Types Of Ion Channels Research Articles

Computational approaches for identifications of altered ion channels in keratoconus.

Keratoconus is an etiologically complex, degenerative corneal disease that eventually leads to loss of corneal integrity. Cells in corneal epithelium and endothelium express various types of ion channels that play important roles in ocular pathology. This emphasizes the need of understanding alterations of ion channels in keratoconus. Differential gene expression analysis was performed to identify deregulated ion channels in keratoconus patients using transcriptomic data. Thereafter correlation analysis of ion channel expression was performed to obtain the changed correlation between ion channels' expression in keratoconus patients versus control samples. Moreover, Protein-protein interaction networks and a pathway map was constructed to identify cellular processes altered due to the deregulation of ion channels. Furthermore, drugs interacting with deregulated ion channels were identified. Total 75 ion channels were found to be deregulated in keratoconus, of which 12 were upregulated and 63 were downregulated. Correlations between ion channel expressions found to be different in control and keratoconus samples. Thereafter, protein-protein interactions network was generated to identify hub ion channels in network. Furthermore, the pathway map was constructed to depict calcium signalling, MAPK signalling, synthesis and secretion of cortisol, and cAMP signalling. The 19 FDA- approved drugs that interact with the 6 deregulated ion channels were identified. Down-regulation of voltage-gated calcium channels can be attributed to reduced cell proliferation and differentiation. Additionally, deregulated ion channels in 3',5'- cyclic adenosine monophosphate signalling may be responsible for elevated cortisol level in progressive keratoconus patients.

Olfactory cilia, regulation and control of olfaction.

The sense of smell is still considered a fuzzy sensation. Softly wafting aromas can stimulate the appetite and trigger memories; however, there are many unexplored aspects of its underlying mechanisms, and not all of these have been elucidated. Although the final sense of smell takes place in the brain, it is greatly affected during the preliminary stage, when odorants are converted into electrical signals. After signal conversion through ion channels in olfactory cilia, action potentials are generated through other types of ion channels located in the cell body. Spike trains through axons transmit this information as digital signals to the brain, however, before odorants are converted into digital electric signals, such as an action potential, modification of the transduction signal has already occurred. This review focuses on the early stages of olfactory signaling. Modification of signal transduction mechanisms and their effect on the human sense of smell through three characteristics (signal amplification, olfactory adaptation, and olfactory masking) produced by olfactory cilia, which is the site of signal transduction are being addressed in this review.

Voltage-gated ion channel’s gene expression in the myocardium of embryo and adult chickens

The functioning of the cardiovascular system is critical for embryo survival. Cardiac contractions depend on the sequential activation of different classes of voltage-gated ion channels. Understanding the fundamental features of these interactions is important for identifying the mechanisms of pathologies development in the myocardium. However, at present there is no consensus on which ion channels are involved in the formation of automaticity in the early embryonic stages. The aim of this study was to elucidate the expression of genes encoding various types of ion channels that are involved in the generation of electrical activity chicken heart at different stages of ontogenesis. We analyzed the expression of 14 genes from different families of ion channels. It was revealed that the expression profiles of ion channel genes change depending on the stages of ontogenesis. The HCN4, CACNA1D, SCN1A, SCN5A, KCNA1 genes have maximum expression at the tubular heart stage. In adult, a switch occurs to the higher expression of CACNA1C, KCNH6, RYR and SLC8A1 genes. This data correlated with the results obtained by the microelectrode method. It can be assumed that the automaticity of the tubular heart is mainly due to the mechanism of the «membrane–clock» (hyperpolarization-activated current (If), Ca2+–current L–type (ICaL), Na+–current (INa) and the slow component of the delayed rectifier K+–current (IKs)). Whereas in adult birds, the mechanism for generating electrical impulses is determined by both « membrane– clock» and «Ca2+–clock».

Multiplexed volumetric CLEM enabled by scFvs provides insights into the cytology of cerebellar cortex

Mapping neuronal networks is a central focus in neuroscience. While volume electron microscopy (vEM) can reveal the fine structure of neuronal networks (connectomics), it does not provide molecular information to identify cell types or functions. We developed an approach that uses fluorescent single-chain variable fragments (scFvs) to perform multiplexed detergent-free immunolabeling and volumetric-correlated-light-and-electron-microscopy on the same sample. We generated eight fluorescent scFvs targeting brain markers. Six fluorescent probes were imaged in the cerebellum of a female mouse, using confocal microscopy with spectral unmixing, followed by vEM of the same sample. The results provide excellent ultrastructure superimposed with multiple fluorescence channels. Using this approach, we documented a poorly described cell type, two types of mossy fiber terminals, and the subcellular localization of one type of ion channel. Because scFvs can be derived from existing monoclonal antibodies, hundreds of such probes can be generated to enable molecular overlays for connectomic studies.

Senso-immunology: the hidden relationship between sensory system and immune system.

The primary sensory neurons involved in pain perception express various types of receptor-type ion channels at their nerve endings. These molecules are responsible for triggering neuronal excitation, translating environmental stimuli into pain signals. Recent studies have shown that acute nociception, induced by neuronal excitation, not only serves as a sensor for signaling life-threatening situations but also modulates our pathophysiological conditions. This modulation occurs through the release of neuropeptides by primary sensory neurons excited by nociceptive stimuli, which directly or indirectly affect peripheral systems, including immune function. Senso-immunology, an emerging research field, integrates interdisciplinary studies of pain and immunology and has garnered increasing attention in recent years. This review provides an overview of the systemic pathophysiological functions regulated by receptor-type ion channels, such as transient receptor potential (TRP) channels in primary sensory neurons, from the perspective of senso-immunology.

The odyssey of the TR(i)P journey to the cellular membrane.

Ion channels are integral membrane proteins mediating ion flow in response to changes in their environment. Among the different types of ion channels reported to date, the super-family of TRP channels stands out since its members have been linked to many pathophysiological processes. The family comprises 6 subfamilies and 28 members in mammals, which are widely distributed throughout most tissues and organs and have an important role in several aspects of cellular physiology. It has been evidenced that abnormal expression, post-translational modifications, and channel trafficking are associated with several pathologies, such as cancer, cardiovascular disease, diabetes, and brain disorders, among others. In this review, we present an updated summary of the mechanisms involved in the subcellular trafficking of TRP channels, with a special emphasis on whether different post-translational modifications and naturally occurring mutagenesis affect both expression and trafficking. Additionally, we describe how such changes have been associated with the development and progress of diverse pathologies associated with the gain or loss of functional phenotypes. The study of these processes will not only contribute to a better understanding the role of TRP channels in the different tissues but will also present novel possible therapeutic targets in diseases where their activity is dysregulated.

Ion Channels Remodeling in the Regulation of Vascular Hyporesponsiveness During Shock.

Shock is characterized with vascular hyporesponsiveness to vasoconstrictors, thereby to cause refractory hypotension, insufficient tissue perfusion, and multiple organ dysfunction. The vascular hyporeactivity persisted even though norepinephrine and fluid resuscitation were administrated, it is of critical importance to find new potential target. Ion channels are crucial in the regulation of cell membrane potential and affect vasoconstriction and vasodilation. It has been demonstrated that many types of ion channels including K+ channels, Ca2+ permeable channels, and Na+ channels exist in vascular smooth muscle cells and endothelial cells, contributing to the regulation of vascular homeostasis and vasomotor function. An increasing number of studies suggested that the structural and functional alterations of ion channels located in arteries contribute to vascular hyporesponsiveness during shock, but the underlying mechanisms remained to be fully clarified. Therefore, the expression and functional changes in ion channels in arteries associated with shock are reviewed, to pave the way for further exploring the potential of ion channel-targeted compounds in treating refractory hypotension in shock.

The Role of Alpha-7 Nicotinic Acetylcholine Receptors in Pain: Potential Therapeutic Implications.

Chronic pain represents a prevalent and costly medical challenge globally. Nicotinic acetylcholine receptors (nAChRs), one type of ligand-gated ion channels found extensively in both the central and peripheral nervous systems, have emerged as promising therapeutic targets for chronic pain. Although there are currently no FDA-approved analgesics specifically targeting nAChRs, accumulating preclinical and clinical evidence suggest that selective ligands for alpha 7 (α7) nAChRs show potential for treating chronic pain, boasting a reduced incidence of side effects compared with other nicotinic receptor types. The recent structural resolution of human α7 nAChRs has confirmed their negative association with heightened pain, providing a valuable foundation for the development of targeted medications. This review presents a comprehensive overview, encompassing insights into the roles of α7 nAChRs derived from structural and functional studies, recent advancements in pharmacology, and investigations into their involvement in the pathophysiology of chronic pain. Moreover, the review addresses the variability in analgesic effects based on the type of receptor agonist and highlights the current research limitations. As such, this review offers potential therapeutic approaches for the development of innovative strategies for chronic pain management.

Insight into the pathophysiological advances and molecular mechanisms underlying cerebral stroke: current status.

Molecular pathways involved in cerebral stroke are diverse. The major pathophysiological events that are observed in stroke comprises of excitotoxicity, oxidative stress, mitochondrial damage, endoplasmic reticulum stress, cellular acidosis, blood-brain barrier disruption, neuronal swelling and neuronal network mutilation. Various biomolecules are involved in these pathways and several major proteins are upregulated and/or suppressed following stroke. Different types of receptors, ion channels and transporters are activated. Fluctuations in levels of various ions and neurotransmitters have been observed. Cells involved in immune responses and various mediators involved in neuro-inflammation get upregulated progressing the pathogenesis of the disease. Despite of enormity of the problem, there is not a single therapy that can limit infarction and neurological disability due to stroke. This is because of poor understanding of the complex interplay between these pathophysiological processes. This review focuses upon the past to present research on pathophysiological events that are involved in stroke and various factors that are leading to neuronal death following cerebral stroke. This will pave a way to researchers for developing new potent therapeutics that can aid in the treatment of cerebral stroke.

Direct Inhibition of BK Channels by Cannabidiol, One of the Principal Therapeutic Cannabinoids Derived from Cannabis sativa.

Cannabidiol (CBD), one of the main Cannabis sativa bioactive compounds, is utilized in the treatment of major epileptic syndromes. Its efficacy can be attributed to a multimodal mechanism of action that includes, as potential targets, several types of ion channels. In the brain, CBD reduces the firing frequency in rat hippocampal neurons, partly prolonging the duration of action potentials, suggesting a potential blockade of voltage-operated K+ channels. We postulate that this effect might involve the inhibition of the large-conductance voltage- and Ca2+-operated K+ channel (BK channel), which plays a role in the neuronal action potential's repolarization. Thus, we assessed the impact of CBD on the BK channel activity, heterologously expressed in HEK293 cells. Our findings, using the patch-clamp technique, revealed that CBD inhibits BK channel currents in a concentration-dependent manner with an IC50 of 280 nM. The inhibition is through a direct interaction, reducing both the unitary conductance and voltage-dependent activation of the channel. Additionally, the cannabinoid significantly delays channel activation kinetics, indicating stabilization of the closed state. These effects could explain the changes induced by CBD in action potential shape and duration, and they may contribute to the observed anticonvulsant activity of this cannabinoid.

Ruthenium red: Blocker or antagonist of TRPV channels?

Ruthenium red (RR) is a widely used inhibitor of Transient Receptor Potential (TRP) cation channels and other types of ion channels. Although RR has been generally accepted to inhibit TRP channels by physically blocking the ion permeation pathway, recent structural evidence suggests that it might also function as an antagonist, inducing conformational changes in the channel upon binding that result in closure of the pore. In a recent manuscript published in EMBO Reports, Ruth A. Pumroy and collaborators solve structures of TRPV2 and TRPV5 channels in the presence and absence of activators and RR. The data sheds light on the mechanism of inhibition by RR, while also opening new questions for further investigation.

Single shot detection of alterations across multiple ionic currents from assimilation of cell membrane dynamics

The dysfunction of ion channels is a causative factor in a variety of neurological diseases, thereby defining the implicated channels as key drug targets. The detection of functional changes in multiple specific ionic currents currently presents a challenge, particularly when the neurological causes are either a priori unknown, or are unexpected. Traditional patch clamp electrophysiology is a powerful tool in this regard but is low throughput. Here, we introduce a single-shot method for detecting alterations amongst a range of ion channel types from subtle changes in membrane voltage in response to a short chaotically driven current clamp protocol. We used data assimilation to estimate the parameters of individual ion channels and from these we reconstructed ionic currents which exhibit significantly lower error than the parameter estimates. Such reconstructed currents thereby become sensitive predictors of functional alterations in biological ion channels. The technique correctly predicted which ionic current was altered, and by approximately how much, following pharmacological blockade of BK, SK, A-type K+ and HCN channels in hippocampal CA1 neurons. We anticipate this assay technique could aid in the detection of functional changes in specific ionic currents during drug screening, as well as in research targeting ion channel dysfunction.

Exploring the Role of Surface and Mitochondrial ATP-Sensitive Potassium Channels in Cancer: From Cellular Functions to Therapeutic Potentials.

ATP-sensitive potassium (KATP) channels are found in plasma membranes and mitochondria. These channels are a type of ion channel that is regulated by the intracellular concentration of adenosine triphosphate (ATP) and other nucleotides. In cell membranes, they play a crucial role in linking metabolic activity to electrical activity, especially in tissues like the heart and pancreas. In mitochondria, KATP channels are involved in protecting cells against ischemic damage and regulating mitochondrial function. This review delves into the role of KATP channels in cancer biology, underscoring their critical function. Notably responsive to changes in cellular metabolism, KATP channels link metabolic states to electrical activity, a feature that becomes particularly significant in cancer cells. These cells, characterized by uncontrolled growth, necessitate unique metabolic and signaling pathways, differing fundamentally from normal cells. Our review explores the intricate roles of KATP channels in influencing the metabolic and ionic balance within cancerous cells, detailing their structural and operational mechanisms. We highlight the channels' impact on cancer cell survival, proliferation, and the potential of KATP channels as therapeutic targets in oncology. This includes the challenges in targeting these channels due to their widespread presence in various tissues and the need for personalized treatment strategies. By integrating molecular biology, physiology, and pharmacology perspectives, the review aims to enhance the understanding of cancer as a complex metabolic disease and to open new research and treatment avenues by focusing on KATP channels. This comprehensive approach provides valuable insights into the potential of KATP channels in developing innovative cancer treatments.

Experimental Research on the Influence of Ion Channels on the Healing of Skin Wounds in Rats

At the level of skin wounds, an electrical potential difference develops between the edges of the wound and the center of the wound, which favors the migration of cells in the process of their healing. Cells migrate in an electric field because they have a certain electrical membrane potential. This potential is due to differences in the transmembrane electrochemical gradient. The transmembrane electrochemical gradient is due to the migration of sodium, potassium, and calcium ions into the corresponding ion channels. If this is the case, the modification of the functionality of these ion channels should influence the membrane potential and, as a consequence, the wound healing process. In this experiment, we set out to investigate whether the chemical manipulation of ion channels by amiodarone influences the wound healing process. Amiodarone blocks several types of ion channels, but at different concentrations: at low concentrations, it blocks only potassium channels; at medium concentrations, potassium and calcium channels; and at high concentrations, it blocks potassium, calcium, and sodium channels. We worked on rats that were given experimental skin lesions and evaluated the influence of the healing of these lesions upon the topical administration of amiodarone in three concentrations, 200 nM, 2000 nM and 200,000 nM, compared to an untreated group and a group treated with benzyl alcohol, the amiodarone solvent. In our experimental conditions, low concentration amiodarone promoted wound healing both in terms of duration of healing and also in terms of speed of healing. This means that blocking some ions, possibly potassium channels, might promote wound healing.

Role of 5-hydroxytryptamine type 3 receptors in the regulation of anxiety reactions.

5-Hydroxytryptamine (5-HT) type 3 receptor (5-HT3R) is the only type of ligand-gated ion channel in the 5-HT receptor family. Through the high permeability of Na+, K+, and Ca2+ and activation of subsequent voltage-gated calcium channels (VGCCs), 5-HT3R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system (CNS). 5-HT3Rs are widely expressed in the medial prefrontal cortex (mPFC), amygdala (AMYG), hippocampus (HIP), periaqueductal gray (PAG), and other brain regions closely associated with anxiety reactions. They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions. 5-HT3Rs mediate the activation of the cholecystokinin (CCK) system in the AMYG, and the γ‍-aminobutyric acid (GABA) "disinhibition" mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons (IINs). In contrast, a 5-HT3R-induced GABA "disinhibition" mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects. 5-HT2R-mediated regulation of anxiety reactions are also activated by 5-HT3R-activated 5-HT release in the HIP and PAG. This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT3Rs. However, given the circuit specific modulation of 5-HT3Rs on emotion, systemic use of 5-HT3R agonism or antagonism alone seems unlikely to remedy anxiety, which deeply hinders the current clinical application of 5-HT3R drugs. Therefore, the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.

Transplantation of olfactory ensheathing cells can alleviate neuroinflammatory responses in rats with trigeminal neuralgia

Trigeminal neuralgia (TN) is a common form of facial pain, which primarily manifests as severe pain similar to facial acupuncture and electric shock. Olfactory ensheathing cells (OECs) are glial cells with high bioactivity; these cells are essential for the periodic regeneration of the olfactory nerve and have been utilized for the repair of nerve injuries. A member of the P2X receptor family, P2X7R, is an ion channel type receptor that has been confirmed to participate in various pain response processes. In this study, we transplanted OECs into trigeminal nerve–model rats with distal infraorbital nerve ligation to observe the therapeutic effect of transplanted OECs in rats. Additionally, we utilized the P2X7R-specific inhibitor brilliant blue G (BBG) to study the therapeutic mechanisms of cell transplantation. The facial mechanical pain threshold of these rats significantly increased following cell transplantation. The immunohistochemistry, immunoblotting, and RT-qPCR results demonstrated that the levels of P2X7R, (NOD)-like receptor protein-3 (NLRP3), nuclear factor-κB (NF-κB), interleukin (IL)-1β, and IL-18 in the trigeminal ganglion of rats treated with OEC transplantation or BBG treatment were significantly lower than those in the injured group without treatment. Overall, our results demonstrate that OEC transplantation can alleviate TN in rats, and it can reduce the expression of P2X7R related inflammatory factors in TN rats, reducing neuroinflammatory response in TG.

Nodopathy: clinic, diagnosis, treatment. Clinical description

AIM: Evaluation of the significance and possibilities of laboratory-instrumental diagnostic methods in establishing the diagnosis and selection of targeted therapy in patients with nodopathies.
 MATERIALS AND METHODS: System analysis of data from foreign and domestic literature with the presentation of a clinical case.
 RESULTS: Polyneuropathies are classified as demyelinating or axonal based on electrophysiological studies. However, in 2015, in addition to axonal and demyelinating neuropathies, it was proposed to distinguish a separate pathophysiological group — nodopathies. The pathogenesis of nodopathies may differ depending on the type of ion channels involved in the process, but always leads to a loss of excitability of the axon membrane; in the nodal region the membrane becomes inexcitable. Such neuropathies are characterized by transient conduction blocks followed by the development of axonal degeneration. Typical examples of nodopathies are acute motor axonal neuropathy, as well as multifocal motor neuropathy. Current pathophysiological understanding of specialized nodal regions (nodes of Ranvier) and associated axoglial proteins is growing. Hypotheses have been put forward about their role in the pathogenesis of immune-mediated attack on the peripheral myelinated axon. Recently, high titers of antibodies directed against a number of key adhesion molecules have been identified in both acute and chronic inflammatory neuropathies. These facts add to the differences in differential diagnosis between axonal and demyelinating peripheral neuropathies. New disease classification schemes based on seropositivity, improved electrophysiological and ultrasound classification, and identification of putative underlying pathological targets and mechanisms are being rapidly developed.
 CONCLUSION: Using our clinical example, we demonstrated the capabilities of laboratory and instrumental diagnostic methods in establishing a diagnosis in a patient with one of the forms of nodopathies — multifocal motor neuropathy.

The Involvement of Calcium Channels in the Endoplasmic Reticulum Membrane in Nonalcoholic Fatty Liver Disease Pathogenesis.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent and complex condition that affects millions of people globally. It occurs when fat, primarily triglycerides, accumulates in liver cells, leading to inflammation and damage. Calcium, an essential mineral, is involved in various physiological processes, including the regeneration process following liver injury. The endoplasmic reticulum (ER), a complex organelle involved in protein synthesis and lipid metabolism, regulates intracellular calcium levels. Dysregulation of this process can lead to calcium overload, oxidative stress, and cellular damage, all of which are hallmarks of NAFLD. Inositol 1,4,5-trisphosphate receptor (IP3R), a type of calcium ion channel, is found throughout the body, including the liver. IP3R is classified into three subtypes: IP3R1, IP3R2, and IP3R3, and it plays a critical role in regulating intracellular calcium levels. However, excessive calcium accumulation in the mitochondria due to an overload of calcium ions or increased IP3R activity can lead to NAFLD. Therefore, targeting calcium channels in the ER membrane may represent a promising therapeutic strategy for preventing and treating this increasingly prevalent metabolic disorder.It may help prevent mitochondrial calcium accumulation and reduce the risk of hepatic damage. This review article aimed to review the relationship between IP3R modulation and the pathogenicity of NAFLD, providing valuable insights to help researchers develop more effective treatments for the condition.

Single-cell RNAseq analysis of spinal locomotor circuitry in larval zebrafish

Identification of the neuronal types that form the specialized circuits controlling distinct behaviors has benefited greatly from the simplicity offered by zebrafish. Electrophysiological studies have shown that in addition to connectivity, understanding of circuitry requires identification of functional specializations among individual circuit components, such as those that regulate levels of transmitter release and neuronal excitability. In this study, we use single-cell RNA sequencing (scRNAseq) to identify the molecular bases for functional distinctions between motoneuron types that are causal to their differential roles in swimming. The primary motoneuron, in particular, expresses high levels of a unique combination of voltage-dependent ion channel types and synaptic proteins termed functional ‘cassettes.’ The ion channel types are specialized for promoting high-frequency firing of action potentials and augmented transmitter release at the neuromuscular junction, both contributing to greater power generation. Our transcriptional profiling of spinal neurons further assigns expression of this cassette to specific interneuron types also involved in the central circuitry controlling high-speed swimming and escape behaviors. Our analysis highlights the utility of scRNAseq in functional characterization of neuronal circuitry, in addition to providing a gene expression resource for studying cell type diversity.

Single-cell RNAseq analysis of spinal locomotor circuitry in larval zebrafish.

Identification of the neuronal types that form the specialized circuits controlling distinct behaviors has benefited greatly from the simplicity offered by zebrafish. Electrophysiological studies have shown that in addition to connectivity, understanding of circuitry requires identification of functional specializations among individual circuit components, such as those that regulate levels of transmitter release and neuronal excitability. In this study, we use single-cell RNA sequencing (scRNAseq) to identify the molecular bases for functional distinctions between motoneuron types that are causal to their differential roles in swimming. The primary motoneuron, in particular, expresses high levels of a unique combination of voltage-dependent ion channel types and synaptic proteins termed functional 'cassettes.' The ion channel types are specialized for promoting high-frequency firing of action potentials and augmented transmitter release at the neuromuscular junction, both contributing to greater power generation. Our transcriptional profiling of spinal neurons further assigns expression of this cassette to specific interneuron types also involved in the central circuitry controlling high-speed swimming and escape behaviors. Our analysis highlights the utility of scRNAseq in functional characterization of neuronal circuitry, in addition to providing a gene expression resource for studying cell type diversity.