Potassium Channel Gene Research Articles

14-3-3 promotes sarcolemmal expression of cardiac CaV1.2 and nucleates isoproterenol-triggered channel superclustering

The L-type Ca2+ channel (CaV1.2) is essential for cardiac excitation-contraction coupling. To contribute to the inward Ca2+ flux that drives Ca2+-induced-Ca2+-release, CaV1.2 channels must be expressed on the sarcolemma; thus the regulatory mechanisms that tune CaV1.2 expression to meet contractile demand are an emerging area of research. A ubiquitously expressed protein called 14-3-3 has been proposed to affect Ca2+ channel trafficking in nonmyocytes; however, whether 14-3-3 has similar effects on CaV1.2 in cardiomyocytes is unknown. 14-3-3 preferentially binds phospho-serine/threonine residues to affect many cellular processes and is known to regulate cardiac ion channels including NaV1.5 and the human ether-à-go-go-related gene (hERG) potassium channel. Altered 14-3-3 expression and function have been implicated in cardiac pathologies including hypertrophy. Accordingly, we tested the hypothesis that 14-3-3 interacts with CaV1.2 in a phosphorylation-dependent manner and regulates cardiac CaV1.2 trafficking and recycling. Confocal imaging, proximity ligation assays, superresolution imaging, and coimmunoprecipitation revealed a population of 14-3-3 colocalized and closely associated with CaV1.2. The degree of 14-3-3/CaV1.2 colocalization increased upon stimulation of β-adrenergic receptors with isoproterenol. Notably, only the 14-3-3-associated CaV1.2 population displayed increased cluster size with isoproterenol, revealing a role for 14-3-3 as a nucleation factor that directs CaV1.2 superclustering. Isoproterenol-stimulated augmentation of sarcolemmal CaV1.2 expression, Ca2+ currents, and Ca2+ transients in ventricular myocytes were strengthened by 14-3-3 overexpression and attenuated by 14-3-3 inhibition. These data support a model where 14-3-3 interacts with CaV1.2 in a phosphorylation-dependent manner to promote enhanced trafficking/recycling, clustering, and activity during β-adrenergic stimulation.

Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes

Variants in genes encoding for voltage-gated K+ (Kv) channels are frequent cause of drug-resistant pediatric epilepsies. Obtaining a molecular diagnosis gives the opportunity to assess the efficacy of pharmacological strategies based on in vitro features of mutant channels. In this retrospective observational study, we selected patients with drug-resistant pediatric epilepsies caused by variants in potassium channel encoding genes, followed at the Fondazione IRCCS Istituto Neurologico Carlo Besta of Milan, Italy. After the experimental characterization of variants’ functional properties in transiently transfected Chinese Hamster Ovary (CHO) cells, we identified drugs to be used as pharmacological approaches. We recruited six patients carrying different missense variants in four Kv channels (Kv7.2, Kv7.3, Kv3.1, and KNa1.1). In vitro experiments demonstrated that variants in Kv7 channels induced loss-of-function (LoF) effects, while those affecting Kv3.1 or KNa1.1 led to gain-of-function (GoF). Moreover, we found that the Kv7 channels activator gabapentin was able to revert the LoF effects caused by Kv7.2/Kv7.3 variants, and the potassium channel-blocker fluoxetine counteracted the GoF effects in Kv3.1 or KNa1.1 variants. According to experimental data, patients carrying Kv7 variants were treated with gabapentin. While this treatment resulted successful in two patients (#1, Kv7.2 G310S variant; #3, Kv7.3 V359L + Kv7.3 D542N), it resulted detrimental in the remaining case (#2, Kv7.2 D535E), requiring drug withdrawal. The application in vivo of fluoxetine to counteract GoF effects induced by Kv3.1 or KNa1.1 variants determined a significant reduction of both seizure frequency and behavior disturbances in patient #4 (Kv3.1 V425M), and in both subjects carrying KNa1.1 variants (#5, S937G and #6, R262Q). However, for the latter case, this drug was halted due to severe behavioral side effects. For most of the patients herein reported, pharmacological strategies, selected according to the in vitro functional properties of Kv-channels pathogenic variants, resulted in a significant improvement of both epileptic and cognitive features.

Development of an efficient NUPR1 inhibitor with anticancer activity

Pancreatic cancer is highly lethal and has limited treatment options available. Our team had previously developed ZZW-115, a promising drug candidate that targets the nuclear protein 1 (NUPR1), which is involved in pancreatic cancer development and progression. However, clinical translation of ZZW-115 was hindered due to potential cardiotoxicity caused by its interaction with the human Ether-à-go-go-Related Gene (hERG) potassium channel. To address this, we have performed a high-throughput screening of 10,000 compounds from the HitFinder Chemical Library, and identified AJO14 as a lead compound that binds to NUPR1, without having favorable affinity towards hERG. AJO14 induced cell death through apoptosis, necroptosis, and parthanatos (induced by the poly-ADP ribose polymerase (PARP) overactivation), driven by mitochondrial catastrophe and decreased ATP production. This process seemed to be mediated by the hyperPARylation (an excessive modification of proteins by PARP, leading to cellular dysfunction), as it could be reversed by Olaparib, a PARP inhibitor. In xenografted mice, AJO14 demonstrated a dose-dependent tumor reduction activity. Furthermore, we attempted to improve the anti-cancer properties of AJO14 by molecular modification of the lead compound. Among the 51 candidates obtained and tested, 8 compounds exhibited a significant increase in efficacy and have been retained for further studies, especially LZX-2-73. These AJO14-derived compounds offer potent NUPR1 inhibition for pancreatic cancer treatment, without cardiotoxicity concerns.

Toxicity of Flonicamid to Diaphorina citri (Hemiptera: Liviidae) and Its Identification and Expression of Kir Channel Genes.

Flonicamid is a selective insecticide effective against piercing-sucking insects. Although its molecular target has been identified in other species, the specific effects and detailed mechanism of action in Diaphorina citri Kuwayama remain poorly understood. In this study, we determined that the LC50 of flonicamid for D. citri adults was 16.6 mg AI L-1 after 4 days of exposure. To explore the relevant mechanisms, the treatments with acetone and with 20 mg AI L-1 flonicamid for 96 h were collected as samples for RNA-Seq. The analysis of the transcriptomes revealed 345 differentially expressed genes (DEGs) in D. citri adults subjected to different treatments. Among these DEGs, we focused on the inward-rectifying potassium (Kir) channel genes, which have been extensively studied as potential targets of flonicamid. Three Kir subunit genes (Dckir1, Dckir2, Dckir3) in D. citri were successfully cloned and identified. Furthermore, the expression profiles of these DcKirs were investigated using RT-qPCR and showed that their expression significantly increased after D. citri eclosion to adulthood, particularly for DcKir3. The DcKirs were predominantly expressed in gut tissues, with DcKir1 and DcKir2 exhibiting high expression levels in the hindgut and midgut, respectively, while DcKir3 showing high expression in the midgut and Malpighian tubules. This study provides insights into the potential roles of Kir subunits in D. citri and enhances our understanding of the physiological effects of flonicamid in this pest.

HERGBoost: A gradient boosting model for quantitative IC50 prediction of hERG channel blockers

The human ether-a-go-go-related gene (hERG) potassium channel is pivotal in drug discovery due to its susceptibility to blockage by drug candidate molecules, which can cause severe cardiotoxic effects. Consequently, identifying and excluding potential hERG channel blockers at the earliest stages of drug development is crucial. Most traditional machine learning models predict a molecule's cardiotoxicity or non-cardiotoxicity typically at 10 μM, which doesn't account for compounds with low IC50 values that are non-toxic at therapeutic levels due to their high effectiveness at lower concentrations. To address the need for more precise, quantitative predictions, we developed hERGBoost, a cutting-edge machine learning model employing a gradient-boosting algorithm. This model demonstrates superior accuracy in predicting the IC50 of drug candidates. Trained on a specially curated dataset for this study, hERGBoost not only exhibited excellent performance in external validation, achieving an R2 score of 0.394 and a low root mean square error of 0.616 but also significantly outstripped previous models in both qualitative and quantitative assessments. Representing a notable leap forward in the prediction of hERG channel blockers, the hERGBoost model and its datasets are freely available to the drug discovery community on our web server at. http://ssbio.cau.ac.kr/software/hergboost This resource promises to be invaluable in advancing safer pharmaceutical development.

Potassium inwardly-rectifying channel subfamily J member 11 (KCNJ11) gene polymorphism in Egyptian type 2 diabetic patients: a single-center study.

The KCNJ11 gene belongs to the potassium channel gene family. It has a major role inthe secretion of insulin. Genetic variations in KCNJ11 are possibly responsible for the progression of type 2 diabetes mellitus (T2DM). In this study, we investigated the possible correlation between KCNJ11 (rs5210) gene polymorphism and T2DM. This study included 92 individuals divided into two groups. Group 1 included 46 type 2 diabetic patients. Group 2 (control group) included 46 healthy participants. A complete history was taken and a full physical examination was performed. Anthropometric data were measured. Laboratory investigations included fasting blood glucose (FBG), two hours post-prandial blood glucose (2HPPBG), glycated hemoglobin (HbA1c), and fasting lipid profile. KCNJ11 (rs5210) single nucleotide polymorphism was detected by polymerase chain reaction restriction-fragment length polymorphism (PCR-RFLP). Both AG and GG genotypes were associated with increased risk for T2DM (OR 5.2, 95% CI 1.32-20.5, P = 0.01 for AG; and OR 18.2, 95% CI 2.99-31.7, P = 0.002 for GG). Also, the frequency of the G allele was significantly higher in type 2 diabetic patients compared to healthy controls (50% versus 23.9%, respectively). The G allele of rs5210 in KCNJ11 contributed to an increased risk of T2DM (OR 3.18, 95% CI 1.31-7.75, P = 0.01). There was a statistically significant association between increased 2HPPBG and HbA1c levels and the carrier of AG and GG genotypes (P = 0.01 and 0.007, respectively). There was a statistically significant association between total cholesterol(TC), low-density lipoprotein-cholesterol (LDL-c), and high-density lipoprotein-cholesterol (HDL-c) levels and the carrier of AG and GG genotypes (P < 0.001, 0.02, and 0.007, respectively). Regression analysis detected that body mass index (BMI), 2HPPBG, TC, triglycerides (TG), and the G allele of rs5210 in KCNJ11 gene showed a significant association with T2DM (P = 0.004, 0.042, 0.003, 0.006, and 0.01, respectively) while no association was observed with FBG, HbA1c, LDL-c or HDL-c (P = 0.099, 0.123, 0.522, and 0.765, respectively). KCNJ11 rs5210 genetic polymorphism may raise the risk for the occurrence ofT2DM among Egyptians.

Chromosome-level genome of diamondback terrapin provides insight into the genetic basis of salinity adaptation.

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 22435 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.

Heterozygous expression of a Kcnt1 gain-of-function variant has differential effects on somatostatin- and parvalbumin-expressing cortical GABAergic neurons

More than 20 recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (KNa) channel gene KCNT1 in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of a Kcnt1 GOF variant (Kcnt1Y777H) on KNa currents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominant KCNT1 GOF variants in DEEs. Although the Kcnt1Y777H variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold KNa currents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Kcnt1Y777H variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Kcnt1Y777H variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.

Heterozygous expression of a Kcnt1 gain-of-function variant has differential effects on somatostatin- and parvalbumin-expressing cortical GABAergic neurons.

More than 20 recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (KNa) channel gene KCNT1 in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of a Kcnt1 GOF variant (Kcnt1Y777H) on KNa currents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominant KCNT1 GOF variants in DEEs. Although the Kcnt1Y777H variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold KNa currents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Kcnt1Y777H variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Kcnt1Y777H variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.

Knot data analysis using multiscale Gauss link integral

In the past decade, topological data analysis has emerged as a powerful algebraic topology approach in data science. Although knot theory and related subjects are a focus of study in mathematics, their success in practical applications is quite limited due to the lack of localization and quantization. We address these challenges by introducing knot data analysis (KDA), a paradigm that incorporates curve segmentation and multiscale analysis into the Gauss link integral. The resulting multiscale Gauss link integral (mGLI) recovers the global topological properties of knots and links at an appropriate scale and offers a multiscale geometric topology approach to capture the local structures and connectivities in data. By integration with machine learning or deep learning, the proposed mGLI significantly outperforms other state-of-the-art methods across various benchmark problems in 13 intricately complex biological datasets, including protein flexibility analysis, protein-ligand interactions, human Ether-à-go-go-Related Gene potassium channel blockade screening, and quantitative toxicity assessment. Our KDA opens a research area-knot deep learning-in data science.

Voltage-gated potassium channels and genetic epilepsy.

Recent advances in exome and targeted sequencing have significantly improved the aetiological diagnosis of epilepsy, revealing an increasing number of epilepsy-related pathogenic genes. As a result, the diagnosis and treatment of epilepsy have become more accessible and more traceable. Voltage-gated potassium channels (Kv) regulate electrical excitability in neuron systems. Mutate Kv channels have been implicated in epilepsy as demonstrated in case reports and researches using gene-knockout mouse models. Both gain and loss-of-function of Kv channels lead to epilepsy with similar phenotypes through different mechanisms, bringing new challenges to the diagnosis and treatment of epilepsy. Research on genetic epilepsy is progressing rapidly, with several drug candidates targeting mutated genes or channels emerging. This article provides a brief overview of the symptoms and pathogenesis of epilepsy associated with voltage-gated potassium ion channels dysfunction and highlights recent progress in treatments. Here, we reviewed case reports of gene mutations related to epilepsy in recent years and summarized the proportion of Kv genes. Our focus is on the progress in precise treatments for specific voltage-gated potassium channel genes linked to epilepsy, including KCNA1, KCNA2, KCNB1, KCNC1, KCND2, KCNQ2, KCNQ3, KCNH1, and KCNH5.

6966 A Rhythmic Life-Threatening Enigma Unveiled: KCNH2 Mutation-Associated Torsades de Points Unmasking Primary Hyperaldosteronism in Cardiological Realm

Abstract Disclosure: S. Dejprapasorn: None. N. Nopparatana: None. S. Soonthornpun: None. R. Leelawattana: None. N. Kietsiriroje: None. S. Limumpornpetch: None. T. Nilmoje: None. W. Lohawijarn: None. T. Wongsuttipakorn: None. P. Choochuen: None. P. Limumpornpetch: None. Introduction: Primary hyperaldosteronism (PA) is characterized by hypertension and hypokalemia. However, its ability to masquerade life-threatening Torsades de Pointes makes it an unusual and dismissed diagnosis, revealing the link between PA and serious arrythmia. Clinical Case A 30-year-old female experienced three episodes of palpitations, followed by syncope. Upon admission, her blood pressure was 147/87 mmHg. ECG showed prolonged QT intervals with potassium level was 2.6 mmol/L (3.5-5.0 mmol/L). Continuous cardiac monitoring captured Torsades de Pointes. Despite potassium replacement, long QT still persisted. Pathogenic variant, c.2592+1G&amp;gt;A, within KCNH2 was discovered. Aldosterone concentration showed 69.65 ng/dL (9.70-62.60 ng/dL) and plasma renin activity was 0.12 ng/mL/h (1.50-5.70 ng/mL/h). Aldosterone-to-renin ratio was 580. Aldosterone post 4-h saline infusion test was 31.71 ng/dL which were consistent with PA. Adrenal unenhanced CT scan identified bilateral adrenal nodules (right 1.3 cm, left 1.1 cm). After receiving a cardioverter-defibrillator and spironolactone, the patient has had no palpitations, and their potassium level has remained normal. Clinical lessons: PA rarely presents ventricular arrhythmia. KCNH2 mutation may link between long QT syndrome (LQTS) and PA arises. LQTS type 2 is attributable to KCNH2 mutations, impacting potassium channel subunits crucial for adjusting currents during sympathetic activation. This is essential for shortening the QT interval with increasing heart rate. KCNH2 mutations disrupt this process, prolonging the QT interval and heightening the risk of arrhythmias. Aldosterone synthesis relies on calcium signaling triggered by potassium currents. Adrenal cortex hosts approximately 90 potassium channels genes, including KCNJ5 and KCNH2. Mutations in gene can disrupt the calcium signaling cascade, leading to excessive aldosterone production. While KCNJ5 mutation is well-documented in PA, the potential correlation between KCNH2 mutations and a similar mechanism remains unexplored in clinical reports to date. This case highlights the importance of a thorough comprehension of genetic cause contributing to pathogenesis of PA with complex clinical presentations. Presentation: 6/1/2024

Identification and Characterization of Shaker Potassium Channel Gene Family and Response to Salt and Chilling Stress in Rice.

Shaker potassium channel proteins are a class of voltage-gated ion channels responsible for K+ uptake and translocation, playing a crucial role in plant growth and salt tolerance. In this study, bioinformatic analysis was performed to identify the members within the Shaker gene family. Moreover, the expression patterns of rice Shaker(OsShaker) K+ channel genes were analyzed in different tissues and salt treatment by RT-qPCR. The results revealed that there were eight OsShaker K+ channel genes distributed on chromosomes 1, 2, 5, 6 and 7 in rice, and their promoters contained a variety of cis-regulatory elements, including hormone-responsive, light-responsive, and stress-responsive elements, etc. Most of the OsShaker K+ channel genes were expressed in all tissues of rice, but at different levels in different tissues. In addition, the expression of OsShaker K+ channel genes differed in the timing, organization and intensity of response to salt and chilling stress. In conclusion, our findings provide a reference for the understanding of OsShaker K+ channel genes, as well as their potential functions in response to salt and chilling stress in rice.

Potassium dependent structural changes in the selectivity filter of HERG potassium channels

The fine tuning of biological electrical signaling is mediated by variations in the rates of opening and closing of gates that control ion flux through different ion channels. Human ether-a-go-go related gene (HERG) potassium channels have uniquely rapid inactivation kinetics which are critical to the role they play in regulating cardiac electrical activity. Here, we exploit the K+ sensitivity of HERG inactivation to determine structures of both a conductive and non-conductive selectivity filter structure of HERG. The conductive state has a canonical cylindrical shaped selectivity filter. The non-conductive state is characterized by flipping of the selectivity filter valine backbone carbonyls to point away from the central axis. The side chain of S620 on the pore helix plays a central role in this process, by coordinating distinct sets of interactions in the conductive, non-conductive, and transition states. Our model represents a distinct mechanism by which ion channels fine tune their activity and could explain the uniquely rapid inactivation kinetics of HERG.

Associations Between Preoperative Shortness of Breath and Potassium Channels Gene Variations in Women With Breast Cancer.

Shortness of breath is a common symptom in patients with cancer. However, the mechanisms that underlie this troublesome symptom are poorly understood. Therefore, this study aimed to determine the prevalence of and associated risk factors for shortness of breath in women prior to breast cancer surgery and identify associations between shortness of breath and polymorphisms for potassium channel genes. Patients were recruited prior to breast cancer surgery and completed a self-report questionnaire on the occurrence of shortness of breath. Genotyping of single nucleotides polymorphism (SNPs) in potassium channel genes was performed using a custom array. Multiple logistic regression analyses were done to identify associations between the occurrence of shortness of breath and SNPs in ten candidate genes. Of the 398 patients, 11.1% reported shortness of breath. These patients had a lower annual household income, a higher comorbidity burden, and a lower functional status. After controlling for functional status, comorbidity burden, genomic estimates of ancestry and self-reported race and ethnicity, the genetic associations that remained significant in the multiple regression analyses were for potassium voltage-gated channel subfamily D (KCND2) rs12673992, potassium voltage-gated channel modifier subfamily S (KCNS1) rs4499491, and potassium two pore channel subfamily K (KCNK2) rs4411107. While these findings warrant replication, they suggest that alterations in potassium channel function may contribute to the occurrence of shortness of breath in women prior to breast cancer surgery.

Heterozygous expression of a Kcnt1 gain-of-function variant has differential effects on SST- and PV-expressing cortical GABAergic neurons.

More than twenty recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (KNa) channel gene KCNT1 in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of a Kcnt1 GOF variant (Y777H) on KNa currents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominant KCNT1 GOF variants in DEEs. Although the Kcnt1-Y777H variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold KNa currents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Y777H variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Y777H variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.

Analysis of Molecular Mechanisms of Chronic Irradiation Effects on Electrical Signals in Wheat Plants

The effect of ionizing radiation (IR) on plants is mainly realized by altering the status of signaling systems and modifying stress signals. Variation potential (VP) is one of the types of electrical signals in plants. IR contributes to an increase in the amplitude of the VP, but the mechanisms of such influence are practically unknown. A possible way to implement changes arising from the action of IR is the regulation of gene expression. In the present work, the changes in the gene expression of participants in the generation and propagation of VP in irradiated plants are investigated. The experiments were performed on 14–15-day-old soft wheat plants (Triticum aestivum L.) grown under chronic irradiation (source 90Sr-90Y) with a dose rate of 31.3 μGy/h. The maximum accumulated dose was about 11.3 mGy. The irradiated plants showed no changes in the expression of calcium (TPC1), anionic (ALMT1 and CLC1), potassium (AKT1) channels, H+-ATPase (HA1), and NADPH oxidase (RBOHs) genes. A decrease in the expression of the SKOR potassium channel gene was revealed. The potassium channel blocker, tetraethylammonium chloride, caused an increase in response amplitude in control plants comparable to the increase in amplitude in the irradiated group. The obtained results indicate that one of the ways IR influences the electrical signals of plants is to inhibit the expression of the potassium channel.

Novel KCNQ2 missense variant expands the genotype spectrum of DEE7.

KCNQ is a voltage-gated K + channel that controls neuronal excitability and is mutated in epilepsy and autism spectrum disorder (ASD). We focus on the KV7.2 voltage-gated potassium channel gene (KCNQ2), which is known for its association with developmental delay and various seizures (including self-limited benign familial neonatal epilepsy and epileptic encephalopathy). But the pathogenicity of many variants remains unproven, potentially leading to misinterpretation of their functional consequences. In this study, we studied a patient who visited Nanhua Hospital. Targeted next-generation sequencing and Sanger sequencing were used to identify the pathogenic variants. Meanwhile, computational models, including hydrogen bonding and docking analyses, suggest that variants cause functional impairment. In addition, functional validation was performed in the drosophila to further evaluate the missense variant in the KCNQ2 gene as the cause of this patient. A new missense variant in the KCNQ2 gene was identified: NM_172107.4:c.1007C > A(p.ALa336Glu), which resulted in the change from alanine to glutamate at amino acid position 336 in the KCNQ2 gene. After computational modeling, including hydrogen bond analysis and docking analysis, it is indicated that the variants cause functional impairment. Furthermore, RNAi-mediated KCNQ knockout in flies led to the onset of epileptic behavior, lifespan and climbing capacity were affected, expression of the normal human KCNQ2 rescues the in flies RNAi-mediated KCNQ knockout behavioral abnormalities. Our findings expands the genetic profile of KCNQ2 and enhances the genotype - phenotype link.

The Role of KACh Channels in Atrial Fibrillation.

This manuscript explores the intricate role of acetylcholine-activated inward rectifier potassium (KACh) channels in the pathogenesis of atrial fibrillation (AF), a common cardiac arrhythmia. It delves into the molecular and cellular mechanisms that underpin AF, emphasizing the vital function of KACh channels in modulating the atrial action potential and facilitating arrhythmogenic conditions. This study underscores the dual nature of KACh activation and its genetic regulation, revealing that specific variations in potassium channel genes, such as Kir3.4 and K2P3.1, significantly influence the electrophysiological remodeling associated with AF. Furthermore, this manuscript identifies the crucial role of the KACh-mediated current, IKACh, in sustaining arrhythmia through facilitating shorter re-entry circuits and stabilizing the re-entrant circuits, particularly in response to vagal nerve stimulation. Experimental findings from animal models, which could not induce AF in the absence of muscarinic activation, highlight the dependency of AF induction on KACh channel activity. This is complemented by discussions on therapeutic interventions, where KACh channel blockers have shown promise in AF management. Additionally, this study discusses the broader implications of KACh channel behavior, including its ubiquitous presence across different cardiac regions and species, contributing to a comprehensive understanding of AF dynamics. The implications of these findings are profound, suggesting that targeting KACh channels might offer new therapeutic avenues for AF treatment, particularly in cases resistant to conventional approaches. By integrating genetic, cellular, and pharmacological perspectives, this manuscript offers a holistic view of the potential mechanisms and therapeutic targets in AF, making a significant contribution to the field of cardiac arrhythmia research.

Self-Reported Cancer-Related Cognitive Impairment in Patients With Breast Cancer Is Associated With Potassium Channel Gene Polymorphisms.

To evaluate for associations of polymorphisms for potassium channel genes in patients with breast cancer who were classified as having high or low-moderate levels of cancer-related cognitive impairment (CRCI). 397 women who were scheduled to undergo surgery for breast cancer on one breast were recruited from breast care centers located in a comprehensive cancer center, two public hospitals, and four community practices. CRCI was assessed using the Attentional Function Index prior to and for six months after surgery. The attentional function classes were identified using growth mixture modeling. Differences between patients in the high versus low-moderate attentional function classes were evaluated. Six single nucleotide polymorphisms for potassium channel genes were associated with low-moderate class membership. The results contribute to knowledge of the mechanisms for CRCI. These findings may lead to the identification of high-risk patients and the development of novel therapeutics.