Potassium channels activity unveils cancer vulnerability.

"No cell could exist without ion channels" (Clay Armstrong; 1999). Since the discovery in the early 1950s, that ions move across biological membranes, the idea that changes of ionic gradients can generate biological signals has fascinated scientists in any fields. Soon later (1960s) it was found that ionic flows were controlled by a class of specific and selective proteins called ion channels. Thus, it became clear that the concerted activities of these proteins can initiate, arrest, and finely tune a variety of biochemical cascades which offered the opportunity to better understand both biology and pathology. Cancer is a disease that is notoriously difficult to treat due its heterogeneous nature which makes it the deadliest disease in the developed world. Recently, emerging evidence has established that potassium channels are critical modulators of several hallmarks of cancer including tumor growth, metastasis, and metabolism. Nevertheless, the role of potassium ion channels in cancer biology and the therapeutic potential offered by targeting these proteins has not been explored thoroughly. This chapter is addressed to both cancer biologists and ion channels scientists and it aims to shine a light on the established and potential roles of potassium ion channels in cancer biology and on the therapeutic benefit of targeting potassium channels with activator molecules.

Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial.

Importance: Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics. Objective: To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs). Design, Setting, and Participants: This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe. Interventions: Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose). Main Outcomes and Measures: The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted. Results: A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P < .001 vs placebo; IQR, -80.4% to -16.9%) for 25 mg, 46.4% (P < .001 vs placebo; IQR, -76.7% to -14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, -61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, -37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported. Conclusions and Relevance: The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs. Trial Registration: ClinicalTrials.gov Identifier: NCT03796962.

Potassium Channels in Parkinson's Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the midbrain. The loss of neurons results in a subsequent reduction of dopamine in the striatum, which underlies the core motor symptoms of PD. To date, there are no effective treatments to stop, slow, or reverse the pathologic progression of dopaminergic neurodegeneration. This unfortunate predicament is because of the current early stages in understanding the biologic targets and pathways involved in PD pathogenesis. Ion channels have become emerging targets for new therapeutic development for PD due to their essential roles in neuronal function and neuroinflammation. Potassium channels are the most prominent ion channel family and have been shown to be critically important in PD pathology because of their roles in modulating neuronal excitability, neurotransmitter release, synaptic transmission, and neuroinflammation. In this review, members of the subfamilies of voltage-gated K+ channels, inward rectifying K+ channels, and Ca2+-activated K+ channels are described. Evidence of the role of these channels in PD etiology is discussed together with the latest views on related pathologic mechanisms and their potential as biologic targets for developing neuroprotective drugs for PD. SIGNIFICANCE STATEMENT: Parkinson's disease (PD) is the second most common neurodegenerative disorder, featuring progressive degeneration of dopaminergic neurons in the midbrain. It is a multifactorial disease involving multiple risk factors and complex pathobiological mechanisms. Mounting evidence suggests that ion channels play vital roles in the pathogenesis and progression of PD by regulating neuronal excitability and immune cell function. Therefore, they have become "hot" biological targets for PD, as demonstrated by multiple clinical trials of drug candidates targeting ion channels for PD therapy.

Prenatal alcohol exposure enhanced alcohol preference and susceptibility to PTSD in a sex-dependent manner through the synaptic HCN1 channel.

BACKGROUND: Prenatal alcohol exposure (PAE) adversely affects the neurobiological and behavioral functions of offspring. Increasing evidence indicates that alcohol-use disorders and post-traumatic stress disorder (PTSD) commonly co-occur. Enhanced function of hyperpolarization-activated gated channel 1 (HCN1) may be involved in the pathogenesis of PTSD. This study aimed to explore the effect of PAE on fear extinction, spontaneous recovery, alcohol preference, and function of HCN1 channels in offspring of both sexes. METHODS: The PAE model was established with a 20 % (m/V) ethanol solution, and offspring were treated with 0.5, 1, and 2 µg/mL ZD7288 to block the HCN1 channel. Behavioral tests were used to detect the mental state and fear of extinction of the mice. Western blot was used to detect HCN1 expression in the synaptosomes. The BDNF/TrkB-pmTOR pathway was also examined. RESULTS: ZD7288 administration ameliorated PAE-induced impairment of fear extinction and depression-like behavior. ZD7288 administration also alleviated PAE-induced inhibition of the HCN1 channel in the prefrontal cortex (PFC) and the BDNF/TrkB-pmTOR pathway in the hippocampus of offspring. In addition, the therapeutic effect of ZD7288 in males was better than that in females. CONCLUSIONS: Overall, these results suggest that PAE enhances alcohol preference and susceptibility to PTSD through synaptic HCN1 channels in the PFC. In addition, ZD7288 may be a promising candidate for preventing alcohol-associated PTSD-like syndrome, particularly in males. LIMITATIONS: The effects of ZD7288 were only studied in PAE animals and not in healthy animals.

New use for an old drug: quinidine in KCNT1-related epilepsy therapy.

KCNT1 has been known to encode a subunit of the tetrameric sodium activated potassium channel (KNa1.1). Pathogenic variants of KCNT1, especially gain-of-function (GOF) variants, are associated with multiple epileptic disorders which are often refractory to conventional anti-seizure medications and summarized as KCNT1-related epilepsy. Although the detailed pathogenic mechanisms of KCNT1-related epilepsy remain unknown, increasing studies attempt to find effective medications for those patients by utilizing quinidine to inhibit hyperexcitable KNa1.1. However, it has been shown that controversial outcomes among studies and partial success in some individuals may be due to multiple factors, such as poor blood-brain barrier (BBB) penetration, mutation-dependent manner, phenotype-genotype associations, and rational therapeutic schedule. In recent years, with higher resolution of KNa1.1 structure in different activation states and advanced synthetic techniques, it improves the process performance of therapy targeting at KNa1.1 channel to achieve more effective outcomes. Here, we systematically reviewed the study history of quinidine on KCNT1-related epilepsy and its corresponding therapeutic effects. Then, we analyzed and summarized the possible causes behind the different outcomes of the application of quinidine. Finally, we outlooked the recent advances in precision medicine treatment for KCNT1-related epilepsy.

Efficacy of antiseizure medication in a mouse model of HCN1 developmental and epileptic encephalopathy.

Acquisition of drug-sensitivity profiles is challenging in rare epilepsies. Anecdotal evidence suggests that antiseizure medications that block sodium channels as their primary mechanism of action exacerbate seizures in HCN1 developmental and epileptic encephalopathies (DEEs), whereas sodium valproate is effective for some patients. The Hcn1 M294L heterozygous knock-in (Hcn1M294L ) mouse carries the homologue of the recurrent gain-of-function HCN1 M305L pathogenic variant and recapitulates the seizure and some behavioral phenotypes observed in patients. We used this mouse model to study drug efficacy in HCN1 DEE. Hcn1M294L mice display epileptiform spiking on electrocorticography (ECoG), which we used as a quantifiable measure of drug effect. Phenytoin, lamotrigine, and retigabine significantly increased ECoG spike frequency, with lamotrigine and retigabine triggering seizures in a subset of the mice tested. In addition, there was a strong trend for carbamazepine to increase spiking. In contrast, levetiracetam, diazepam, sodium valproate, and ethosuximide all significantly reduced ECoG spike frequency. Drugs that reduced spiking did not cause any consistent ECoG spectral changes, whereas drugs that increased spiking all increased power in the slower delta and/or theta bands. These data provide a framework on which to build our understanding of gain-of-function HCN1 DEE pharmacosensitivity in the clinical setting.

Identification of the Involvement of Potassium Channels in Fibromyalgia.

Fibromyalgia is a central sensitivity syndrome that presents with chronic pain, fatigue, cognitive dysfunction, and disordered sleep. The pathophysiology which due to multisensory hypersensitivity of the central nervous system involves neuronal excitability leading to central sensitization. Treatments of the challenges associated with the complexities of fibromyalgia involve combinations of pharmacological and non-pharmacological therapeutic approaches which often offer limited benefit. Potassium (K+) channels play a fundamental role in establishing and maintaining stability of neuronal activity. The large molecular diversity and distribution of K+ channels support involvement in a broad range of physiological functions. In nociceptive pathways, neuronal hyperexcitability leading to pain sensation has been associated with reduced function of K+ channels and loss of cellular control. This article reviews the evidence of involvement of K+ channels in fibromyalgia. A potential role both in the pathophysiological processes responsible for the symptoms of fibromyalgia and as therapeutic targets for the management of the condition is considered.

The effect of AUT00206, a Kv3 potassium channel modulator, on dopamine synthesis capacity and the reliability of [18F]-FDOPA imaging in schizophrenia.

BACKGROUND: Current treatments for schizophrenia act directly on dopamine (DA) receptors but are ineffective for many patients, highlighting the need to develop new treatment approaches. Striatal DA dysfunction, indexed using [18F]-FDOPA imaging, is linked to the pathoetiology of schizophrenia. We evaluated the effect of a novel drug, AUT00206, a Kv3.1/3.2 potassium channel modulator, on dopaminergic function in schizophrenia and its relationship with symptom change. Additionally, we investigated the test-retest reliability of [18F]-FDOPA PET in schizophrenia to determine its potential as a biomarker for drug discovery. METHODS: Twenty patients with schizophrenia received symptom measures and [18F]-FDOPA PET scans, before and after being randomised to AUT00206 or placebo groups for up to 28 days treatment. RESULTS: AUT00206 had no significant effect on DA synthesis capacity. However, there was a correlation between reduction in striatal dopamine synthesis capacity (indexed as Kicer) and reduction in symptoms, in the AUT00206 group (r = 0.58, p = 0.03). This was not observed in the placebo group (r = -0.15, p = 0.75), although the placebo group may have been underpowered to detect an effect. The intraclass correlation coefficients of [18F]-FDOPA indices in the placebo group ranged from 0.83 to 0.93 across striatal regions. CONCLUSIONS: The relationship between reduction in DA synthesis capacity and improvement in symptoms in the AUT00206 group provides evidence for a pharmacodynamic effect of the Kv3 channel modulator. The lack of a significant overall reduction in DA synthesis capacity in the AUT00206 group could be due to variability and the low number of subjects in this study. These findings support further investigation of Kv3 channel modulators for schizophrenia treatment. [18F]-FDOPA PET imaging showed very good test-retest reliability in patients with schizophrenia.

Interplay of potassium channel, gastric parietal cell and proton pump in gastrointestinal physiology, pathology and pharmacology.

Gastric acid secretion plays a pivotal role in the physiology of gastrointestinal tract. The functioning of the system encompasses a P2 ATPase pump (which shuttles electroneutral function at low pH) along with different voltage sensitive/neutral ion channels, cytosolic proteins, acid sensor receptors as well hormonal regulators. The increased acid secretion is a pathological marker of several diseases like peptic ulcer, gastroesophageal reflux disease (GERD), chronic gastritis, and the bug Helicobacter pylori (H. pylori) has also a critical role, which altogether affects the patient's quality of life. This review comprehensively described the nature of potassium ion channel and its mediators, the different clinical strategy to control acid rebound, and some basic experimental observations performed to study the interplay of ion channels, pumps, as well as mediators during acid secretion. Different aspects of regulation of gastric acid secretion have been focused either in terms of physiology of secretion or molecular interactions. The importance of H pylori infection and its treatment has also been discussed. Furthermore, the relevance of calcium signaling during acid secretion has been reviewed. The entire theme will make anyone understand in detail the gastric secretion machinery in general.

Cardiomyocyte Progenitor Cells as a Functional Gene Delivery Vehicle for Long-Term Biological Pacing.

Sustained pacemaker function is a challenge in biological pacemaker engineering. Human cardiomyocyte progenitor cells (CMPCs) have exhibited extended survival in the heart after transplantation. We studied whether lentivirally transduced CMPCs that express the pacemaker current If (encoded by HCN4) can be used as functional gene delivery vehicle in biological pacing. Human CMPCs were isolated from fetal hearts using magnetic beads coated with Sca-1 antibody, cultured in nondifferentiating conditions, and transduced with a green fluorescent protein (GFP)- or HCN4-GFP-expressing lentivirus. A patch-clamp analysis showed a large hyperpolarization-activated, time-dependent inward current (-20 pA/pF at -140 mV, n = 14) with properties typical of If in HCN4-GFP-expressing CMPCs. Gap-junctional coupling between CMPCs and neonatal rat ventricular myocytes (NRVMs) was demonstrated by efficient dye transfer and changes in spontaneous beating activity. In organ explant cultures, the number of preparations showing spontaneous beating activity increased from 6.3% in CMPC/GFP-injected preparations to 68.2% in CMPC/HCN4-GFP-injected preparations (P < 0.05). Furthermore, in CMPC/HCN4-GFP-injected preparations, isoproterenol induced a significant reduction in cycle lengths from 648 ± 169 to 392 ± 71 ms (P < 0.05). In sum, CMPCs expressing HCN4-GFP functionally couple to NRVMs and induce physiologically controlled pacemaker activity and may therefore provide an attractive delivery platform for sustained pacemaker function.

Effect of mitochondrial potassium channel on the renal protection mediated by sodium thiosulfate against ethylene glycol induced nephrolithiasis in rat model

Purpose: Sodium thiosulfate (STS) is clinically reported to be a promising drug in preventing nephrolithiasis. However, its mechanism of action remains unclear. In the present study, we investigated the role of mitochondrial KATP channel in the renal protection mediated by STS. Materials and Methods: Nephrolithiasis was induced in Wistar rats by administrating 0.4% ethylene glycol (EG) along with 1% ammonium chloride for one week in drinking water followed by only 0.75% EG for two weeks. Treatment groups received STS, mitochondrial KATP channel opener and closer exclusively or in combination with STS for two weeks. Results: Animals treated with STS showed normal renal tissue architecture, supported by near normal serum creatinine, urea and ALP activity. Diazoxide (mitochondria KATP channel opening) treatment to the animal also showed normal renal tissue histology and improved serum chemistry. However, an opposite result was shown by glibenclamide (mitochondria KATP channel closer) treated rats. STS administered along with diazoxide negated the renal protection rendered by diazoxide alone, while it imparted protection to the glibenclamide treated rats, formulating a mitochondria modulated STS action. Conclusion: The present study confirmed that STS render renal protection not only through chelation and antioxidant effect but also by modulating the mitochondrial KATP channel for preventing urolithiasis.

Emerging potassium channel targets for the treatment of pain.

PURPOSE OF REVIEW: Poor management of chronic pain remains a significant cause of misery with huge socioeconomic costs. Accumulating research in potassium (K+) channel physiology has uncovered several promising leads for the development of novel analgesics. RECENT FINDINGS: We now recognize that certain K+ channel subunits are directly gated to pain-relevant stimuli (Kv1.1, K2P) whereas others are specifically modulated by inflammatory processes (Kv7, BKCA, K2P). Genetic analyses illustrate that K+ channel gene variation can predict pain sensitivity (KCNS1, GIRKs), risk for persistent pain (KCNS1, GIRKs, TRESK) and analgesic effectiveness (GIRK2). Importantly, preclinical studies confirm that K+ channel dysfunction can be a pain trigger in traumatic neuropathies (Kv9.1/Kv2.1, Kv7, Kv1.2) and migraine (TRESK). Finally, emerging data suggest that even pain in diabetes, bone cancer and autoimmune neuropathies may have K+ channel dysfunction constituents. SUMMARY: There is a long-sought need for superior pharmacotherapy of pain syndromes. Although universal enhancement of K+ channel function in the periphery can decrease nociceptive excitability irrespective of the underlying cause, a more refined targeting of subunits with dominant nociceptive roles could yield highly efficacious treatments with fewer side-effects. The ongoing characterization of molecular interactions linking K+ channel dysfunction to pain is instrumental for identifying candidates with the most therapeutic potential.

Effect of mitochondrial potassium channel on the renal protection mediated by sodium thiosulfate against ethylene glycol induced nephrolithiasis in rat model.

PURPOSE: Sodium thiosulfate (STS) is clinically reported to be a promising drug in preventing nephrolithiasis. However, its mechanism of action remains unclear. In the present study, we investigated the role of mitochondrial KATP channel in the renal protection mediated by STS. MATERIALS AND METHODS: Nephrolithiasis was induced in Wistar rats by administrating 0.4% ethylene glycol (EG) along with 1% ammonium chloride for one week in drinking water followed by only 0.75% EG for two weeks. Treatment groups received STS, mitochondrial KATP channel opener and closer exclusively or in combination with STS for two weeks. RESULTS: Animals treated with STS showed normal renal tissue architecture, supported by near normal serum creatinine, urea and ALP activity. Diazoxide (mitochondria KATP channel opening) treatment to the animal also showed normal renal tissue histology and improved serum chemistry. However, an opposite result was shown by glibenclamide (mitochondria KATP channel closer) treated rats. STS administered along with diazoxide negated the renal protection rendered by diazoxide alone, while it imparted protection to the glibenclamide treated rats, formulating a mitochondria modulated STS action. CONCLUSION: The present study confirmed that STS render renal protection not only through chelation and antioxidant effect but also by modulating the mitochondrial KATP channel for preventing urolithiasis.

Intrathecal TRESK gene recombinant adenovirus attenuates spared nerve injury-induced neuropathic pain in rats.

TRESK gene recombinant adenovirus (10 IU/ml), which has been constructed successfully in our previous study, was implemented through an intrathecal injection. The fact that the method can effectively upregulate the expression of TRESK mRNA in the dorsal root ganglia of spared nerve injury in rats was verified. We also investigated the role of TRESK gene recombinant adenovirus in attenuating tactile allodynia and thermal hyperalgesia in spared nerve injury rats. Spared nerve injury to the sciatic nerve induced persistent tactile allodynia, but had no effect on thermal hyperalgesia. Intrathecal injection of TRESK gene recombinant adenovirus (25 µl) into the region of lumbar enlargement in advance reduced tactile allodynia. Moreover, intrathecal injection of TRESK gene recombinant adenovirus (25 µl) significantly alleviated the activation of astrocytes in spinal cord induced by spared nerve injury. The current study shows that an intrathecal injection of the TRESK gene recombinant adenovirus attenuated the activity of astrocytes in spinal cord, which contributed to relieving neuropathic pain in spared nerve injury rats. According to the result reported in our previous study, attenuating the expression of TRESK in dorsal root ganglia was involved in the development of neuropathic pain. On the basis of these results, we theorized that the therapeutic utility of upregulation of TRESK in dorsal root ganglia was effective in relieving neuropathic pain syndromes induced by peripheral nerve injury.

Vaccinating against GD3 ganglioside using BEC2 anti-idiotypic monoclonal antibody.

GD3, a ganglioside expressed on tumors of neuroectodermal origin such as melanoma and small-cell lung carcinoma (SCLC), is an attractive vaccine target but is poorly immunogenic. Our group has pursued several strategies designed to immunize patients against GD3 including using BEC2, an anti-idiotypic monoclonal antibody that mimics GD3. Pilot trials in melanoma and SCLC indicate that BEC2 can induce an anti-GD3 antibody response in a subset of patients and also suggests that immunization with BEC2 is associated with improved survival. A phase III trial is underway in SCLC patients to determine the effects of BEC2 on overall survival.

Pharmacological management of detrusor instability.

Urinary incontinence and lower urinary tract dysfunction remain an important cause of morbidity, affecting at least 14% of women over the age of 30 years. Whilst the etiology and pathophysiology of detrusor instability remains to be elucidated drug therapy remains important in the management of women with the irritative symptoms of urgency, frequency and urge incontinence. The number of drugs which have been developed illustrates the point that none are ideal, often having systemic adverse effects limiting their therapeutic usage and affecting compliance. This review aims to assess the current pharmacological management of detrusor instability as well as examining recent progress in the development of new agents, some of which may prove to be efficacious.

Potential therapeutic targets for treatment of the overactive bladder.

Muscarinic receptor antagonists remain the main therapy for the treatment of the overactive bladder yet severe adverse effects make them unsuitable for a large number of patients. The development of new drugs with novel mechanisms of action for the treatment of this condition is therefore essential. This article considers some of the targets currently under investigation for the development of such compounds. Beta-adrenoceptor agonists and KATP channel openers inhibit detrusor muscle activity and remain targets for drug development. There is also evidence that alpha-adrenoceptor antagonists may be effective in the overactive bladder, but the mechanism involved in this action is unclear. Finally the role of tachykinins in regulating bladder function through both the sensory and the motor innervation make them a potential target for drug development, but as with the the others, a selective action on the bladder must remain the goal of drug development.

Lambert-Eaton myasthenic syndrome: electrodiagnostic findings and response to treatment.

The authors reviewed the incidence of cancer, repetitive nerve stimulation findings, and response to treatment in 73 patients with Lambert-Eaton myasthenic syndrome. Thirty-one patients (42%) had lung cancer, 29 small cell. Doubling of the compound motor action potential amplitude in three tested distal muscles was seen in only 41% of patients. Treatment with 3, 4-diaminopyridine produced moderate to marked self-reported functional improvement in 79% of the 53 treated patients.

Reduction by ATP-sensitive potassium channel opener, YM934, of experimental myocardial infarct size in anesthetized dogs.

The present study was undertaken to examine whether the ATP-sensitive potassium channel opener, YM934, would be effective in reducing infarct size in a model of myocardial infarction in anesthetized dogs. For this purpose the effects of nifedipine, a calcium channel blocker, and hydralazine, a vasodilator with unknown mechanisms, were also investigated for comparison. Severe, irreversible myocardial injury was produced by a 90-min occlusion of the proximal left anterior descending coronary artery followed by 5 h of reperfusion. Infusion of YM934 (0.1 microg/kg/min i.c.) during the last 15 min of pre-ischemia reduced the myocardial infarct size and attenuated the release of creatine kinase MB eluted from the hearts without alteration in hemodynamic parameters including regional myocardial blood flow. In contrast, the other vasodilators, hydralazine and nifedipine, did not reduce myocardial infarct size under the same coronary vasodilatory conditions. These observations indicate that intracoronary YM934 is cardioprotective and that this effect is independent of alterations in regional myocardial blood flow.