata using high‐coverage and high‐depth genomic sequencing data generated on multiple platforms. The M. t. centrata genome contains 25 chromosomes and the scaffold N50 of ∼143.75 Mb, demonstrating high continuity and accuracy. In total, 53.82% of the genome assembly was composed of repetitive sequences, and 22 435 protein‐coding genes were predicted. Our phylogenetic analysis indicated that M. t. centrata was closely related to the red‐eared slider turtle (Trachemys scripta elegans), with divergence approximately ∼23.6 million years ago (Mya) during the early Neogene period of the Cenozoic era. The population size of M. t. centrata decreased significantly over the past ∼14 Mya during the Cenozoic era. Comparative genomic analysis indicated that 36 gene families related to ion transport were expanded and several genes (AQP3, solute carrier subfamily, and potassium channel genes) underwent specific amino acid site mutations in the M. t. centrata genome. Changes to these ion transport‐related genes may have contributed to the remarkable salinity adaptability of diamondback terrapin. The results of this study not only provide a high‐quality reference genome for M. t. centrata but also elucidate the possible genetic basis for salinity adaptation in this species. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implication KCNT1 encodes a sodium‐activated potassium channel (Slack channel), and its mutation can cause several forms of epilepsy. Traditional antiepileptic medications have limited efficacy in treating patients with KCNT1 mutations. Here, we describe one heterozygous KCNT1 mutation, M267T, in a patient with EIMFS. The pathological channel properties of this mutation and its effect on neuronal excitability were investigated. Additionally, this study aimed to develop a medication for effective prevention of KCNT1 mutation‐induced seizures.Wild‐type or mutant KCNT1 plasmids were expressed heterologously in Xenopus laevis oocytes, and channel property assessment and drug screening were performed based on two‐electrode voltage‐clamp recordings. The single‐channel properties were investigated using the excised inside‐out patches from HEK293T cells. Through in utero electroporation, WT and M267T Slack channels were expressed in the hippocampal CA1 pyramidal neurons in male mice, followed by the examination of the electrical properties using the whole‐cell current‐clamp technique. The kainic acid‐induced epilepsy model in male mice was used to evalute the antiseizure effects of carvedilol.The KCNT1 M267T mutation enhanced Slack channel function by increasing single‐channel open probability. Through screening 16 FDA‐approved ion channel blockers, we found that carvedilol effectively reversed the mutation‐induced gain‐of‐function channel properties. Notably, the KCNT1 M267T mutation in the mouse hippocampal CA1 pyramidal neurons affected afterhyperpolarization properties and induced neuronal hyperexcitability, which was inhibited by carvedilol. Additionally, carvedilol exhibited antiseizure effects in the kainic acid‐induced epilepsy model.Our findings suggest carvedilol as a new potential candidate for treatment of epilepsies. [ABSTRACT FROM AUTHOR]

The synthetic nitro‐alcohol 2‐nitro‐1‐phenyl‐1‐propanol (NPP) has endothelium‐independent relaxing properties in isolated preparations of rat aorta and mesenteric artery. In this study, we investigated whether the vasodilator effects occur in coronary vessels and explored whether hyperpolarization is involved in the underlying mechanism of NPP‐induced smooth muscle relaxation. The relaxing responses were studied in isolated preparations of the left anterior descending coronary (ADC) and the septal coronary (SC) arteries, which had been previously maintained under sustained contraction induced by the thromboxane A2 analogue U‐46619. Administered cumulatively, NPP elicited concentration‐dependent vasorelaxation with similar potency in both vessels. The relaxant effect remained unaffected by the nitric oxide synthase inhibitor L‐NAME, the protein kinase C inhibitor bisindolylmaleimide IV and the Rho‐associated protein kinase inhibitor Y‐27632. However, it was significantly diminished by the adenylyl cyclase inhibitor MDL‐12,330A, the guanylyl cyclase inhibitor ODQ, as well as the K+ channel inhibitors tetraethylammonium and CsCl. In ADC preparations impaled with intracellular micropipettes, NPP hyperpolarized the vascular preparation. When the isolated preparation was precontracted by 5‐hydroxytryptamine or 80 mM KCl, NPP‐induced relaxation with lower pharmacological potency compared to the vessels contracted by U‐46619. In conclusion, NPP exhibits vasorelaxant effects on rat coronary arteries, likely involving pathways that include cyclic nucleotide production and membrane hyperpolarization. [ABSTRACT FROM AUTHOR]

The 17th Eilat Conference on New Antiepileptic Drugs and Devices took place in Madrid, Spain on May 5–8, 2024. As usual, the core part of the conference consisted of presentations on investigational drugs at various stages of development for epilepsy‐related indications. Summaries of information on compounds in preclinical or early clinical development are included in an accompanying publication (Part I). In this article, we provide summaries for five compounds in more advanced clinical development, i.e. compounds for which some information on antiseizure activity in individuals with epilepsy is available. These investigational treatments include azetukalner (XEN1101), a potent, KV7.2/7.3‐specific potassium channel opener in development for the treatment of focal seizures, generalized tonic–clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5‐HT2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit‐containing N‐methyl‐D‐aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain‐of‐function mutations in the GRIN1, −2A, ‐2B, or ‐2D genes; soticlestat (TAK‐935), a selective inhibitor of cholesterol 24‐hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome; and STK‐001, an antisense oligonucleotide designed to upregulate Nav1.1 protein expression and improve outcomes in individuals with Dravet syndrome. The diversity in mechanisms of action of these agents illustrates different approaches being pursued in the discovery of novel treatments for seizures and epilepsy. For two of the compounds discussed in this report (azetukalner and soticlestat), clinical evidence of efficacy has already been obtained in a randomized placebo‐controlled adjunctive‐therapy trial. For the other compounds, adequately powered placebo‐controlled efficacy trials have not been completed to date. [ABSTRACT FROM AUTHOR]

Hypotension is one of the main characteristics of the systemic inflammation, basically caused by endothelial dysfunction. Studies have shown that the amino acid L‐kynurenine (KYN) causes vasodilation in mammals, leading to hypotensive shock. In hypotensive shock, when activated by the KYN, the voltage‐gated potassium channel encoded by the family KCNQ (Kv7) gene can cause vasodilation. Fructose‐1,6‐bisphosphate (FBP) it is being considered in studies an anti‐inflammatory, antioxidant, immunomodulator, and a modulator of some ion channels (Ca2+, Na+, and K+). We analyzed the effects of KYN and FBP on mean blood pressure (MBP), systolic and diastolic (DBP) blood pressure, and heart rate variability (HRV) in Wistar rats. Results demonstrated that the administration of KYN significant decreased MBP, DBP, and increased HRV. Importantly, the FBP treatment reversed the KYN effects on MBP, DBP, and HRV. Molecular Docking Simulations suggested that KYN and FBP present a very close estimated free energy of binding and the same position into structure of KCNQ4. Our results did demonstrate that FBP blunted the decrease in BP, provoked by KYN. Results raise new hypotheses for future and studies in the treatment of hypotension resulting from inflammation. [ABSTRACT FROM AUTHOR]

Potassium metal batteries (PMBs) are regarded as viable candidates for future electrochemical energy storage devices with potential high energy density and low cost. However, uncontrollable potassium dendrite growth and huge volume expansion severely inhibit the practical application of PMBs. Herein, inspired by the structure and functionalities of tree bark, an antimony (Sb) nano‐clusters decorated N‐doped interconnected carbon nanospheres/potassium composite electrode with biomimetic fast ionic channels is developed to realize the dendrite‐free potassium metal batteries. The composite electrode provides abundant nucleation sites and interconnected ion transport channels, facilitating rapid ion transport kinetics and highly reversible potassium plating/stripping behaviors. Consequently, the assembled symmetric cell exhibits an ultra‐long cycle life (1100 h at 1.0 mA cm−2/1.0 mAh cm−2) in carbonate electrolyte. Moreover, the K full cells demonstrate enhanced cycling stability (1500 cycles at 8 C) and rate capacity (117.27 mAh g−1 at 20 C). This novel biomimetic design of composite anode presents an effective and rational approach for achieving stable PMBs. [ABSTRACT FROM AUTHOR]

Background and purpose: Pulmonary arterial hypertension (PAH) is a progressive disease in which chronic membrane potential (Em) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative Em is mainly set by two pore domain potassium (K2P) channels, of which the TASK‐1 has been extensively investigated. Experimental Approach: Ion channel currents and membrane potential of primary cultured human(h) PASMCs were measured using the voltage‐ and current clamp methods. Intracellular [Ca2+] was monitored using fluorescent microscopy. Pulmonary BP and vascular tone measurements were also performed ex vivo using a rat PAH model. Key Results: TREK‐1 was the most abundantly expressed K2P in hPASMCs of healthy donors and idiopathic(I) PAH patients. Background K+‐current was similar in hPASMCs for both groups and significantly enhanced by the TREK activator ML‐335. In donor hPASMCs, siRNA silencing or pharmacological inhibition of TREK‐1 caused depolarisation, reminiscent of the electrophysiological phenotype of idiopathic PAH. ML‐335 hyperpolarised donor hPASMCs and normalised the Em of IPAH hPASMCs. A close link was found between TREK‐1 activity and intracellular Ca2+‐signalling using a channel activator, ML‐335, and an inhibitor, spadin. In the rat, ML‐335 relaxed isolated pre‐constricted pulmonary arteries and significantly decreased pulmonary arterial pressure in the isolated perfused lung. Conclusions and Implications: These data suggest that TREK‐1is a key factor in Em setting and Ca2+ homeostasis of hPASMC, and therefore, essential for maintenance of a low resting pulmonary vascular tone. Thus TREK‐1 may represent a new therapeutic target for PAH. [ABSTRACT FROM AUTHOR]

Background and Purpose: The canonical Kir6.2/SUR2A ventricular KATP channel is highly ATP‐sensitive and remains closed under normal physiological conditions. These channels activate only when prolonged metabolic compromise causes significant ATP depletion and then shortens the action potential to reduce contractile activity. Pharmacological activation of KATP channels is cardioprotective, but physiologically, it is difficult to understand how these channels protect the heart if they only open under extreme metabolic stress. The presence of a second KATP channel population could help explain this. Here, we characterise the biophysical and pharmacological behaviours of a constitutively active Kir6.1‐containing KATP channel in ventricular cardiomyocytes. Experimental Approach: Patch‐clamp recordings from rat ventricular myocytes in combination with well‐defined pharmacological modulators was used to characterise these newly identified K+ channels. Action potential recording, calcium (Fluo‐4) fluorescence measurements and video edge detection of contractile function were used to assess functional consequences of channel modulation. Key Results: Our data show a ventricular K+ conductance whose biophysical characteristics and response to pharmacological modulation were consistent with Kir6.1‐containing channels. These Kir6.1‐containing channels lack the ATP‐sensitivity of the canonical channels and are constitutively active. Conclusion and Implications: We conclude there are two functionally distinct populations of ventricular KATP channels: constitutively active Kir6.1‐containing channels that play an important role in fine‐tuning the action potential and Kir6.2/SUR2A channels that activate with prolonged ischaemia to impart late‐stage protection against catastrophic ATP depletion. Further research is required to determine whether Kir6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens. [ABSTRACT FROM AUTHOR]

This article explores the concept of paraptosis, a type of programmed cell death that is different from apoptosis and necrosis. It discusses the mechanisms of paraptosis and highlights the potential of natural products to induce paraptosis in cancer cells, offering an alternative to traditional cancer therapies. The article also mentions the potential of paraptosis in enhancing tumor immunogenicity and triggering immune responses against cancer cells. Clinical trials are being conducted to test the efficacy and safety of paraptosis in cancer treatment, although challenges such as the lack of rigorous clinical trials and difficulties in large-scale isolation and standardization of natural products exist. Overall, the article provides valuable insights into the field of paraptosis and its potential applications in cancer therapy. [Extracted from the article]

Key Clinical Message: Gliosarcoma, a rare cerebral neoplasm, has not been linked to hippocampal changes in cats. We report a case of complex partial seizures with orofacial involvement, revealing gliosarcoma concurrent with bilateral hippocampal sclerosis. A 16‐year‐old neutered female domestic shorthair cat presented with acute inappetence, ataxia, disorientation, and vacant staring. Brain MRI revealed an ill‐defined, round, intra‐axial mass in the right piriform lobe, showing hyperintensity on T2W, T2‐FLAIR, and T2*W, and hypointensity on T1W images. The lesion exhibited mass effect and contrast enhancement in its center. Bilateral hyperintensity on T2‐FLAIR images and contrast enhancement were observed in the hippocampus. Brain histologic and immunohistochemical analysis revealed cerebral gliosarcoma with concurrent hippocampal sclerosis. Feline LGI1‐antibody testing on the serum and/or CSF was not performed due to insufficient biomaterial. Although retrospective testing on brain tissue was considered, it ultimately proved unfeasible, preventing us from ruling out antibody‐associated limbic encephalitis. In conclusion, cerebral gliosarcoma should be included in feline intracranial tumor differentials, warranting brain MRI and feline LGI1‐antibody testing in cats showing complex partial seizures with orofacial involvement. In our case, the prognosis remained poor due to the presence of a high‐grade glioma. [ABSTRACT FROM AUTHOR]

Experimental evolution was carried out to investigate the adaptive responses of extremotolerant fungi to a stressful environment. For 12 cultivation cycles, the halotolerant black yeasts Aureobasidium pullulans and Aureobasidium subglaciale were grown at high NaCl or glycerol concentrations, and the halophilic basidiomycete Wallemia ichthyophaga was grown close to its lower NaCl growth limit. All evolved Aureobasidium spp. accelerated their growth at low water activity. Whole genomes of the evolved strains were sequenced. No aneuploidies were detected in any of the genomes, contrary to previous studies on experimental evolution at high salinity with other species. However, several hundred single‐nucleotide polymorphisms were identified compared with the genomes of the progenitor strains. Two functional groups of genes were overrepresented among the genes presumably affected by single‐nucleotide polymorphisms: voltage‐gated potassium channels in A. pullulans at high NaCl concentration, and hydrophobins in W. ichthyophaga at low NaCl concentration. Both groups of genes were previously associated with adaptation to high salinity. Finally, most evolved Aureobasidium spp. strains were found to have increased intracellular and decreased extracellular glycerol concentrations at high salinity, suggesting that the strains have optimised their management of glycerol, their most important compatible solute. Experimental evolution therefore not only confirmed the role of potassium transport, glycerol management, and cell wall in survival at low water activity, but also demonstrated that fungi from extreme environments can further improve their growth rates under constant extreme conditions in a relatively short time and without large scale genomic rearrangements. [ABSTRACT FROM AUTHOR]

Background and Purpose: Nicorandil, a selective opener of potassium channels, used to treat angina, has drawn attention for its potential in mitigating lung injury, positioning it as a promising therapeutic approach to treat drug‐induced lung toxicity. This study aimed to explore the protective role of nicorandil in arsenic trioxide (ATO)‐induced lung injury and to elucidate the underlying mechanistic pathways. Experimental Approach: We assessed the effects of nicorandil (15 mg·kg−1, p.o.) in a rat model of pulmonary injury induced by ATO (5 mg·kg−1, i.p.). The assessment included oxidative stress biomarkers, inflammatory cytokine levels, and other biomarkers, including sirtuin‐1, sirtuin‐3, STAT3, TFAM, and JAK in lung tissue. Histological examination using H&E staining and molecular investigations using western blotting and PCR techniques were conducted. Key Results: In our model of lung injury, treatment with nicorandil ameliorated pathological changes as seen with H&E staining, reduced tissue levels of toxicity markers, and exerted significant antioxidant and anti‐inflammatory actions. On a molecular level, treatment with nicorandil down‐regulated JAK, STAT3, PPARγ, Nrf2, VEGF, p53, and micro‐RNA 132 while up‐regulating Sirt1, 3, TFAM, AMPK, and ERR‐α in lung tissue. Conclusions and Implications: The results presented here show nicorandil as a significant agent in attenuating lung injury induced by ATO in a rodent model. Nonetheless, further clinical studies are warranted to strengthen these findings. [ABSTRACT FROM AUTHOR]

Voltage‐dependent K+ (Kv) channels play an important role in restoring the membrane potential to its resting state, thereby maintaining vascular tone. In this study, native smooth muscle cells from rabbit coronary arteries were used to investigate the inhibitory effect of quetiapine, an atypical antipsychotic agent, on Kv channels. Quetiapine showed a concentration‐dependent inhibition of Kv channels, with an IC50 of 47.98 ± 9.46 μM. Although quetiapine (50 μM) did not alter the steady‐state activation curve, it caused a negative shift in the steady‐state inactivation curve. The application of 1 and 2 Hz train steps in the presence of quetiapine significantly increased the inhibition of Kv current. Moreover, the recovery time constants from inactivation were prolonged in the presence of quetiapine, suggesting that its inhibitory action on Kv channels is use (state)‐dependent. The inhibitory effects of quetiapine were not significantly affected by pretreatment with Kv1.5, Kv2.1, and Kv7 subtype inhibitors. Based on these findings, we conclude that quetiapine inhibits Kv channels in both a concentration‐ and use (state)‐dependent manner. Given the physiological significance of Kv channels, caution is advised in the use of quetiapine as an antipsychotic due to its potential side effects on cardiovascular Kv channels. The primary goal of this study was to examine the direct effect of quetiapine on vascular Kv channels. Our results indicate that quetiapine reduces Kv currents in both concentration‐ and use (state)‐dependent manners. This inhibition is characterized by a shift in the steady‐state inactivation curve, with no effect on the activation curve. [ABSTRACT FROM AUTHOR]

The involvement of inwardly rectifying potassium channel 4.1 (Kir4.1) in neuropathic pain has been established. However, there is limited understanding of the downstream mechanism through which Kir4.1 contributes to orofacial neuropathic pain. The objective of this study was to examine the regulation of Kir4.1 on the expression of pannexin 3 (Panx3) in the trigeminal ganglion (TG) and the underlying mechanism in the context of orofacial neuropathic pain caused by chronic constriction injury of the infraorbital nerve (CCI‐ION). The study observed a significant increase in Panx3 expression in the TG of mice with CCI‐ION. Inhibition of Panx3 in the TG of CCI‐ION mice resulted in alleviation of orofacial mechanical allodynia. Furthermore, conditional knockdown (CKD) of Kir4.1 in the TG of both male and female mice led to mechanical allodynia and upregulation of Panx3 expression. Conversely, overexpression of Kir4.1 decreased Panx3 levels in the TG and relieved mechanical allodynia in CCI‐ION mice. In addition, silencing Kir4.1 in satellite glial cells (SGCs) decreased Panx3 expression and increased the phosphorylation of P38 MAPK. Moreover, silencing Kir4.1 in SGCs increased the levels of reactive oxygen species (ROS). The elevated phosphorylation of P38 MAPK resulting from Kir4.1 silencing was inhibited by using a superoxide scavenger known as the tempol. Silencing Panx3 in the TG in vivo attenuated the mechanical allodynia caused by Kir4.1 CKD. In conclusion, these findings suggest that the reduction of Kir4.1 promotes the expression of Panx3 by activating the ROS‐P38 MAPK signalling pathway, thus contributing to the development of orofacial neuropathic pain. [ABSTRACT FROM AUTHOR]

This study investigated how membrane thickness and tension modify the gating of KcsA potassium channels when simultaneously varied. The KcsA channel undergoes global conformational changes upon gating: expansion of the cross‐sectional area and longitudinal shortening upon opening. Thus, membranes impose differential effects on the open and closed conformations, such as hydrophobic mismatches. Here, the single‐channel open probability was recorded in the contact bubble bilayer, by which variable thickness membranes under a defined tension were applied. A fully open channel in thin membranes turned to sporadic openings in thick membranes, where the channel responded moderately to tension increase. Quantitative gating analysis prompted the hypothesis that tension augmented the membrane deformation energy when hydrophobic mismatch was enhanced in thick membranes. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of autosomal dominant movement disorders. Among the SCAs associated with impaired ion channel function, SCA19/22 is caused by pathogenic variants in KCND3, which encodes the voltage‐gated potassium channel Kv4.3. SCA19/22 is clinically characterized by ataxia, dysarthria and oculomotor dysfunction in combination with other signs and symptoms, including mild cognitive impairment, peripheral neuropathy and pyramidal signs. The known KCND3 pathogenic variants are localized either in the transmembrane segments, the connecting loops, or the C‐terminal region of Kv4.3. We have identified a novel pathogenic variant, c.455A>G (p.D152G), localized in the N‐terminus of Kv4.3. It is located in the immediate neighbourhood of the T1 domain, which is responsible for multimerization with the β‐subunit KChIP2b and thus for the formation of functional heterooctamers. Electrophysiological studies showed that p.D152G does not affect channel gating, but reduces the ionic current in Kv4.3, even though the variant is not located in the transmembrane domains. Impaired channel trafficking to the plasma membrane may contribute to this effect. In a patient with a clinical picture corresponding to SCA19/22, p.D152G is the first pathogenic variant in the N‐terminus of Kv4.3 to be described to date with an effect on ion channel activity. [ABSTRACT FROM AUTHOR]

The voltage‐gated Kv3.1/KCNC1 channel is abundantly expressed in fast‐spiking principal neurons and GABAergic inhibitory interneurons throughout the ascending auditory pathway and in various brain regions. Inactivating mutations in the KCNC1 gene lead to forms of epilepsy and a decline in the expression of the Kv3.1 channel is involved in age‐related hearing loss. As oxidative stress plays a fundamental role in the pathogenesis of epilepsy and age‐related hearing loss, we hypothesized that an oxidative insult might affect the function of this channel. To verify this hypothesis, the activity and expression of endogenous and ectopic Kv3.1 were measured in models of oxidative stress‐related aging represented by cell lines exposed to 100 mM d‐galactose. In these models, intracellular reactive oxygen species, thiobarbituric acid reactive substances, sulfhydryl groups of cellular proteins, and the activity of catalase and superoxide dismutase were dysregulated, while the current density of Kv3.1 was significantly reduced. Importantly, the antioxidant melatonin reverted all these effects. The reduction of function of Kv3.1 was not determined by direct oxidation of amino acid side chains of the protein channel or reduction of transcript or total protein levels but was linked to reduced trafficking to the cell surface associated with Src phosphorylation as well as metabolic and endoplasmic reticulum stress. The data presented here specify Kv3.1 as a novel target of oxidative stress and suggest that Kv3.1 dysfunction might contribute to age‐related hearing loss and increased prevalence of epilepsy during aging. The pharmacological use of the antioxidant melatonin can be protective in this setting. [ABSTRACT FROM AUTHOR]

Copy number variations (CNVs) are large‐scale changes in the DNA sequence that can affect the genetic structure and phenotype of an organism. The purpose of this study was to investigate the existing CNVs and their associations with the shank diameter (ShD) and shank length (ShL) traits using data from an F2 crossbred chicken population. To carry out the study, 312 chickens were genotyped using the Illumina 60k SNP Beadchip. The shank traits of the birds were measured from day 1 to 12 weeks of age. penncnv and cnvruler tools were used to find copy numbers and regions with copy number changes (CNVR), respectively. The CNVRanger package was used to perform a genome‐wide association study between shank traits and CNVs. Gene ontology research in CNVRs was carried out using the david database. In this investigation, 966 CNVs and 606 regions with copy number changes were discovered. The copy number states and variations were randomly distributed along the length of the autosomal chromosomes. Weeks 1–4, 9 and 12 of growth revealed a significant association of copy number variations with shank traits, false discovery rate (FDR‐corrected p‐value < 0.01), and the majority of CNVs that were statistically significant were found on chromosomes 1–3. These CNV segments are nearby genes such as KCNJ12, FGF6 and MYF5, which are fundamental to growth and development. In addition, gene set analyses revealed terms related to muscle physiology, regulation of cellular processes and potassium channels. [ABSTRACT FROM AUTHOR]

Background and Purpose: Neuropathic pain, a debilitating condition with unmet medical needs, can be characterised as hyperexcitability of nociceptive neurons caused by dysfunction of ion channels. Voltage‐gated potassium channels type 7 (Kv7), responsible for maintaining neuronal resting membrane potential and thus excitability, reside under tight control of G protein‐coupled receptors (GPCRs). Calcium‐sensing receptor (CaSR) is a GPCR that regulates the activity of numerous ion channels, but whether CaSR can control Kv7 channel function has been unexplored until now. Experimental Approach: Experiments were conducted in recombinant cell models, mouse dorsal root ganglia (DRG) neurons and human induced pluripotent stem cell (hiPSC)‐derived nociceptive‐like neurons using patch‐clamp electrophysiology and molecular biology techniques. Key Results: Our results demonstrate that CaSR is expressed in recombinant cell models, hiPSC‐derived nociceptive‐like neurons and mouse DRG neurons, and its activation induced depolarisation via Kv7.2/7.3 channel inhibition. The CaSR‐Kv7.2/7.3 channel crosslink was mediated via the Gi/o protein‐adenylate cyclase‐cyclicAMP‐protein kinase A signalling cascade. Suppression of CaSR function demonstrated a potential to rescue hiPSC‐derived nociceptive‐like neurons from algogenic cocktail‐induced hyperexcitability. Conclusion and Implications: This study demonstrates that the CaSR‐Kv7.2/7.3 channel crosslink, via a Gi/o protein signalling pathway, effectively regulates neuronal excitability, providing a feasible pharmacological target for neuronal hyperexcitability management in neuropathic pain. [ABSTRACT FROM AUTHOR]

Sodium and potassium channels, especially Nav1.5 and Kir2.1, play key roles in the formation of action potentials in cardiomyocytes. These channels interact with, and are regulated by, synapse‐associated protein 97 (SAP97). However, the regulatory role of SAP97 in myocyte remains incompletely understood. Here, we investigate the function of SAP97 phosphorylation in the regulation of Nav1.5 and Kir2.1 channel complexes and the upstream regulation of SAP97. We found that SAP97 is phosphorylated by casein kinase II (CK2) in vitro. In addition, transfection of casein kinase 2 interacting protein‐1 (CKIP‐1) into cardiomyocytes to drive CK2 from the nucleus to the cytoplasm, increased SAP97 phosphorylation and Nav1.5 and Kir2.1 current activity. These findings demonstrated that CKIP‐1 modulates the subcellular translocation of CK2, which regulates Nav1.5 and Kir2.1 channel complex formation and activity in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Background: The two‐pore domain potassium (K2P) channels are a major type of potassium channels that maintain the cell membrane potential by conducting passive potassium leak currents independent of voltage change. They play prominent roles in multiple physiological processes, including neuromodulation, perception of pain, breathing and mood control, and response to volatile anesthetics. Mutations in K2P channels have been linked to many human diseases, such as neuronal and cardiovascular disorders and cancers. Significant progress has been made to understand their protein structures, physiological functions, and pharmacological modifiers. However, their expression and function during embryonic development remain largely unknown. Results: We employed the zebrafish model and identified 23 k2p genes using BLAST search and gene cloning. We first analyzed vertebrate K2P channel evolution by phylogenetic and syntenic analyses. Our data revealed that the six subtypes of the K2P genes have already evolved in invertebrates long before the emergence of vertebrates. Moreover, the vertebrate K2P gene number increased, most likely due to two whole‐genome duplications. Furthermore, we examined zebrafish k2p gene expression during early embryogenesis by in situ hybridization. Each subgroup's genes showed similar but distinct gene expression domains with some exceptions. Most of them were expressed in neural tissues consistent with their known function of neural excitability regulation. However, a few k2p genes were expressed temporarily in specific tissues or organs, suggesting that these K2P channels may be needed for embryonic development. Conclusions: Our phylogenetic and developmental analyses of K2P channels shed light on their evolutionary history and potential roles during embryogenesis related to their physiological functions and human channelopathies. Key Findings: K2P potassium channels have a deep evolutionary origin, and vertebrates gained more K2p channel genes through whole genome duplications.23 K2P channels were identified in zebrafish, some resulting from the teleost‐specific whole genome duplication.Zebrafish k2p channel genes are expressed in various tissues and organs. K2p genes from the same subtypes showed overlapped expression domains.Some K2P channels may be needed for embryonic development, indicated by their temporary expressions in specific tissues or organs. [ABSTRACT FROM AUTHOR]

Although natural dual‐ion exchangers are indispensable for bio‐organic functions, developing their artificial counterparts remains nearly unexplored. Herein, this work proposes a novel light‐controlled K+/Na+‐transport‐exchanger TE12, realizing an unprecedented reversible switch between K+‐ and Na+‐transmembrane transport by changing its transport mechanism (channel and carrier). The conformational transformation of the azobenzene moiety in TE12 essentially induces this. The K+/Na+ selectivity of K+‐channel Trans‐TE12 is as high as 20.3, making it one of the most selective artificial K+‐transporters. Moreover, considering the scarcity of artificial Na+‐transporters, the Na+‐carrier Cis‐TE12 with high Na+/K+ selectivity (9.25) represents a breakthrough. Cis‐TE12 significantly triggers cell apoptosis by igniting fascinating "Na+ sparks" first observed on cancer cells treated with synthetic channels, while K+‐channel Trans‐TE12 exhibits low toxicity. Importantly, TE12 can function as a spatiotemporally controllable ion interference therapy, enabling in situ 365 nm light‐triggered and 450 nm light‐inhibited cell death. This work realizes sophisticated functions in a simplified structure by the "Less is More" design concept. It opens a shortcut toward the future iterative updating of artificial ion transporters to make them better biological analogs and therapeutic agents. [ABSTRACT FROM AUTHOR]

Both the intrinsic and extrinsic contributions to the high energy storage properties of (K0.5Na0.5)NbO3 were investigated herein by employing Bi(Mg2/3Ta1/3)O3 as a second component to synthesize novel environment‐friendly energy storage ceramics. The role of the second component was confirmed to reduce the intrinsic activation of electrons, which effectively improves the band gap values and reduces the probability of intrinsic breakdown. Phase field simulation was employed to confirm that the smaller grain size of the modified ceramic microstructure enhances the extrinsic breakdown and dielectric breakdown strength. Moreover, ab initio molecular dynamics were used to investigate the critical role of the Mg ions in lowering the initial polarization and forming nanodomains, representing the intrinsic contribution to decreasing the initial polarization. An intrinsic structure with moderate polarization rapidly increases the polarization of ceramics under external electric fields, facilitating high energy storage density. The prepared ceramics achieve a recoverable energy density (Wrec) of 3.86 J/cm3 and energy efficiency (η) of 81.2% at 385 kV/cm. [ABSTRACT FROM AUTHOR]

Background: Epilepsy in dogs and humans is associated with blood‐brain barrier (BBB) dysfunction (BBBD), which may involve dysfunction of tight junction (TJ) proteins, matrix metalloproteases, and astrocytes. Imaging techniques to assess BBB integrity, to identify potential treatment strategies, have not yet been evaluated in veterinary medicine. Hypothesis: Some dogs with idiopathic epilepsy (IE) will exhibit BBBD. Identifying BBBD may improve antiepileptic treatment in the future. Animals: Twenty‐seven dogs with IE and 10 healthy controls. Methods: Retrospective, prospective cohort study. Blood‐brain barrier permeability (BBBP) scores were calculated for the whole brain and piriform lobe of all dogs by using dynamic contrast enhancement (DCE) magnetic resonance imaging (MRI) and subtraction enhancement analysis (SEA). Matrix metalloproteinase‐9 (MMP9) activity in serum and cerebrospinal fluid (CSF) was measured and its expression in the piriform lobe was examined using immunofluorescent staining. Gene expression of TJ proteins and astrocytic transporters was analyzed in the piriform lobe. Results: The DCE‐MRI analysis of the piriform lobe identified higher BBBP score in the IE group when compared with controls (34.5% vs 26.5%; P =.02). Activity and expression of MMP9 were increased in the serum, CSF, and piriform lobe of IE dogs as compared with controls. Gene expression of Kir4.1 and claudin‐5 in the piriform lobe of IE dogs was significantly lower than in control dogs. Conclusions and Clinical Importance: Our findings demonstrate BBBD in dogs with IE and were supported by increased MMP9 activity and downregulation of astrocytic potassium channels and some TJ proteins. Blood brain barrier dysfunction may be a novel antiepileptic therapy target. [ABSTRACT FROM AUTHOR]

Paramecium exhibits responsive behavior to environmental changes, moving either closer to or further away from stimuli. Electrophysiological experiments have revealed that these behavioral responses are controlled by membrane potentials. Anoctamin, a Ca2+‐activated Cl− channel, is involved in the regulation of membrane potential in mammals. However, it remains uncertain whether Cl− channels like anoctamin regulate Paramecium behavior. Herein, replacement of external Cl− ions with acetate ion and application of Cl− channel blocker niflumic acid (NFA, 0.1 μM) increased spontaneous avoiding reactions (sARs). Hence, we hypothesized that anoctamin is involved in the stabilization of membrane potential fluctuation. Paramecium cells in which the anoctamin‐like protein 1 gene was knocked down displayed frequent sARs in the culture medium without external stimulation. Treatment of anoctamin‐like protein 1‐knockdown cells with the Ca2+ chelator BAPTA or Ca‐channel blocker nicardipine reversed the increase in sARs. Electrophysiological experiments revealed extension of membrane depolarization when positive currents were applied to anoctamin‐like protein 1‐knockdown cells. We concluded that anoctamin‐like protein 1 works as a Cl‐channel and stabilizes the membrane potential oscillation, reducing sARs. [ABSTRACT FROM AUTHOR]

Neuropathic pain can occur during the prediabetic stage, even in the absence of hyperglycemia. The presence of prediabetic neuropathic pain (PDNP) poses challenges to the management of individuals with prediabetes. However, the mechanisms underlying this pain remain unclear. This study aims to investigate the underlying mechanism and identify potential therapeutic targets of PDNP. A prediabetic animal model induced by a high‐energy diet exhibits both mechanical allodynia and thermal hyperalgesia. Furthermore, hyperexcitability and decreased potassium currents are observed in the dorsal root ganglion (DRG) neurons of these rats. TREK1 and TREK2 channels, which belong to the two‐pore‐domain K+ channel (K2P) family and play an important role in controlling cellular excitability, are downregulated in DRG neurons. Moreover, this alteration is modulated by Sortilin, a molecular partner that modulates the expression of TREK1. The overexpression of Sortilin negatively affects the expression of TREK1 and TREK2, leading to increased neuronal excitability in the DRG and enhanced peripheral pain sensitivity in rats. Moreover, the downregulation of Sortilin or activation of TREK1 and TREK2 channels by genetic or pharmacological approaches can alleviate PDNP. Therefore, targeting the Sortilin‐mediated TREK1/2 pathway may provide a therapeutic approach for ameliorating PDNP. [ABSTRACT FROM AUTHOR]

SUMMARY: Potassium (K+), being an essential macronutrient in plants, plays a central role in many aspects. Root growth is highly plastic and is affected by many different abiotic stresses including nutrient deficiency. The Shaker‐type K+ channel Arabidopsis (Arabidopsis thaliana) K+ Transporter 1 (AKT1) is responsible for K+ uptake under both low and high external K+ conditions. However, the upstream transcription factor of AKT1 is not clear. Here, we demonstrated that the WRKY6 transcription factor modulates root growth to low potassium (LK) stress in Arabidopsis. WRKY6 showed a quick response to LK stress and also to many other abiotic stress treatments. The two wrky6 T‐DNA insertion mutants were highly sensitive to LK treatment, whose primary root lengths were much shorter, less biomass and lower K+ content in roots than those of wild‐type plants, while WRKY6‐overexpression lines showed opposite phenotypes. A further investigation showed that WRKY6 regulated the expression of the AKT1 gene via directly binding to the W‐box elements in its promoter through EMSA and ChIP‐qPCR assays. A dual luciferase reporter analysis further demonstrated that WRKY6 enhanced the transcription of AKT1. Genetic analysis further revealed that the overexpression of AKT1 greatly rescued the short root phenotype of the wrky6 mutant under LK stress, suggesting AKT1 is epistatic to WRKY6 in the control of LK response. Further transcriptome profiling suggested that WRKY6 modulates LK response through a complex regulatory network. Thus, this study unveils a transcription factor that modulates root growth under potassium deficiency conditions by affecting the potassium channel gene AKT1 expression. Significance Statement: This study has identified a WRKY‐type transcription factor WRKY6, which positively regulates potassium uptake, and mutants and overexpression lines showed opposite phenotypes. It exerts its role by directly binding to the promoter region of the potassium channel gene AKT1 and promoting its expression. [ABSTRACT FROM AUTHOR]

This document provides concise summaries of various scientific studies on a wide range of topics, including genetic diseases, biosensor systems, drug development, therapeutic targets, defense responses in plants, and more. The studies offer valuable insights into their respective fields and were conducted in different countries. For example, one study explores the potential use of microRNAs as a treatment for intracellular infections caused by Staphylococcus aureus, while another study analyzes pathogenic transthyretin variants associated with genetic amyloidosis. Additionally, the document highlights innovative educational approaches, such as an undergraduate course that integrates UN Sustainable Development Goals and critical thinking, as well as an online biochemistry course for medical students using case studies. [Extracted from the article]

The Na+, K+ ATPase (NKA) enzyme is important to generate the transmembrane ion gradient in the gills, intestine, and kidneys, hence, is vital for secondary transport of fluids and different solutes in teleosts. Gill NKA enzyme activity is often used as a proxy for parr–smolt transformation (PST) during which anadromous salmonids prepare for seawater (SW). Increased intensification and production of larger smolts in modern salmonid aquaculture has resulted in reports of gill NKA activity being less reliable as a proxy for smolt quality. Consequently, changes in mRNA nka‐α1b/α1a ratios in gills are increasingly used as indicators of PST. However, nka isoform mRNA abundance may not reflect translation into the functional protein, nor the activity of the mature enzyme. This may limit the predictive power of molecular markers under certain environmental conditions, rearing regimes and biological scenarios. During PST, the osmoregulatory transformations necessary for SW tolerance and survival does not only occur in the gills. Equally important are the changes in ion transporting activities, including NKA activity, in the intestine and kidneys. However, to our knowledge, there are no previous studies addressing the timing and concurrent changes in NKA activity in the three osmoregulatory tissue during PST. Here we present modifications and optimization of the NKA enzyme activity protocols for gill, intestinal and kidney tissue and outline how to best utilize NKA activity measurements as part of a more holistic approach to evaluate overall smolt quality in modern aquaculture. [ABSTRACT FROM AUTHOR]

Variants in potassium channel‐related genes are one of the most important mechanisms underlying abnormal neuronal excitation and disturbances in the cellular resting membrane potential. These variants can cause different forms of epilepsy, which can seriously affect the physical and mental health of patients, especially those with refractory epilepsy or status epilepticus, which are common among pediatric patients and are potentially life‐threatening. Variants in potassium ion channel‐related genes have been reported in few studies; however, to our knowledge, no systematic review has been published. This study aimed to summarize the epilepsy phenotypes, functional studies, and pharmacological advances associated with different potassium channel gene variants to assist clinical practitioners and drug development teams to develop evidence‐based medicine and guide research strategies. PubMed and Google Scholar were searched for relevant literature on potassium channel‐related epilepsy reported in the past 5–10 years. Various common potassium ion channel gene variants can lead to heterogeneous epilepsy phenotypes, and functional effects can result from gene deletions and compound effects. Administration of select anti‐seizure medications is the primary treatment for this type of epilepsy. Most patients are refractory to anti‐seizure medications, and some novel anti‐seizure medications have been found to improve seizures. Use of targeted drugs to correct aberrant channel function based on the type of potassium channel gene variant can be used as an evidence‐based pathway to achieve precise and individualized treatment for children with epilepsy. Plain Language Summary: In this article, the pathogenesis and clinical characteristics of epilepsy caused by different types of potassium channel gene variants are reviewed in the light of the latest research literature at home and abroad, with the expectation of providing a certain theoretical basis for the diagnosis and treatment of children with this type of disease. [ABSTRACT FROM AUTHOR]

Most animal cell types are classified as non‐excitable because they do not generate action potentials observed in excitable cells, such as neurons and muscle cells. Thus, resolving voltage signals in non‐excitable cells demands sensors with exceptionally high voltage sensitivity. In this study, the ultrabright, ultrasensitive, and calibratable genetically encoded voltage sensor rEstus is developed using structure‐guided engineering. rEstus is most sensitive in the resting voltage range of non‐excitable cells and offers a 3.6‐fold improvement in brightness change for fast voltage spikes over its precursor ASAP3. Using rEstus, it is uncovered that the membrane voltage in several non‐excitable cell lines (A375, HEK293T, MCF7) undergoes spontaneous endogenous alterations on a second to millisecond timescale. Correlation analysis of these optically recorded voltage alterations provides a direct, real‐time readout of electrical cell–cell coupling, showing that visually connected A375 and HEK293T cells are also largely electrically connected, while MCF7 cells are only weakly coupled. The presented work provides enhanced tools and methods for non‐invasive voltage imaging in living cells and demonstrates that spontaneous endogenous membrane voltage alterations are not limited to excitable cells but also occur in a variety of non‐excitable cell types. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction contributes to the development of secondary brain injury (SBI) following intracerebral hemorrhage (ICH) and represents a promising therapeutic target. Celastrol, the primary active component of Tripterygium wilfordii, is a natural product that exhibits mitochondrial and neuronal protection in various cell types. This study aims to investigate the neuroprotective effects of celastrol against ICH‐induced SBI and explore its underlying mechanisms. Celastrol improves neurobehavioral and cognitive abilities in mice with autologous blood‐induced ICH, reduces neuronal death in vivo and in vitro, and promotes mitochondrial function recovery in neurons. Single‐cell nuclear sequencing reveals that the cyclic adenosine monophosphate (cAMP)/cAMP‐activated exchange protein‐1 (EPAC‐1) signaling pathways are impacted by celastrol. Celastrol binds to cNMP (a domain of EPAC‐1) to inhibit its interaction with voltage‐dependent anion‐selective channel protein 1 (VDAC1) and blocks the opening of mitochondrial permeability transition pores. After neuron‐specific knockout of EPAC1, the neuroprotective effects of celastrol are diminished. In summary, this study demonstrates that celastrol, through its interaction with EPAC‐1, ameliorates mitochondrial dysfunction in neurons, thus potentially improving SBI induced by ICH. These findings suggest that targeting EPAC‐1 with celastrol can be a promising therapeutic approach for treating ICH‐induced SBI. [ABSTRACT FROM AUTHOR]

Water molecules are actively involved in many catalytic oxidation processes, which require the construction of highly active sites for their activation to accelerate the reaction rate, especially over non‐noble metal catalysts. Herein, K species is embeded into the natural 2*2 channel of α‐MnO2 by a hydrothermal coupled molten salt method, which would make these K species behave in an electron‐rich state and provide more electrons for the activation of water molecules. Compared with surface K modification (namely, the electron‐deficient K species), channel K confinement can lower the activation energy barrier of H2O dissociation on α‐MnO2 to generate hydroxyl species with more nucleophilic oxygen atoms, contributing to the superior HCHO catalytic oxidation activity with a fourfold enhancement. The internal relationship among the confined channel, K species, and catalytic performance is systematically elucidated at the molecular level. This work offers a new ion confinement method and opens up new avenues to construct electron‐rich metal sites with channel structures for the activation of water molecules. [ABSTRACT FROM AUTHOR]

Variations in light intensity induce cytosol pH changes in photosynthetic tissues, providing a possible signal to adjust a variety of biochemical, physiological and developmental processes to the energy status of the cells. It was shown that these pH changes are partially due to the transport of protons in or out of the thylakoid lumen. However, the ion transporters in the chloroplast that transmit these pH changes to the cytosol are not known. KEA1 and KEA2 are K+/H+ antiporters in the chloroplast inner envelope that adjust stromal pH in light‐to‐dark transitions. We previously determined that stromal pH is higher in kea1kea2 mutant cells. In this study, we now show that KEA1 and KEA2 are required to attenuate cytosol pH variations upon sudden light intensity changes in leaf mesophyll cells, showing they are important components of the light‐modulated pH signalling module. The kea1kea2 mutant mesophyll cells also have a considerably less negative membrane potential. Membrane potential is dependent on the activity of the plasma membrane proton ATPase and is regulated by secondary ion transporters, mainly potassium channels in the plasma membrane. We did not find significant differences in the activity of the plasma membrane proton pump but found a strongly increased membrane permeability to protons, especially potassium, of the double mutant plasma membranes. Our results indicate that chloroplast envelope K+/H+ antiporters not only affect chloroplast pH but also have a strong impact on cellular ion homeostasis and energization of the plasma membrane. [ABSTRACT FROM AUTHOR]

Halophyte Halogeton glomeratus mostly grows in saline desert areas in arid and semi‐arid regions and is able to adapt to adverse conditions such as salinity and drought. Earlier transcriptomic studies revealed activation of the HgS2 gene in the leaf of H. glomeratus seedlings when exposed to saline conditions. To identify the properties of HgS2 in H. glomeratus, we used yeast transformation and overexpression in Arabidopsis. Yeast cells genetically transformed with HgS2 exhibited K+ uptake and Na+ efflux compared with control (empty vector). Stable overexpression of HgS2 in Arabidopsis improved its resistance to salt stress and led to a notable rise in seed germination in salinity conditions compared to the wild type (WT). Transgenic Arabidopsis regulated ion homeostasis in plant cells by increasing Na+ absorption and decreasing K+ efflux in leaves, while reducing Na+ absorption and K+ efflux in roots. In addition, overexpression of HgS2 altered transcription levels of stress response genes and regulated different metabolic pathways in roots and leaves of Arabidopsis. These results offer new insights into the role of HgS2 in plants' salt tolerance. [ABSTRACT FROM AUTHOR]

Congenital hyperinsulinism (CHI; OMIM: 256450) is characterized by persistent insulin secretion despite severe hypoglycemia. The most common causes are variants in the ATP‐binding cassette subfamily C member 8(ABCC8) and potassium inwardly‐rectifying channel subfamily J member 11(KCNJ11) genes. These encode ATP‐sensitive potassium (KATP) channel subunit sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) proteins. A 7‐day‐old male infant presented with frequent hypoglycemic episodes and was clinically diagnosed with CHI, underwent trio‐whole‐exome sequencing, revealing compound heterozygous ABCC8 variants (c.307C>T, p.His103Tyr; and c.3313_3315del, p.Ile1105del) were identified. In human embryonic kidney 293 (HEK293) and rat insulinoma cells (INS‐1) transfected with wild‐type and variant plasmids, KATP channels formed by p.His103Tyr were delivered to the plasma membrane, whereas p.Ile1105del or double variants (p.His103Tyr coupled with p.Ile1105del) failed to be transported to the plasma membrane. Compared to wild‐type channels, the channels formed by the variants (p.His103Tyr; p.Ile1105del) had elevated basal [Ca2+]i, but did not respond to stimulation by glucose. Our results provide evidence that the two ABCC8 variants may be related to CHI owing to defective trafficking and dysfunction of KATP channels. [ABSTRACT FROM AUTHOR]

Various disorders are accompanied by histamine‐independent itching, which is often resistant to the currently available therapies. Here, it is reported that the pharmacological activation of Slack (Kcnt1, KNa1.1), a potassium channel highly expressed in itch‐sensitive sensory neurons, has therapeutic potential for the treatment of itching. Based on the Slack‐activating antipsychotic drug, loxapine, a series of new derivatives with improved pharmacodynamic and pharmacokinetic profiles is designed that enables to validate Slack as a pharmacological target in vivo. One of these new Slack activators, compound 6, exhibits negligible dopamine D2 and D3 receptor binding, unlike loxapine. Notably, compound 6 displays potent on‐target antipruritic activity in multiple mouse models of acute histamine‐independent and chronic itch without motor side effects. These properties make compound 6 a lead molecule for the development of new antipruritic therapies targeting Slack. [ABSTRACT FROM AUTHOR]

BeKm‐1 is a peptide toxin from scorpion venom that blocks the pore of the potassium channel hERG (Kv11.1) in the human heart. Although individual protein structures have been resolved, the structure of the complex between hERG and BeKm‐1 is unknown. Here, we used molecular dynamics and ensemble docking, guided by previous double‐mutant cycle analysis data, to obtain an in silico model of the hERG–BeKm‐1 complex. Adding to the previous mutagenesis study of BeKm‐1, our model uncovers the key role of residue Arg20, which forms three interactions (a salt bridge and hydrogen bonds) with the channel vestibule simultaneously. Replacement of this residue even by lysine weakens the interactions significantly. In accordance, the recombinantly produced BeKm‐1R20K mutant exhibited dramatically decreased activity on hERG. Our model may be useful for future drug design attempts. [ABSTRACT FROM AUTHOR]

Mammalian Ca2+‐dependent Slo K+ channels can stably associate with auxiliary γ subunits which fundamentally alter their behavior. By a so far unknown mechanism, the four γ subunits reduce the need for voltage‐dependent activation and, thereby, allow Slo to open independently of an action potential. Here, using cryo‐EM, we reveal how the transmembrane helix of γ1/LRRC26 binds and presumably stabilizes the activated voltage‐sensor domain of Slo1. The activation is further enhanced by an intracellular polybasic stretch which locally changes the charge gradient across the membrane. Our data provide a possible explanation for Slo1 regulation by the four γ subunits and also their different activation efficiencies. This suggests a novel activation mechanism of voltage‐gated ion channels by auxiliary subunits. [ABSTRACT FROM AUTHOR]

Acoustic communication plays important roles in the survival and reproduction of anurans. The perception and discrimination of conspecific sound signals of anurans were always affected by masking background noise. Previous studies suggested that some frogs evolved the high‐frequency hearing to minimize the low‐frequency noise. However, the molecular mechanisms underlying the high‐frequency hearing in anurans have not been well explored. Here, we cloned and obtained the coding regions of a high‐frequency hearing‐related gene (KCNQ4) from 11 representative anuran species and compared them with orthologous sequences from other four anurans. The sequence characteristics and evolutionary analyses suggested the highly conservation of the KCNQ4 gene in anurans, which supported their functional importance. Branch‐specific analysis showed that KCNQ4 genes were under different evolutionary forces in anurans and most anuran lineages showed a generally strong purifying selection. Intriguingly, one significantly positively selected site was identified in the anuran KCNQ4 gene based on FEL model. Positive selection was also found along the common ancestor of Ranidae and Rhacophoridae as well as the ancestral O. tianmuii based on the branch‐site analysis, and the positively selected sites identified were involved in or near the N‐terminal ion transport and the potassium ion channel functional domain of the KCNQ4 genes. The present study revealed valuable information regarding the KCNQ4 genes in anurans and provided some new insights for the underpinnings of the high‐frequency hearing in frogs. [ABSTRACT FROM AUTHOR]

The large conductance, calcium, and voltage‐active potassium channels (BKCa) were originally discovered in Drosophila melanogaster as slowpoke (slo). They are extensively characterized in fly models as ion channels for their roles in neurological and muscular function, as well as aging. BKCa is known to modulate cardiac rhythm and is localized to the mitochondria. Activation of mitochondrial BKCa causes cardioprotection from ischemia–reperfusion injury, possibly via modulating mitochondrial function in adult animal models. However, the role of BKCa in cardiac function is not well‐characterized, partially due to its localization to the plasma membrane as well as intracellular membranes and the wide array of cells present in mammalian hearts. Here we demonstrate for the first time a direct role for BKCa in cardiac function and cardioprotection from IR injury using the Drosophila model system. We have also discovered that the BKCa channel plays a role in the functioning of aging hearts. Our study establishes the presence of BKCa in the fly heart and ascertains its role in aging heart function. [ABSTRACT FROM AUTHOR]

Methadone (R,S‐methadone) can prolong the QT interval. R‐methadone inhibits cardiac potassium channel function less than S‐methadone. We tested if switching from methadone to R‐methadone would reduce corrected QT (QTc) intervals in methadone maintenance treatment (MMT) patients. Nine patients, with automatically read QTc intervals ≥450 ms, were required to detect a 20 ms (clinically relevant) reduction in QTc intervals with 15 ms standard deviation (SD) and 90% power. Nine stabilized MMT patients, using median (range) 70 (40–120) mg methadone, were included. Data (ECG recordings, serum samples, and withdrawal symptoms) were collected both before drug intake (Cmin) and at 3 h after drug intake (Cmax), and were collected on the day before the switch from methadone to equipotent R‐methadone dose and at 14 and 28 days after the switch. A cardiologist calculated QTc intervals retrospectively. Serum electrolytes and methadone concentrations were measured. Mean QTc intervals at Cmin were 472 ms and 422 ms on methadone (automatically and manually read) and 414 ms on R‐methadone (manually read). Mean (SD) change in QTc intervals was −8 (10) ms (p = 0.047) at Cmin but non‐significant at Cmax. R‐methadone showed a concentration‐dependent relationship with QTc intervals. Switching to R‐methadone reduced QTc intervals, but far less than the 20 ms considered clinically relevant. [ABSTRACT FROM AUTHOR]

Neurodegeneration is linked to the progressive loss of neural function and is associated with several diseases. Hypoxia is a hallmark in many of these diseases, and several therapies have been developed to treat this disease, including gene expression therapies that should be tightly controlled to avoid side effects. Cells experiencing hypoxia undergo a series of physiological responses that are induced by the activation of various transcription factors. Modulation of microRNA (miRNA) expression to alter transcriptional regulation has been demonstrated to be beneficial in treating multiple diseases, and in this study, we therefore explored potential miRNA candidates that could influence hypoxia-induced nerve cell death. Our data suggest that in mouse neuroblasts Neuro-2a cells with hypoxia/reoxygenation (H/R), miR-337-3p is downregulated to increase the expression of Potassium channel tetramerization domain containing 11 (KCTD11) and subsequently promote apoptosis. Here, we demonstrate for the first time that KCTD11 plays a role in the cellular response to hypoxia, and we also provide a possible regulatory mechanism by identifying the axis of miR-337-3p/KCTD11 as a promising candidate modulator of nerve cell survival after H/R exposure. [ABSTRACT FROM AUTHOR]

Hard carbon (HC) has attracted considerable research interest as the most promising anode for potassium‐ion batteries (PIBs) due to its tunable interlayer spacing and abundant voids to accommodate K+. However, the practical application of hard carbon is severely hampered by low initial Coulombic efficiency (ICE) and high plateau potential. Herein, a manganese ion‐catalyzed pyrolysis strategy is explored to regulate the graphitic microcrystalline structure and localized electron distribution in hard carbon that greatly improve K+ plateau storage and ICE. Systematic experimental measurements, in situ/ex situ observations, dynamic analysis, and density functional theory calculations elucidate that the introduction of Mn2+ ions could catalyze the formation of short‐ordered graphitic nanodomains in hard carbon to provide abundant insertions of K+, and meanwhile induce localized electron distribution through the Mn─N3─C coordination structure to enable dynamic K+ diffusion and electron transfer kinetics. Consequently, the modulated hard carbon exhibits a high low‐potential–plateau capacity, excellent rate capability, and high initial Coulombic efficiency in potassium half‐cell configurations. More importantly, the charge storage mechanism of "adsorption–intercalation" is proposed based on the correlation between carbon structures and discharge/charge plateau. This work provides an in‐depth insight into the fundamentals of microstructure regulation of hard carbon anode for high‐performance PIBs. [ABSTRACT FROM AUTHOR]

Voltage‐gated K+ (KV) and Ca2+‐activated K+ (KCa) channels are essential proteins for membrane repolarization in excitable cells. They also play important physiological roles in non‐excitable cells. Their diverse physiological functions are in part the result of their auxiliary subunits. Auxiliary subunits can alter the expression level, voltage dependence, activation/deactivation kinetics, and inactivation properties of the bound channel. KV and KCa channels are activated by membrane depolarization through the voltage‐sensing domain (VSD), so modulation of KV and KCa channels through the VSD is reasonable. Recent cryo‐EM structures of the KV or KCa channel complex with auxiliary subunits are shedding light on how these subunits bind to and modulate the VSD. In this review, we will discuss four examples of auxiliary subunits that bind directly to the VSD of KV or KCa channels: KCNQ1–KCNE3, Kv4‐DPP6, Slo1‐β4, and Slo1‐γ1. Interestingly, their binding sites are all different. We also present some examples of how functionally critical binding sites can be determined by introducing mutations. These structure‐guided approaches would be effective in understanding how VSD‐bound auxiliary subunits modulate ion channels. [ABSTRACT FROM AUTHOR]

SUR2, similar to SUR1, is a regulatory subunit of the ATP‐sensitive potassium channel (KATP), which plays a key role in numerous important physiological processes and is implicated in various diseases. Recent structural studies have revealed that, like SUR1, SUR2 can undergo ligand‐dependent dynamic conformational changes, transitioning between an inhibitory inward‐facing conformation and an activating occluded conformation. In addition, SUR2 possesses a unique inhibitory Regulatory helix (R helix) that is absent in SUR1. The binding of the activating Mg‐ADP to NBD2 of SUR2 competes with the inhibitory Mg‐ATP, thereby promoting the release of the R helix and initiating the activation process. Moreover, the signal generated by Mg‐ADP binding to NBD2 might be directly transmitted to the TMD of SUR2, prior to NBD dimerization. Furthermore, the C‐terminal 42 residues (C42) of SUR2 might allosterically regulate the kinetics of Mg‐nucleotide binding on NBD2. These distinctive properties render SUR2 intricate sensors for intracellular Mg‐nucleotides. [ABSTRACT FROM AUTHOR]