Voltage-gated Potassium Channels Research Articles

Shaker/Kv1 potassium channel SHK-1 protects against pathogen infection and oxidative stress in C. elegans

The Shaker/Kv1 subfamily of voltage-gated potassium (K+) channels is essential for modulating membrane excitability. Their loss results in prolonged depolarization and excessive calcium influx. These channels have also been implicated in a variety of other cellular processes, but the underlying mechanisms remain poorly understood. Through comprehensive screening of K+ channel mutants in C. elegans, we discovered that shk-1 mutants are highly susceptible to bacterial pathogen infection and oxidative stress. This vulnerability is associated with reduced glycogen levels and substantial mitochondrial dysfunction, including decreased ATP production and dysregulated mitochondrial membrane potential under stress conditions. SHK-1 is predominantly expressed and functions in body wall muscle to maintain glycogen storage and mitochondrial homeostasis. RNA-sequencing data reveal that shk-1 mutants have decreased expression of a set of cation-transporting ATPases (CATP), which are crucial for maintaining electrochemical gradients. Intriguingly, overexpressing catp-3, but not other catp genes, restores the depolarization of mitochondrial membrane potential under stress and enhances stress tolerance in shk-1 mutants. This finding suggests that increased catp-3 levels may help restore electrochemical gradients disrupted by shk-1 deficiency, thereby rescuing the phenotypes observed in shk-1 mutants. Overall, our findings highlight a critical role for SHK-1 in maintaining stress tolerance by regulating glycogen storage, mitochondrial homeostasis, and gene expression. They also provide insights into how Shaker/Kv1 channels participate in a broad range of cellular processes.

Functions and clinical significance of KCNB1 in esophageal squamous cell carcinoma.

Voltage-gated potassium channel subfamily B member 1 (KCNB1) encodes the α-subunit of the Kv2.1 channel and mediates transmembrane potassium transport. The functions and mechanisms underlying KCNB1 activation have been examined in various cancer types; however, its role in esophageal squamous cell carcinoma (ESCC) remains unclear. Therefore, the present study investigated the involvement of KCNB1 in tumor progression and the clinicopathological significance of its expression in ESCC. Knockdown experiments using KCNB1 small interfering RNA were performed on the human ESCC cell lines, KYSE70 and TE5, and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. Gene expression profiles were examined using a microarray analysis. An immunohistochemical (IHC) analysis was performed on 129 primary tumor samples from ESCC patients who underwent curative esophagectomy. Cell proliferation, G2-M phase progression, migration, and invasion were inhibited, and apoptosis was induced in KCNB1-depleted cells. Microarray results showed that KCNB1 gene expression affected Ephrin receptor signaling by suppressing EPHB1, EPHB2, and ERK1/2 gene expression. IHC results revealed a relationship between high KCNB1 expression and a poor prognosis. High KCNB1 expression was extracted as an independent prognostic factor in a multivariate analysis of 5-year relapse-free survival in ESCC patients (p = 0.0197). Cell proliferation is controlled by KCNB1 through its regulation of ERK1/2 gene expression via ephrin receptor signaling. A relationship was observed between KCNB1 and the prognosis of ESCC patients, indicating its potential as a biomarker for cancer progression and in targeted therapy for ESCC.

The calcium channel blocker nimodipine inhibits spinal reflex pathways in humans.

Voltage-sensitive calcium channels contribute to depolarization of both motor neurons and interneurons in animal studies, but less is known of their contribution to human motor control and whether blocking them has potential in future antispasmodic treatment in humans. Therefore, this study investigated the acute effect of nimodipine on the transmission of human spinal reflex pathways involved in spasticity. In a double-blinded, crossover study, we measured soleus muscle stretch reflexes and H reflexes and tibialis anterior cutaneous reflexes in 19 healthy subjects before and after nimodipine (tablet 60 mg) or baclofen (tablet 25 mg). Baclofen was used as a control to compare nimodipine's effects with known antispastic treatment. Changes in the size of the maximum H reflex (Hmax)/maximum direct motor response in muscle (Mmax) ratio and stretch and cutaneous reflexes following intervention with nimodipine and baclofen, respectively, were analyzed with a one-way repeated-measures (RM) ANOVA. Nimodipine significantly reduced the Hmax/Mmax ratio [F(2.5,42) = 15; P < 0.0001] and the normalized soleus stretch reflex [F(2.6,47) = 4.8; P = 0.0073] after administration. A similar tendency was seen after baclofen [Hmax/Mmax ratio: F(2.1,39) = 4.0, P = 0.024; normalized stretch reflex: F(2.8,50) = 2.4; P = 0.083]. The Mmax response was unaffected by either intervention. Interestingly, during voluntary soleus activation, the stretch reflex remained unchanged with either treatment. For the cutaneous reflexes, there was a trend toward reduced early inhibition [F(1.6,9.3) = 4.5; P = 0.050] and subsequent facilitation [F(1.3,8.0) = 4.3; P = 0.065] after nimodipine. No severe adverse effects were reported after nimodipine. These findings suggest that nimodipine acutely reduced electrophysiological measures related to spasticity in healthy individuals. The effect seemed located at the spinal level, and voluntary contraction counterbalanced the reduction of the stretch reflex, highlighting its relevance for future studies on antispastic therapies.NEW & NOTEWORTHY The calcium channel antagonist nimodipine significantly reduces the size of the soleus H reflex and stretch reflex in healthy individuals without affecting maximum direct motor response (Mmax) or the stretch reflex during voluntary activation. This underscores the importance of exploring nimodipine as a potential antispastic medication in the future.

P-913. Etiologies, Clinical Characteristics and Prognostic impact of Increased Intracranial Pressure in Adults with Encephalitis

Abstract Background Encephalitis involves symptoms like reduced consciousness and seizures, diagnosed via lumbar puncture and brain imaging. Increased intracranial pressure (ICP) and its effect is well described in meningitis/ventriculitis and serve as poor prognostic factors. Data on ICP in encephalitis is limited, highlighting the need for further research.Table 1.Demographic, Clinical Characteristics, and Initial Presentations of 647 Adults with Encephalitis by Opening Pressure Measurement Status and DegreeAbbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; GCS, Glasgow Coma Scale; MAP, Mean Arterial Pressure; qSOFA, Quick Sequential Organ Failure Assessment. Methods Retrospective study at University of Texas and Johns Hopkins, 2002-2023, on 647 patients over 17 years old with encephalitis. Data analyzed via SPSS software.Table 2.Laboratory Findings, Etiology, and Imaging Results in Encephalitis Patients by Opening Pressure Measurement Status and DegreeAbbreviations: CSF, cerebral spinal fluid; CT, computed tomography; EEG, electroencephalogram; HSV, herpes simplex virus; MRI, magnetic resonance imaging; PMN, polymorphonuclear leukocyte; RBC, red blood cell; VZV, varicella zoster virus; WBC, white blood cell. Results Our study had 647 patients, with ICP measured in 298 (46%). Patients were categorized by ICP levels: &amp;lt; 30mmHg (242) and ≥30mmHg (56). Demographics such as gender, race, and age showed no variance across ICP. Comorbidity profiles were similar, though immunocompromised patients more frequently had ICP measurement (p=0.010). Symptoms like photophobia were uniformly distributed, but seizures and fever were more common in those measured for ICP (p=0.007 &amp; p=0.013). Nuchal rigidity was higher in those with ICP ≥30mmHg (31% vs. 15%, p=0.031). Blood and cerebrospinal fluid analyses did not differ across groups. The leading etiologies identified were viral (32.9%) and autoimmune (18.1%), with no cause specifically linked to elevated ICP. Neuroimaging was more likely to be abnormal in patients with ICP measured (65% vs. 53%, p=0.004). Those with abnormal EEGs were more likely to have ICP measured (82% vs. 74%, p=0.050), but abnormal EEGs were less common in patients with ICP &amp;gt;30mmHg (p=0.008). No differences were found in given treatments like vancomycin, acyclovir, or steroids between ICP groups. ICU admission, vasopressor support, and ventilation needs were comparable, though patients with higher ICP had longer median hospital stays (12 days vs. 10 days, p=0.012) and mechanical ventilation (1.5 days vs. 0 days, p=0.005). Mortality and readmission rates showed no differences, but patients with higher ICP had worse Glasgow Outcome Scale (GOS) scores (61% vs. 46%, p=0.045).Table 3.Management Approaches and Outcomes in Encephalitis Patients Categorized by Opening Pressure LevelsAbbreviations: ICU, intensive care unit; GOS, Glasgow outcome scale. Conclusion This retrospective study on ICP in encephalitis across two centers emphasizes presentation variability and the need for standardized diagnostic and management protocols. Noted differences include ventilation duration, hospital stays, and GOS in patients with higher ICP.Figure 1.Breakdown of 647 cases of encephalitis, categorized by their determined etiologies and ICP measurements. The chart illustrates the distribution across three groups: OP not measured, OP &amp;lt;30mmHg, and OP ≥30mmHg, detailing the total number of cases alongside the percentages for each etiological category, including viral, bacterial, autoimmune, and unknown origins.CMV; Cytomegalovirus, EBV; Epstein-Barr Virus, HSV; Herpes Simplex Virus, JCV; JC Virus, MTB; Mycobacterium tuberculosis NMDA; N-Methyl-D-Aspartate, T. pallidum; Treponema pallidum, VGKC; Voltage-Gated Potassium Channel, WNV; West Nile Virus. Disclosures John Probasco, MD, Genentech: Study site investigator for multicenter study Rodrigo Hasbun, MD MPH FIDSA, Biomeriaux: Grant/Research Support|Biomeriaux: Honoraria

Biophysical modeling and experimental analysis of the dynamics of C. elegans body-wall muscle cells.

This study combines experimental techniques and mathematical modeling to investigate the dynamics of C. elegans body-wall muscle cells. Specifically, by conducting voltage clamp and mutant experiments, we identify key ion channels, particularly the L-type voltage-gated calcium channel (EGL-19) and potassium channels (SHK-1, SLO-2), which are crucial for generating action potentials. We develop Hodgkin-Huxley-based models for these channels and integrate them to capture the cells' electrical activity. To ensure the model accurately reflects cellular responses under depolarizing currents, we develop a parallel simulation-based inference method for determining the model's free parameters. This method performs rapid parallel sampling across high-dimensional parameter spaces, fitting the model to the responses of muscle cells to specific stimuli and yielding accurate parameter estimates. We validate our model by comparing its predictions against cellular responses to various current stimuli in experiments and show that our approach effectively determines suitable parameters for accurately modeling the dynamics in mutant cases. Additionally, we discover an optimal response frequency in body-wall muscle cells, which corresponds to a burst firing mode rather than regular firing mode. Our work provides the first experimentally constrained and biophysically detailed muscle cell model of C. elegans, and our analytical framework combined with robust and efficient parametric estimation method can be extended to model construction in other species.

Targeting Kv7 Potassium Channels for Epilepsy.

Voltage-gated Kv7 potassium channels, particularly Kv7.2 and Kv.7.3 channels, play a critical role in modulating susceptibility to seizures, and mutations in genes that encode these channels cause heterogeneous epilepsy phenotypes. On the basis of this evidence, activation of Kv7.2 and Kv.7.3 channels has long been considered an attractive target in the search for novel antiseizure medications. Ezogabine (retigabine), the first Kv7.2/3 activator introduced in 2011 for the treatment of focal seizures, was withdrawn from the market in 2017 due to declining use after discovery of its association with pigmentation changes in the retina, skin, and mucosae. A novel formulation of ezogabine for pediatric use (XEN496) has been recently investigated in children with KCNQ2-related developmental and epileptic encephalopathy, but the trial was terminated prematurely for reasons unrelated to safety. Among novel Kv7.2/3 openers in clinical development, azetukalner has shown dose-dependent efficacy against drug-resistant focal seizures with a good tolerability profile and no evidence of pigmentation-related adverse effects in early clinical studies, and it is now under investigation in phase III trials for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder. Another Kv7.2/3 activator, BHV-7000, has completed phase I studies in healthy subjects, with excellent tolerability at plasma drug concentrations that exceed the median effective concentrations in a preclinical model of anticonvulsant activity, but no efficacy data in patients with epilepsy are available to date. Among other Kv7.2/3 activators in clinical development as potential antiseizure medications, pynegabine and CB-003 have completed phase I safety and pharmacokinetic studies, but results have not been yet reported. Overall, interest in targeting Kv7 channels for the treatment of epilepsy and for other indications remains strong. Future breakthroughs in this area could come from exploitation of mechanistic differences in the action of Kv7 activators, and from the development of molecules that combine Kv7 activation with other mechanisms of action.

Activation of the voltage-Gated Potassium channels by Amphiphilic Glycopeptides.

Voltage-gated ion channels (VGICs) are allosterically modulated by glycosaminoglycan proteoglycans and sialic acid glycans. However, the structural diversity and heterogeneity of these biomolecules pose significant challenges to precisely delineate their underlying structure-activity relationships. Herein, we demonstrate how heparan sulfate (HS) and sialic acid synthetic glycans appended on amphiphilic glycopeptide backbone influence cell membrane persistence and modulate the gating of the Kv2.1 channel. Utilizing a panel of amphiphilic glycopeptides comprising HS disaccharides and sialic acid trisaccharide glycans, we observed that sulfation of HS and flexible α(2-6) sialylation result in prolonged persistence of glycopeptides on the cell membrane compared to non-sulfated HS and α(2-3) sialylation respective. This variation in glycocalyx composition was associated with a noticeable difference in the effects of these compounds on the activation and inactivation properties of the voltage-gated Kv2.1 channel with our strongest membrane associating compound demonstrating the most potent channel-activation propensity. Our findings demonstrate that sulfation charges on glycopeptide play a critical role in their membrane association propensities and endow them with VGIC activation properties. and provide a valuable insight into the role of cell surface glycans in VGIC activities.

Integrating Forensic Autopsies with Proteomic Profiling for Suicide Risk Assessment: A Comprehensive Review of Literature.

Suicide is a major global public health concern that affects people of all ages, with over 700000 individuals intentionally ending their lives every year. Suicide is a multifactorial event related to multiple risk factors interlocking with each other, among which neurobiological factors are considered to be an objective measure of the incidence of this phenomenon and can be used as a measurable tool for evaluating suicidal tendencies. The aim of this study is to thoroughly examine available data and assess candidate proteins as prospective biomarkers for predicting suicides and ascertaining the manner of death in forensic cases. An electronic search was conducted on PubMed, Science Direct Scopus, and the Excerpta Medica Database. The systematic review adhered to PRISMA guidelines and encompassed case series, prospective and retrospective studies, and short communications published in English. The focus was on proteomics and suicide, specifically, those studies where researchers conducted human proteomic analyses on specimens obtained from individuals who completed or attempted suicide. A total of 14 studies met the inclusion criteria, resulting in a dataset of numerous candidate protein biomarkers. These include tenascin-C, potassium voltage-gated channel subfamily Q member 3, vimentin-immunoreactive astrocytes, glutathione S-transferase theta 1, iron transport proteins, Acrystallin chain B, manganese superoxide dismutase, glial fibrillary acidic protein, various glycolytic pathway proteins, 14-3-3 eta and 14-3-3 theta proteins, specific cytoskeleton proteins, C-reactive protein, serum amyloid A protein 1, extrinsic coagulation pathway proteins, the vacuolar-type proton pump ATPase subunit, plasma apolipoprotein A-IV, and ER stress proteins. These proteins are proposed as a panel of biomarkers to be evaluated in conjunction with other clinical predictors of suicide. This review aims to provide a comprehensive summary of all proteomic studies conducted on cases of attempted or completed suicide. By doing so, it seeks to bridge existing gaps in knowledge and pave the way for future investigations. The ultimate goal is to potentially identify a suicide biomarker.

A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance.

Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective therapies. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes invivo and applied this to sonic hedgehog (SHH) medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we identified the voltage-gated potassium channel KCNB2 as a candidate maintenance driver. KCNB2 governs cell volume of MB-propagating cells (MPCs), with KCNB2 depletion causing osmotic swelling, decreased plasma membrane tension, and elevated endocytic internalization of epidermal growth factor receptor (EGFR), thereby mitigating proliferation of MPCs to ultimately impair MB growth. KCNB2 is largely dispensable for mouse development and KCNB2 knockout synergizes with anti-SHH therapy in treating MB. These results demonstrate the utility of the Lazy Piggy functional genomic approach in identifying cancer maintenance drivers and elucidate a mechanism by which potassium homeostasis integrates biomechanical and biochemical signaling to promote MB aggression.

Molecular Dynamics Study of Protein-Mediated Electroporation of Kv Channels Induced by nsPEFs: Advantages of Bipolar Pulses.

Nanosecond pulsed electric fields (nsPEFs) can induce protein-mediated electroporation (PMEP) in voltage-gated ion channels. However, their effects on the tetrameric structure of voltage-gated potassium (Kv) channels remain unexplored. Our study pioneered the molecular dynamics (MD) investigation of the open-state (O) Kv channel to understand the effects of PMEP under unipolar and bipolar pulses (UP and BP). Our findings revealed that BP induces pore formation more effectively than UP. Additionally, the frequency of pore formation shows a more consistent decline with increased pulse interval under BP. We further examined three other distinct functional states─intermediate (C*), inactivated (I), and resting closed (C)─of Kv channels under BP. SF pores formed exclusively in the O state, while complex pores formed only in the O and C states. In conclusion, our study highlights BP's role in enhancing pore formation and specificity, offering insights into Kv channel PMEP and its therapeutic potential.

Noninvasive Imaging of Immune Cell Activity in Myocardial Infarction Phases Using 99mTc-HYNIC-mAbKv1.3 SPECT/CT.

Acute myocardial infarction (MI) remains a leading cause of mortality worldwide, with inflammatory and reparative phases playing critical roles in disease progression. Currently, there is a pressing need for in vivo imaging techniques to monitor immune cell infiltration and inflammation activity during these phases. We developed a novel probe, 99mTc-HYNIC-mAbKv1.3, utilizing a monoclonal antibody that targets the voltage-gated potassium channel 1.3 (Kv1.3). This probe enables in vivo visualization of immune cells that express high levels of Kv1.3 proteins. In a murine MI model, SPECT/CT imaging with 99mTc-HYNIC-mAbKv1.3 demonstrated specific uptake in an infarcted myocardium during the inflammatory phase, reflecting immune cell infiltration and activity. During the reparative phase, the probe exhibited prolonged retention in the infarcted area, suggestive of ongoing immune cell proliferation. Immunofluorescence staining confirmed the probe's specificity. Biodistribution analysis indicated preferential accumulation in the infarcted myocardium and liver, consistent with SPECT/CT findings. Combined with [18F]FDG PET/CT, these modalities provided comprehensive insights into myocardial viability and inflammation. This study highlights the potential of 99mTc-HYNIC-mAbKv1.3 SPECT/CT as a noninvasive tool to monitor immune cell activity in different phases of MI, guide therapeutic interventions, and predict disease progression. Further translational studies are warranted to explore its clinical applicability in cardiac pathologies.

De novo KCNB1 missense variant causing developmental and epileptic encephalopathy: Two case reports.

Developmental and epileptic encephalopathy (DEE) defines a group of severe and heterogeneous neurodevelopmental disorders. The voltage-gated potassium channel subfamily 2 voltage-gated potassium channel α subunit encoded by the KCNB1 gene is essential for neuronal excitability. Previous studies have shown that KCNB1 variants can cause DEE. Herein, we report the cases of 2 children with DEE caused by pathogenic variants in the KCNB1 gene. Trio whole-exome sequencing identified novel KCNB1 genotypes, c. 1160C > A and c.1012C > T, which had not been reported previously, in 2 unrelated patients. Two children were admitted to our hospital for a detailed evaluation of frequent seizures. And both of these children have abnormal electroencephalogram and brain magnetic resonance imaging results, accompanied by developmental delay. A genetic study using trio-whole-exome sequencing confirmed the diagnosis of KCNB1-related developmental and epileptic encephalopathy. Both patients accepted the treatment of antiepileptic drugs. 1 patient had seizure remission with a combination of sodium valproate and lamotrigine, and the other was lost to follow-up. Trio-whole-exome sequencing technology was used to determine the etiology of the 2 children with DEE. This study confirmed that genetic testing provides a basis for the diagnosis of children with abnormal electroencephalogram and brain magnetic resonance imaging findings and developmental delay, and provides data supporting a future phenotype-genotype correlation study.

Competition of two time scales determines the performance of a voltage-gated potassium channel

Competition of two time scales determines the performance of a voltage-gated potassium channel

Functional large-conductance calcium and voltage-gated potassium channels in extracellular vesicles act as gatekeepers of structural and functional integrity

Extracellular vesicles (EVs) are associated with intercellular communications, immune responses, viral pathogenicity, cardiovascular diseases, neurological disorders, and cancer progression. EVs deliver proteins, metabolites, and nucleic acids into recipient cells to effectively alter their physiological and biological response. During their transportation from the donor to the recipient cell EVs face differential ionic concentrations, which can be detrimental to their integrity and impact their cargo content. EVs are known to possess ion channels and transporters in their membrane but neither the function nor the role of these channels in EVs is known. In this study, we discover a functional calcium-activated large-conductance potassium channel (BKCa) in the membrane of EVs. Furthermore, we establish that BKCa is essential for the structural and functional integrity of EVs. Together, these findings establish the critical role of ion channels such as BKCa in functioning as gatekeepers and maintaining EV-mediated signaling.

Cracking the code: the clinical and molecular impact of aminopyridines; a review (2019-2024).

Aminopyridines belong to a class of compounds that are monoamino and diamino derivatives of pyridine. They work primarily by blocking voltage-gated potassium channels in a dose-dependent manner. Essential heterocycles used extensively in synthetic, natural products, and medicinal chemistry are aminopyridine and its derivatives. A vast array of biological and pharmacological effects can result from the interaction of aminopyridine rings with different enzymes and receptors, due to their unique structural properties. Aminopyridine research is continually growing, and there are now greater expectations for how it may aid in the treatment of numerous disorders. This review article will serve as an innovative platform for researchers investigating aminopyridine compounds, intending thoroughly to examine both traditional and novel synthesis strategies in addition to investigating the various biological characteristics displayed by these adaptable heterocycles. We attempt to provide valuable insights that will contribute to further progress in the synthesis and utilization of aminopyridines in various fields.

The Voltage-Gated Potassium Channel Shal (Kv4) Contributes to Active Hearing in Drosophila.

The full complement of ion channels which influence insect auditory mechanotransduction and the mechanisms by which their influence is exerted remain unclear. Shal (Kv4), a Shaker family member encoding voltage-gated potassium channels in Drosophila melanogaster, has been shown to localize to dendrites in some neuron types, suggesting the potential role of Shal in Drosophila hearing, including mechanotransduction. A GFP trap was used to visualize the localization of the Shal channel in Johnston's organ neurons responsible for hearing in the antenna. Shal protein was localized strongly to the cell body and inner dendritic segment of sensory neurons. It was also detectable in the sensory cilium, suggesting its involvement not only in general auditory function but specifically in mechanotransduction. Electrophysiological recordings to assess neural responses to auditory stimuli in mutant Shal flies revealed significant decreases in auditory responses. Laser Doppler vibrometer recordings indicated abnormal antennal free fluctuation frequencies in mutant lines, indicating an effect on active antennal tuning, and thus active transduction mechanisms. This suggests that Shal participates in coordinating energy-dependent antennal movements in Drosophila that are essential for tuning the antenna to courtship song frequencies.

Inhibition of Kv1.1 channels ameliorates Cu(II)-induced microglial activation and cognitive impairment in mice.

Microglia-mediated neuroinflammation plays a critical role in neuronal damage in neurodegenerative disorders such as Alzheimer's disease. Evidence shows that voltage-gated potassium (Kv) channels regulate microglial activation. We previously reported that copper dyshomeostasis causes neuronal injury via activating microglia. This study was designed to explore the role of Kv1.1 channels in copper-evoked microglial neuroinflammation. BV-2 microglial cells were treated with Cu(II). DiBAC4(3) was used to measure membrane potential. Microglial activation and neuronal loss were detected by enzyme-linked immunosorbent assay, Western blotting, and immunostaining. Learning and memory function was assessed with Morris water maze task. Cu(II) caused a hyperpolarized membrane potential in microglial cells, an effect abolished by functional Kv1.1 blockade. Blockade of Kv1.1 and knock-down of Kv1.1 with small interfering RNA repressed Cu(II)-induced microglial production of pro-inflammatory mediators. Also, Kv1.1 inhibition attenuated activation of PI3K/Akt-ERK1/2 signaling pathway and production of mitochondrial reactive oxidative species as well as nuclear factor-κB activation in Cu(II)-stimulated microglia. Moreover, the Cu(II)-caused, microglia-mediated neurotoxicity (indicated by reduced neuronal survival and increased dendritic loss) was attenuated by Kv1.1 knock-down. In an in vivo mouse model, hippocampal injection of Cu(II) caused elevated Kv1.1 mRNA (but not other Kv1 channels) expression and enhanced microglial Kv1.1 immunoreactivity in the hippocampus. Furthermore, blockade of Kv1.1 attenuated Cu(II)-induced microglial activation and neuronal dendritic loss in the hippocampus and learning and memory dysfunction. These findings suggest that inhibition of Kv1.1 ameliorates Cu(II)-induced microglial activation and cognitive impairment. Thus, it might represent a potential molecular target for anti-inflammatory therapy of neurodegenerative disorders.

Amiodarone Advances the Apoptosis of Cardiomyocytes by Repressing Sigmar1 Expression and Blocking KCNH2-related Potassium Channels.

Heart failure (HF) is the ultimate transformation result of various cardiovascular diseases. Mitochondria-mediated cardiomyocyte apoptosis has been uncovered to be associated with this disorder. This study mainly delves into the mechanism of the anti-arrhythmic drug amiodarone on mitochondrial toxicity of cardiomyocytes. The viability of H9c2 cells treated with amiodarone at 0.5, 1, 2, 3, and 4 μM was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and Sigmar1 expression was examined by quantitative real-time PCR (qRTPCR). After transfection, the viability, apoptosis, reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), and potassium voltage-gated channel subfamily H member 2 (KCNH2) expression in H9c2 cells were assessed by MTT, flow cytometry, ROS assay kit, mitochondria staining kit, and Western blot. Amiodarone at 1-4 μM notably weakened H9c2 cell viability with IC50 value of 2.62 ± 0.43 μM. Amiodarone at 0.5-4 μM also evidently suppressed the Sigmar1 level in H9c2 cells. Amiodarone repressed H9c2 cell viability and KCNH2 level and triggered apoptosis, ROS production and mitochondrial depolarization, while Sigmar1 upregulation reversed its effects. Moreover, KCNH2 silencing neutralized the combined modulation of amiodarone and Sigmar1 up-regulation on H9c2 cell viability, apoptosis, and ROS production. Amiodarone facilitates the apoptosis of H9c2 cells by restraining Sigmar1 expression and blocking KCNH2-related potassium channels.

Longitudinally persisting KCNA2-autoantibodies in mild amnestic dementia with Alzheimer´s pathology - Report and literature review.

Neural autoantibodies are being increasingly detected in conjunction with neurodegenerative dementias such as Alzheimer's disease dementia (AD), yet their significance is not well clarified. In this case report, we report the previously unreported long-lasting persistence of potassium voltage-gated channel subfamily A member 2 (KCNA2) antibodies in biomarker-supported AD. We report on a 77-year-old, male patient evaluated in our outpatient memory clinic of the Department of Psychiatry and Psychotherapy, University Medical Center Göttingen. Neuropsychological test results and autoantibody testing in serum over a period of 4-5 years is provided. Our patient exhibited mild dementia syndrome and was diagnosed with AD on the basis of a prototypical biomarker profile (reduced Aβ42/40 ratio and elevated p-tau181 protein in cerebrospinal fluid). Within a 5-year follow-up with regular visits to our memory clinic, we observed a nearly stable neuropsychological profile of mild, amnestic variant dementia that did not noticeably progress. KCNA2 autoantibodies were also detectable in serum over 4 years with increasing titers over time. Combined anti-dementia therapy with donepezil, multimodal therapy including non-pharmacological cognitive therapy, and immunotherapy with intravenous methylprednisolone was carried out as an individual treatment approach. KCNA2 autoantibody persistence in biomarker-supported AD does not necessarily trigger a poor outcome in the long-term, as cognitive impairment did not progress subsequently. At the same time, mild immunotherapy did not result in less immunoreactivity in conjunction with the detection of KCNA2 autoantibodies. This detection of KCNA2 autoantibodies in AD could provide indices of a potentially benign long-term AD course that should be further evaluated in studies.

Immunomodulatory effect of selective COX-2 inhibitor celecoxib on the neuropathological disorders and immunoinflammatory response induced by Kaliotoxin from Androctonus australis venom.

The immune response is increasingly being linked to the pathogenic processes underlying neurological disorders including potassium channel malfunction. Few investigations, meanwhile, have shown how cyclooxygenase-2 (COX-2) is involved in the neuroimmunopathology linked to potassium channel failure. Thus, using an animal model of neuropathology caused by kaliotoxin, an exclusive blocker of voltage-gated potassium channels from the scorpion venom of Androctonus australis hector, we examined the immunomodulatory impact of celecoxib (selective inhibitor of COX-2). The neural and systemic pathogenic effects of KTX can be considerably reduced by celecoxib-mediated COX-2 inhibition, according to the results. It most certainly works via controlling the immunoinflammatory exposure by raising IL-10 levels; decreasing proinflammatory cytokine levels including mostly TNFα and IL-6, and balancing oxidative status. Along with that, by significantly promoting tissue healing, COX-2 inhibitor also enhances cellular metabolism. One potential treatment approach for immunoinflammatory exacerbations linked to neurodegenerative is the COX-2 inhibitor.