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Toxins May 2024Polyamines (PAs) are polycationic biogenic amines ubiquitously present in all life forms and are involved in molecular signaling and interaction, determining cell fate... (Review)
Review
Polyamines (PAs) are polycationic biogenic amines ubiquitously present in all life forms and are involved in molecular signaling and interaction, determining cell fate (e.g., cell proliferation, dif-ferentiation, and apoptosis). The intricate balance in the PAs' levels in the tissues will determine whether beneficial or detrimental effects will affect homeostasis. It's crucial to note that endoge-nous polyamines, like spermine and spermidine, play a pivotal role in our understanding of neu-rological disorders as they interact with membrane receptors and ion channels, modulating neuro-transmission. In spiders and wasps, monoamines (histamine, dopamine, serotonin, tryptamine) and polyamines (spermine, spermidine, acyl polyamines) comprise, with peptides and other sub-stances, the low molecular weight fraction of the venom. Acylpolyamines are venom components exclusively from spiders and a species of solitary wasp, which cause inhibition chiefly of iono-tropic glutamate receptors (AMPA, NMDA, and KA iGluRs) and nicotinic acetylcholine receptors (nAChRs). The first venom acylpolyamines ever discovered (argiopines, Joro and Nephila toxins, and philanthotoxins) have provided templates for the design and synthesis of numerous analogs. Thus far, analogs with high potency exert their effect at nanomolar concentrations, with high se-lectivity toward their ionotropic and ligand receptors. These potent and selective acylpolyamine analogs can serve biomedical purposes and pest control management. The structural modification of acylpolyamine with photolabile and fluorescent groups converted these venom toxins into use-ful molecular probes to discriminate iGluRs and nAchRs in cell populations. In various cases, the linear polyamines, like spermine and spermidine, constituting venom acyl polyamine backbones, have served as cargoes to deliver active molecules via a polyamine uptake system on diseased cells for targeted therapy. In this review, we examined examples of biogenic amines that play an essential role in neural homeostasis and cell signaling, contributing to human health and disease outcomes, which can be present in the venom of arachnids and hymenopterans. With an empha-sis on the spider and wasp venom acylpolyamines, we focused on the origin, structure, derivatiza-tion, and biomedical and biotechnological application of these pharmacologically attractive, chemically modular venom components.
Topics: Animals; Polyamines; Spider Venoms; Insecticides; Wasps; Humans; Spiders
PubMed: 38922129
DOI: 10.3390/toxins16060234 -
Cells Jun 2024Neuroplasticity in the amygdala and its central nucleus (CeA) is linked to pain modulation and pain behaviors, but cellular mechanisms are not well understood. Here, we...
Dysfunction of Small-Conductance Ca-Activated Potassium (SK) Channels Drives Amygdala Hyperexcitability and Neuropathic Pain Behaviors: Involvement of Epigenetic Mechanisms.
Neuroplasticity in the amygdala and its central nucleus (CeA) is linked to pain modulation and pain behaviors, but cellular mechanisms are not well understood. Here, we addressed the role of small-conductance Ca-activated potassium (SK) channels in pain-related amygdala plasticity. The facilitatory effects of the intra-CeA application of an SK channel blocker (apamin) on the pain behaviors of control rats were lost in a neuropathic pain model, whereas an SK channel activator (NS309) inhibited pain behaviors in neuropathic rats but not in sham controls, suggesting the loss of the inhibitory behavioral effects of amygdala SK channels. Brain slice electrophysiology found hyperexcitability of CeA neurons in the neuropathic pain condition due to the loss of SK channel-mediated medium afterhyperpolarization (mAHP), which was accompanied by decreased SK2 channel protein and mRNA expression, consistent with a pretranscriptional mechanisms. The underlying mechanisms involved the epigenetic silencing of the SK2 gene due to the increased DNA methylation of the CpG island of the SK2 promoter region and the change in methylated CpG sites in the CeA in neuropathic pain. This study identified the epigenetic dysregulation of SK channels in the amygdala (CeA) as a novel mechanism of neuropathic pain-related plasticity and behavior that could be targeted to control abnormally enhanced amygdala activity and chronic neuropathic pain.
Topics: Animals; Male; Rats; Amygdala; Behavior, Animal; DNA Methylation; Epigenesis, Genetic; Neuralgia; Neurons; Rats, Sprague-Dawley; Small-Conductance Calcium-Activated Potassium Channels
PubMed: 38920682
DOI: 10.3390/cells13121055 -
Cells Jun 2024This manuscript explores the intricate role of acetylcholine-activated inward rectifier potassium (K) channels in the pathogenesis of atrial fibrillation (AF), a common... (Review)
Review
This manuscript explores the intricate role of acetylcholine-activated inward rectifier potassium (K) 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 K channels in modulating the atrial action potential and facilitating arrhythmogenic conditions. This study underscores the dual nature of K activation and its genetic regulation, revealing that specific variations in potassium channel genes, such as Kir3.4 and K3.1, significantly influence the electrophysiological remodeling associated with AF. Furthermore, this manuscript identifies the crucial role of the K-mediated current, , 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 K channel activity. This is complemented by discussions on therapeutic interventions, where K channel blockers have shown promise in AF management. Additionally, this study discusses the broader implications of K 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 K 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.
Topics: Atrial Fibrillation; Humans; Animals; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Action Potentials; Acetylcholine
PubMed: 38920645
DOI: 10.3390/cells13121014 -
Journal of Biosciences 2024Cystic fibrosis (CF) is a life-threatening monogenic disease affecting thousands of people worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) is an... (Review)
Review
Cystic fibrosis (CF) is a life-threatening monogenic disease affecting thousands of people worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that facilitates transportation of water and salts across epithelial cell membranes through the conductance of Cl and other anions. A dysfunctional CFTR due to abnormalities in the gene causes CF, which is believed to be a rare disease in India mainly due to mis/underdiagnosis. Although numerous diagnostic methods and treatment options are available for CF globally, most of these are unaffordable for developing countries like India. Currently, CF symptoms are managed with mucolytics, antibiotics, anti-inflammatory drugs, and various CFTR modulators based on the type of defect. While a definitive cure for CF remains elusive, advancements in stem cell and gene therapies hold promise for permanent cure in the near future. In this review, we discuss the prevalence of CF cases in India, affordable diagnostic methods, and treatment options amenable for developing countries. We further emphasize the scope for the universal newborn screening programme.
Topics: Cystic Fibrosis; Humans; India; Cystic Fibrosis Transmembrane Conductance Regulator; Developing Countries; Genetic Therapy; Neonatal Screening; Infant, Newborn; Mutation
PubMed: 38920104
DOI: No ID Found -
F1000Research 2024Epilepsy affects millions of people worldwide, and there is an urgent need to develop safe and effective therapeutic agents. Animal venoms contain diverse bioactive... (Review)
Review
Epilepsy affects millions of people worldwide, and there is an urgent need to develop safe and effective therapeutic agents. Animal venoms contain diverse bioactive compounds like proteins, peptides, and small molecules, which may possess medicinal properties against epilepsy. In recent years, research has shown that venoms from various organisms such as spiders, ants, bees, wasps, and conus snails have anticonvulsant and antiepileptic effects by targeting specific receptors and ion channels. This review underscores the significance of purified proteins and toxins from these sources as potential therapeutic agents for epilepsy. In conclusion, this review emphasizes the valuable role of animal venoms as a natural resource for further exploration in epilepsy treatment research.
Topics: Animals; Anticonvulsants; Humans; Venoms; Epilepsy
PubMed: 38919947
DOI: 10.12688/f1000research.147027.1 -
Frontiers in Cellular Neuroscience 2024Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with a ubiquitous distribution in numerous tissues and with various functions in both neuronal and...
Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with a ubiquitous distribution in numerous tissues and with various functions in both neuronal and non-neuronal cells. IGF-1 provides trophic support for many neurons of both the central and peripheral nervous systems. In the central nervous system (CNS), IGF-1R signaling regulates brain development, increases neuronal firing and modulates synaptic transmission. IGF-1 and IGF-IR are not only expressed in CNS neurons but also in sensory dorsal root ganglion (DRG) nociceptive neurons that convey pain signals. DRG nociceptive neurons express a variety of receptors and ion channels that are essential players of neuronal excitability, notably the ligand-gated cation channel TRPV1 and the voltage-gated M-type K channel, which, respectively, triggers and dampens sensory neuron excitability. Although many lines of evidence suggest that IGF-IR signaling contributes to pain sensitivity, its possible modulation of TRPV1 and M-type K channel remains largely unexplored. In this study, we examined the impact of IGF-1R signaling on DRG neuron excitability and its modulation of TRPV1 and M-type K channel activities in cultured rat DRG neurons. Acute application of IGF-1 to DRG neurons triggered hyper-excitability by inducing spontaneous firing or by increasing the frequency of spikes evoked by depolarizing current injection. These effects were prevented by the IGF-1R antagonist NVP-AEW541 and by the PI3Kinase blocker wortmannin. Surprisingly, acute exposure to IGF-1 profoundly inhibited both the TRPV1 current and the spike burst evoked by capsaicin. The Src kinase inhibitor PP2 potently depressed the capsaicin-evoked spike burst but did not alter the IGF-1 inhibition of the hyperexcitability triggered by capsaicin. Chronic IGF-1 treatment (24 h) reduced the spike firing evoked by depolarizing current injection and upregulated the M-current density. In contrast, chronic IGF-1 markedly increased the spike burst evoked by capsaicin. In all, our data suggest that IGF-1 exerts complex effects on DRG neuron excitability as revealed by its dual and opposite actions upon acute and chronic exposures.
PubMed: 38919332
DOI: 10.3389/fncel.2024.1391858 -
Frontiers in Pharmacology 2024Ion channels are critical drug targets for a range of pathologies, such as epilepsy, pain, itch, autoimmunity, and cardiac arrhythmias. To develop effective and safe...
Ion channels are critical drug targets for a range of pathologies, such as epilepsy, pain, itch, autoimmunity, and cardiac arrhythmias. To develop effective and safe therapeutics, it is necessary to design small molecules with high potency and selectivity for specific ion channel subtypes. There has been increasing implementation of structure-guided drug design for the development of small molecules targeting ion channels. We evaluated the performance of two RosettaLigand docking methods, RosettaLigand and GALigandDock, on the structures of known ligand-cation channel complexes. Ligands were docked to voltage-gated sodium (Na), voltage-gated calcium (Ca), and transient receptor potential vanilloid (TRPV) channel families. For each test case, RosettaLigand and GALigandDock methods frequently sampled a ligand-binding pose within a root mean square deviation (RMSD) of 1-2 Å relative to the experimental ligand coordinates. However, RosettaLigand and GALigandDock scoring functions cannot consistently identify experimental ligand coordinates as top-scoring models. Our study reveals that the proper scoring criteria for RosettaLigand and GALigandDock modeling of ligand-ion channel complexes should be assessed on a case-by-case basis using sufficient ligand and receptor interface sampling, knowledge about state-specific interactions of the ion channel, and inherent receptor site flexibility that could influence ligand binding.
PubMed: 38919257
DOI: 10.3389/fphar.2024.1411428 -
Acta Dermatovenerologica Alpina,... Jun 2024This study explores the immunogenetic associations of human leukocyte antigens (HLA) and the calcium release-activated calcium modulator 1 (ORAI1) and stromal...
INTRODUCTION
This study explores the immunogenetic associations of human leukocyte antigens (HLA) and the calcium release-activated calcium modulator 1 (ORAI1) and stromal interaction molecule 1 (STIM1) genes in HIV-1‒positive patients with HIV-related skin disorders.
METHODS
This study assessed the distribution of variants of HLA class II alleles and expression levels of ORAI1 and STIM1 genes in the blood between HIV-1‒positive patients with HIV-related skin disorders and the control group with no HIV within the Latvian population.
RESULTS
The research group comprised 115 HIV-1‒positive patients with HIV-related skin disorders, and the control group included 80 healthy individuals. Risk alleles (HLA- DQB1*02:01-0301 and HLA-DQA1*01:01-0501) and protective alleles (HLA-DRB1*07-13, DRB1*01-13, DRB1*04-11, and HLA-DQA1*05:01-0501) showed statistical significance in the groups. In 38 out of 115 patients, higher expression levels of ORAI1 and STIM1 genes were detected in the blood at the beginning of treatment. A significantly higher level of the microribonucleic acid (mRNA) ORAI1 gene was also found in the control group.
CONCLUSIONS
The results demonstrate that HLA class II alleles are associated with a trend toward risk/protection concerning HIV-related skin disorders in HIV-1‒positive patients. It was also shown that a low level of ORAI1 mRNA and the risk allele HLA-DQB1*0201-0301 were simultaneously present in the research group.
Topics: Humans; ORAI1 Protein; Male; Latvia; Female; Stromal Interaction Molecule 1; Adult; HIV Infections; Middle Aged; Polymorphism, Genetic; Skin Diseases; Case-Control Studies; Neoplasm Proteins; Genetic Predisposition to Disease
PubMed: 38918943
DOI: No ID Found -
Cell & Bioscience Jun 2024Polyamines (PA) are polycations with pleiotropic functions in cellular physiology and pathology. In particular, PA have been involved in the regulation of cell... (Review)
Review
Polyamines (PA) are polycations with pleiotropic functions in cellular physiology and pathology. In particular, PA have been involved in the regulation of cell homeostasis and proliferation participating in the control of fundamental processes like DNA transcription, RNA translation, protein hypusination, autophagy and modulation of ion channels. Indeed, their dysregulation has been associated to inflammation, oxidative stress, neurodegeneration and cancer progression. Accordingly, PA intracellular levels, derived from the balance between uptake, biosynthesis, and catabolism, need to be tightly regulated. Among the mechanisms that fine-tune PA metabolic enzymes, emerging findings highlight the importance of noncoding RNAs (ncRNAs). Among the ncRNAs, microRNA, long noncoding RNA and circRNA are the most studied as regulators of gene expression and mRNA metabolism and their alteration have been frequently reported in pathological conditions, such as cancer progression and brain diseases. In this review, we will discuss the role of ncRNAs in the regulation of PA genes, with a particular emphasis on the changes of this modulation observed in health disorders.
PubMed: 38918813
DOI: 10.1186/s13578-024-01235-3 -
Cell Death & Disease Jun 2024Multiple sevoflurane exposures may damage the developing brain. The neuroprotective function of dexmedetomidine has been widely confirmed in animal experiments and human...
Multiple sevoflurane exposures may damage the developing brain. The neuroprotective function of dexmedetomidine has been widely confirmed in animal experiments and human studies. However, the effect of dexmedetomidine on the glymphatic system has not been clearly studied. We hypothesized that dexmedetomidine could alleviate sevoflurane-induced circulatory dysfunction of the glymphatic system in young mice. Six-day-old C57BL/6 mice were exposed to 3% sevoflurane for 2 h daily, continuously for 3 days. Intraperitoneal injection of either normal saline or dexmedetomidine was administered before every anaesthesia. Meanwhile the circulatory function of glymphatic system was detected by tracer injection at P8 and P32. On P30-P32, behavior tests including open field test, novel object recognition test, and Y-maze test were conducted. Primary astrocyte cultures were established and treated with the PI3K activator 740Y-P, dexmedetomidine, and small interfering RNA (siRNA) to silence ΔFosB. We propose for the first time that multiple exposure to sevoflurane induces circulatory dysfunction of the glymphatic system in young mice. Dexmedetomidine improves the circulatory capacity of the glymphatic system in young mice following repeated exposure to sevoflurane through the PI3K/AKT/ΔFosB/AQP4 signaling pathway, and enhances their long-term learning and working memory abilities.
Topics: Animals; Dexmedetomidine; Sevoflurane; Glymphatic System; Proto-Oncogene Proteins c-akt; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Aquaporin 4; Signal Transduction; Astrocytes; Male
PubMed: 38918408
DOI: 10.1038/s41419-024-06845-w