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Neural Regeneration Research Jul 2023Epilepsy is a neurological disorder caused by the pathological hyper-synchronization of neuronal discharges. The fundamental research of epilepsy mechanisms and the... (Review)
Review
Epilepsy is a neurological disorder caused by the pathological hyper-synchronization of neuronal discharges. The fundamental research of epilepsy mechanisms and the targets of drug design options for its treatment have focused on neurons. However, approximately 30% of patients suffering from epilepsy show resistance to standard anti-epileptic chemotherapeutic agents while the symptoms of the remaining 70% of patients can be alleviated but not completely removed by the current medications. Thus, new strategies for the treatment of epilepsy are in urgent demand. Over the past decades, with the increase in knowledge on the role of glia in the genesis and development of epilepsy, glial cells are receiving renewed attention. In a normal brain, glial cells maintain neuronal health and in partnership with neurons regulate virtually every aspect of brain function. In epilepsy, however, the supportive roles of glial cells are compromised, and their interaction with neurons is altered, which disrupts brain function. In this review, we will focus on the role of glia-related processes in epileptogenesis and their contribution to abnormal neuronal activity, with the major focus on the dysfunction of astroglial potassium channels, water channels, gap junctions, glutamate transporters, purinergic signaling, synaptogenesis, on the roles of microglial inflammatory cytokines, microglia-astrocyte interactions in epilepsy, and on the oligodendroglial potassium channels and myelin abnormalities in the epileptic brain. These recent findings suggest that glia should be considered as the promising next-generation targets for designing anti-epileptic drugs that may improve epilepsy and drug-resistant epilepsy.
PubMed: 36571336
DOI: 10.4103/1673-5374.360281 -
Biochemical Pharmacology Jun 2024The voltage-dependent potassium channel Kv1.3 is a promising therapeutic target for the treatment of autoimmune and chronic inflammatory disorders. Kv1.3 blockers are...
The voltage-dependent potassium channel Kv1.3 is a promising therapeutic target for the treatment of autoimmune and chronic inflammatory disorders. Kv1.3 blockers are effective in treating multiple sclerosis (fampridine) and psoriasis (dalazatide). However, most Kv1.3 pharmacological antagonists are not specific enough, triggering potential side effects and limiting their therapeutic use. Functional Kv are oligomeric complexes in which the presence of ancillary subunits shapes their function and pharmacology. In leukocytes, Kv1.3 associates with KCNE4, which reduces the surface abundance and enhances the inactivation of the channel. This mechanism exerts profound consequences on Kv1.3-related physiological responses. Because KCNE peptides alter the pharmacology of Kv channels, we studied the effects of KCNE4 on Kv1.3 pharmacology to gain insights into pharmacological approaches. To that end, we used margatoxin, which binds the channel pore from the extracellular space, and Psora-4, which blocks the channel from the intracellular side. While KCNE4 apparently did not alter the affinity of either margatoxin or Psora-4, it slowed the inhibition kinetics of the latter in a stoichiometry-dependent manner. The results suggested changes in the Kv1.3 architecture in the presence of KCNE4. The data indicated that while the outer part of the channel mouth remains unaffected, KCNE4 disturbs the intracellular architecture of the complex. Various leukocyte types expressing different Kv1.3/KCNE4 configurations participate in the immune response. Our data provide evidence that the presence of these variable architectures, which affect both the structure of the complex and their pharmacology, should be considered when developing putative therapeutic approaches.
PubMed: 38880360
DOI: 10.1016/j.bcp.2024.116368 -
Current Therapeutic Research, Clinical... 2023Cilnidipine is a fourth-generation calcium channel blocker that is clinically used to treat hypertension. It is a dihydropyridine that blocks L- and N-type calcium...
BACKGROUND
Cilnidipine is a fourth-generation calcium channel blocker that is clinically used to treat hypertension. It is a dihydropyridine that blocks L- and N-type calcium channels. The inhibitory effect of cilnidipine on isolated detrusor muscle contractility has not been studied. This study investigated the inhibitory effect of cilnidipine on isolated caprine (goat) detrusor muscle contractility and the reversal of the inhibition by calcium channel openers.
METHODS
Fourteen caprine detrusor strips were made to contract using 80 mM potassium chloride before and after addition of three concentrations (20, 40, and 60 µM) of cilnidipine. Two reversal agents, the L-type calcium channel opener FPL64716, and the N-type calcium channel opener GV-58, were investigated for their ability to reverse the inhibitory effect of 40 µΜ cilnidipine on potassium chloride-induced detrusor contractility.
RESULTS
Cilnidipine caused a dose-dependent and statistically significant inhibition of detrusor contractility at all concentrations of cilnidipine used (20, 40, and 60 µΜ). The inhibitory effect of 40 µM cilnidipine on detrusor contractility was significantly reversed by the addition of FPL64716 and GV-58.
CONCLUSIONS
Cilnidipine inhibits the contractility of the isolated detrusor by blocking L- and N-type calcium channels. Cilnidipine could be evaluated for treating clinical conditions requiring relaxation of the detrusor such as overactive bladder.
PubMed: 37869401
DOI: 10.1016/j.curtheres.2023.100717 -
Frontiers in Physiology 2024Numerous neurodegenerative diseases result from altered ion channel function and mutations. The intracellular redox status can significantly alter the gating... (Review)
Review
Numerous neurodegenerative diseases result from altered ion channel function and mutations. The intracellular redox status can significantly alter the gating characteristics of ion channels. Abundant neurodegenerative diseases associated with oxidative stress have been documented, including Parkinson's, Alzheimer's, spinocerebellar ataxia, amyotrophic lateral sclerosis, and Huntington's disease. Reactive oxygen and nitrogen species compounds trigger posttranslational alterations that target specific sites within the subunits responsible for channel assembly. These alterations include the adjustment of cysteine residues through redox reactions induced by reactive oxygen species (ROS), nitration, and S-nitrosylation assisted by nitric oxide of tyrosine residues through peroxynitrite. Several ion channels have been directly investigated for their functional responses to oxidizing agents and oxidative stress. This review primarily explores the relationship and potential links between oxidative stress and ion channels in neurodegenerative conditions, such as cerebellar ataxias and Parkinson's disease. The potential correlation between oxidative stress and ion channels could hold promise for developing innovative therapies for common neurodegenerative diseases.
PubMed: 38348223
DOI: 10.3389/fphys.2024.1320086 -
BioRxiv : the Preprint Server For... May 2024Ion channels are necessary for proper water and nutrient absorption in the intestine, which supports cellular metabolism and organismal growth. While a role for Na...
Ion channels are necessary for proper water and nutrient absorption in the intestine, which supports cellular metabolism and organismal growth. While a role for Na co-transporters and pumps in intestinal nutrient absorption is well defined, how individual K uniporters function to maintain ion homeostasis is poorly understood. Using , we show that a gain-of-function mutation in , which encodes a two-pore domain K ion channel orthologous to human KCNK3, facilitates nutrient absorption and suppresses the metabolic and developmental defects displayed by impaired intestinal MAP Kinase (MAPK) signaling. Mutations in and which encode two components of this MAPK pathway, cause severe growth defects, reduced lipid storage, and a dramatic increase in autophagic lysosomes, which mirror dietary restriction phenotypes. Additionally, these MAPK mutants display structural defects of the intestine and an impaired defecation motor program. We find that activation of TWK-26 reverses the dietary restriction-like state of the MAPK mutants by restoring intestinal nutrient absorption without correcting the intestinal bloating or defecation defects. This study provides unique insight into the mechanisms by which intestinal K ion channels support intestinal metabolic homeostasis.
PubMed: 38766028
DOI: 10.1101/2024.05.06.592787 -
Journal of Neuroscience Research Nov 2023One group of the K ion channels, the small-conductance Ca -activated potassium channels (K 2.x, also known as SK channels family), is widely expressed in neurons as well... (Review)
Review
One group of the K ion channels, the small-conductance Ca -activated potassium channels (K 2.x, also known as SK channels family), is widely expressed in neurons as well as the heart, endothelial cells, etc. They are named small-conductance Ca -activated potassium channels (SK channels) due to their comparatively low single-channel conductance of about ~10 pS. These channels are insensitive to changes in membrane potential and are activated solely by rises in the intracellular Ca . According to the phylogenic research done on the K 2.x channels family, there are three channels' subtypes: K 2.1, K 2.2, and K 2.3, which are encoded by KCNN1, KCNN2, and KCNN3 genes, respectively. The K 2.x channels regulate neuronal excitability and responsiveness to synaptic input patterns. K 2.x channels inhibit excitatory postsynaptic potentials (EPSPs) in neuronal dendrites and contribute to the medium afterhyperpolarization (mAHP) that follows the action potential bursts. Multiple brain regions, including the hippocampus, express the K 2.2 channel encoded by the KCNN2 gene on chromosome 5. Of particular interest, rat cerebellar Purkinje cells express K 2.2 channels, which are crucial for various cellular processes during development and maturation. Patients with a loss-of-function of KCNN2 mutations typically exhibit extrapyramidal symptoms, cerebellar ataxia, motor and language developmental delays, and intellectual disabilities. Studies have revealed that autosomal dominant neurodevelopmental movement disorders resembling rodent symptoms are caused by heterozygous loss-of-function mutations, which are most likely to induce KCNN2 haploinsufficiency. The K 2.2 channel is a promising drug target for spinocerebellar ataxias (SCAs). SCAs exhibit the dysregulation of firing in cerebellar Purkinje cells which is one of the first signs of pathology. Thus, selective K 2.2 modulators are promising potential therapeutics for SCAs.
Topics: Rats; Animals; Potassium Channels; Endothelial Cells; Neurons; Membrane Potentials; Purkinje Cells
PubMed: 37466411
DOI: 10.1002/jnr.25233 -
Neurobiology of Disease Aug 2023Autoimmune-mediated encephalitis syndromes are increasingly being recognized as important clinical entities. They need to be thought of as differential diagnosis in any... (Review)
Review
Autoimmune-mediated encephalitis syndromes are increasingly being recognized as important clinical entities. They need to be thought of as differential diagnosis in any patient presenting with fast-onset psychosis or psychiatric problems, memory deficits or other cognitive problems, including aphasias, as well as seizures or motor automatisms, but also rigidity, paresis, ataxia or dystonic / parkinsonian symptoms. Diagnosis including imaging and CSF search for antibodies needs to be fast, as progression of these inflammatory processes is often causing scarring of brain tissue, with hypergliosis and atrophy. As these symptoms show, the autoantibodies present in these cases appear to act within the CNS. Several of such antibodies have by now been identified such as IgG directed against NMDA-receptors, AMPA receptors, GABA and GABA receptors, and voltage gated potassium channels and proteins of the potassium channel complex (i.e. LGI1 and CASPR2). These are neuropil / surface antigens where antibody interaction can well be envisaged to cause dysfunction of the target protein, including internalization. Others, such as antibodies directed against GAD65 (an intracellular enzyme responsible for GABA-synthesis from glutamate), are discussed to constitute epiphenomena, but not causal agents in disease progression. This review will focus on the current knowledge of antibody interaction mechanisms, especially discussing cellular excitability changes and synaptic interactions in hippocampal and other brain networks. One challenge in this context is to find viable hypotheses for the emergence of both, hyperexcitability and seizures, and presumably reduced synaptic plasticity and underlying cognitive dysfunction.
Topics: Humans; Nerve Tissue Proteins; Autoimmunity; Intracellular Signaling Peptides and Proteins; Autoantibodies; Seizures; gamma-Aminobutyric Acid
PubMed: 37414365
DOI: 10.1016/j.nbd.2023.106221 -
ELife Aug 2023G-protein-coupled receptors (GPCRs) transmit signals into cells depending on the G protein type. To analyze the functions of GPCR signaling, we assessed the...
G-protein-coupled receptors (GPCRs) transmit signals into cells depending on the G protein type. To analyze the functions of GPCR signaling, we assessed the effectiveness of animal G-protein-coupled bistable rhodopsins that can be controlled into active and inactive states by light application using zebrafish. We expressed Gq- and Gi/o-coupled bistable rhodopsins in hindbrain reticulospinal V2a neurons, which are involved in locomotion, or in cardiomyocytes. Light stimulation of the reticulospinal V2a neurons expressing Gq-coupled spider Rh1 resulted in an increase in the intracellular Ca level and evoked swimming behavior. Light stimulation of cardiomyocytes expressing the Gi/o-coupled mosquito Opn3, pufferfish TMT opsin, or lamprey parapinopsin induced cardiac arrest, and the effect was suppressed by treatment with pertussis toxin or barium, suggesting that Gi/o-dependent regulation of inward-rectifier K channels controls cardiac function. These data indicate that these rhodopsins are useful for optogenetic control of GPCR-mediated signaling in zebrafish neurons and cardiomyocytes.
Topics: Animals; Myocytes, Cardiac; Zebrafish; Optogenetics; Neurons; Potassium Channels, Inwardly Rectifying; Rhodopsin
PubMed: 37589544
DOI: 10.7554/eLife.83974 -
Antioxidants (Basel, Switzerland) Apr 2024Redox reactions exert a profound influence on numerous cellular functions with mitochondria playing a central role in orchestrating these processes. This pivotal... (Review)
Review
Redox reactions exert a profound influence on numerous cellular functions with mitochondria playing a central role in orchestrating these processes. This pivotal involvement arises from three primary factors: (1) the synthesis of reactive oxygen species (ROS) by mitochondria, (2) the presence of a substantial array of redox enzymes such as respiratory chain, and (3) the responsiveness of mitochondria to the cellular redox state. Within the inner mitochondrial membrane, a group of potassium channels, including ATP-regulated, large conductance calcium-activated, and voltage-regulated channels, is present. These channels play a crucial role in conditions such as cytoprotection, ischemia/reperfusion injury, and inflammation. Notably, the activity of mitochondrial potassium channels is intricately governed by redox reactions. Furthermore, the regulatory influence extends to other proteins, such as kinases, which undergo redox modifications. This review aims to offer a comprehensive exploration of the modulation of mitochondrial potassium channels through diverse redox reactions with a specific focus on the involvement of ROS.
PubMed: 38671882
DOI: 10.3390/antiox13040434 -
Proceedings of the National Academy of... Aug 2023Loss-of-function mutations in the (Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks,...
Loss-of-function mutations in the (Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps in skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance the activity of Kv1.1-containing channels and offset the functional defects caused by mutations has been clinically approved. Here, we uncovered that niflumic acid (NFA), a currently prescribed analgesic and anti-inflammatory drug with an excellent safety profile in the clinic, potentiates the activity of Kv1.1 channels. NFA increased Kv1.1 current amplitudes by enhancing the channel open probability, causing a hyperpolarizing shift in the voltage dependence of both channel opening and gating charge movement, slowing the OFF-gating current decay. NFA exerted similar actions on both homomeric Kv1.2 and heteromeric Kv1.1/Kv1.2 channels, which are formed in most brain structures. We show that through its potentiating action, NFA mitigated the EA1 mutation-induced functional defects in Kv1.1 and restored cerebellar synaptic transmission, Purkinje cell availability, and precision of firing. In addition, NFA ameliorated the motor performance of a mouse model of EA1 and restored the neuromuscular transmission and climbing ability in (Kv1.1) mutant flies (). By virtue of its multiple actions, NFA has strong potential as an efficacious single-molecule-based therapeutic agent for EA1 and serves as a valuable model for drug discovery.
Topics: Animals; Mice; Myokymia; Drosophila melanogaster; Ataxia; Drosophila; Kv1.2 Potassium Channel
PubMed: 37487086
DOI: 10.1073/pnas.2207978120