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Genes May 2024The current investigation endeavors to identify differentially expressed alternatively spliced (DAS) genes that exhibit concordant expression with splicing factors (SFs)...
The current investigation endeavors to identify differentially expressed alternatively spliced (DAS) genes that exhibit concordant expression with splicing factors (SFs) under diverse multifactorial abiotic stress combinations in Arabidopsis seedlings. SFs serve as the post-transcriptional mechanism governing the spatiotemporal dynamics of gene expression. The different stresses encompass variations in salt concentration, heat, intensive light, and their combinations. Clusters demonstrating consistent expression profiles were surveyed to pinpoint DAS/SF gene pairs exhibiting concordant expression. Through rigorous selection criteria, which incorporate alignment with documented gene functionalities and expression patterns observed in this study, four members of the serine/arginine-rich (SR) gene family were delineated as SFs concordantly expressed with six DAS genes. These regulated SF genes encompass , -like, , and -like. The identified concordantly expressed DAS genes encode diverse proteins such as the 26.5 kDa heat shock protein, chaperone protein DnaJ, potassium channel GORK, calcium-binding EF hand family protein, DEAD-box RNA helicase, and 1-aminocyclopropane-1-carboxylate synthase 6. Among the concordantly expressed DAS/SF gene pairs, /-box RNA helicase, and -like/ emerge as promising candidates, necessitating further examinations to ascertain whether these SFs orchestrate splicing of the respective DAS genes. This study contributes to a deeper comprehension of the varied responses of the splicing machinery to abiotic stresses. Leveraging these DAS/SF associations shows promise for elucidating avenues for augmenting breeding programs aimed at fortifying cultivated plants against heat and intensive light stresses.
Topics: Arabidopsis; Alternative Splicing; Gene Expression Regulation, Plant; Arabidopsis Proteins; Stress, Physiological; Seedlings; RNA Splicing Factors
PubMed: 38927612
DOI: 10.3390/genes15060675 -
Biomolecules Jun 2024Atherosclerosis (AS) has become the leading cause of cardiovascular disease worldwide. Our previous study had observed that (Nb) infection or its derived products could...
Anti-Inflammatory Responses Produced with -Derived Uridine via the Mitochondrial ATP-Sensitive Potassium Channel and Its Anti-Atherosclerosis Effect in an Apolipoprotein E Gene Knockout Mouse Model.
Atherosclerosis (AS) has become the leading cause of cardiovascular disease worldwide. Our previous study had observed that (Nb) infection or its derived products could inhibit AS development by inducing an anti-inflammatory response. We performed a metabolic analysis to screen Nb-derived metabolites with anti-inflammation activity and evaluated the AS-prevention effect. We observed that the metabolite uridine had higher expression levels in mice infected with the Nb and ES (excretory-secretory) products and could be selected as a key metabolite. ES and uridine interventions could reduce the pro-inflammatory responses and increase the anti-inflammatory responses in vitro and in vivo. The apolipoprotein E gene knockout (ApoE) mice were fed with a high-fat diet for the AS modeling. Following the in vivo intervention, ES products or uridine significantly reduced serum and liver lipid levels, alleviated the formation of atherosclerosis, and reduced the pro-inflammatory responses in serum or plaques, while the anti-inflammatory responses showed opposite trends. After blocking with 5-HD (5-hydroxydecanoate sodium) in vitro, the mRNA levels of M2 markers were significantly reduced. When blocked with 5-HD in vivo, the degree of atherosclerosis was worsened, the pro-inflammatory responses were increased compared to the uridine group, while the anti-inflammatory responses decreased accordingly. Uridine, a key metabolite from , showed anti-inflammatory and anti-atherosclerotic effects in vitro and in vivo, which depend on the activation of the mitochondrial ATP-sensitive potassium channel.
Topics: Animals; Mice; Atherosclerosis; Uridine; Anti-Inflammatory Agents; Nippostrongylus; Mice, Knockout; Apolipoproteins E; Disease Models, Animal; KATP Channels; Male; Mitochondria
PubMed: 38927075
DOI: 10.3390/biom14060672 -
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; Small-Conductance Calcium-Activated Potassium Channels; Neuralgia; Epigenesis, Genetic; Male; Amygdala; Rats; Rats, Sprague-Dawley; DNA Methylation; Behavior, Animal; Neurons
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 -
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 -
Proceedings of the National Academy of... Jul 2024HCN1-4 channels are the molecular determinants of the I/I current that crucially regulates cardiac and neuronal cell excitability. HCN dysfunctions lead to sinoatrial...
HCN1-4 channels are the molecular determinants of the I/I current that crucially regulates cardiac and neuronal cell excitability. HCN dysfunctions lead to sinoatrial block (HCN4), epilepsy (HCN1), and chronic pain (HCN2), widespread medical conditions awaiting subtype-specific treatments. Here, we address the problem by solving the cryo-EM structure of HCN4 in complex with ivabradine, to date the only HCN-specific drug on the market. Our data show ivabradine bound inside the open pore at 3 Å resolution. The structure unambiguously proves that Y507 and I511 on S6 are the molecular determinants of ivabradine binding to the inner cavity, while F510, pointing outside the pore, indirectly contributes to the block by controlling Y507. Cysteine 479, unique to the HCN selectivity filter (SF), accelerates the kinetics of block. Molecular dynamics simulations further reveal that ivabradine blocks the permeating ion inside the SF by electrostatic repulsion, a mechanism previously proposed for quaternary ammonium ions.
Topics: Ivabradine; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Molecular Dynamics Simulation; Humans; Cryoelectron Microscopy; Animals; Potassium Channels; Muscle Proteins
PubMed: 38917012
DOI: 10.1073/pnas.2402259121 -
Proceedings of the National Academy of... Jul 2024Spinal cord dorsal horn inhibition is critical to the processing of sensory inputs, and its impairment leads to mechanical allodynia. How this decreased inhibition...
Spinal cord dorsal horn inhibition is critical to the processing of sensory inputs, and its impairment leads to mechanical allodynia. How this decreased inhibition occurs and whether its restoration alleviates allodynic pain are poorly understood. Here, we show that a critical step in the loss of inhibitory tone is the change in the firing pattern of inhibitory parvalbumin (PV)-expressing neurons (PVNs). Our results show that PV, a calcium-binding protein, controls the firing activity of PVNs by enabling them to sustain high-frequency tonic firing patterns. Upon nerve injury, PVNs transition to adaptive firing and decrease their PV expression. Interestingly, decreased PV is necessary and sufficient for the development of mechanical allodynia and the transition of PVNs to adaptive firing. This transition of the firing pattern is due to the recruitment of calcium-activated potassium (SK) channels, and blocking them during chronic pain restores normal tonic firing and alleviates chronic pain. Our findings indicate that PV is essential for controlling the firing pattern of PVNs and for preventing allodynia. Developing approaches to manipulate these mechanisms may lead to different strategies for chronic pain relief.
Topics: Parvalbumins; Animals; Chronic Pain; Mice; Neurons; Hyperalgesia; Male; Action Potentials; Small-Conductance Calcium-Activated Potassium Channels
PubMed: 38916998
DOI: 10.1073/pnas.2403777121 -
BioRxiv : the Preprint Server For... Jun 2024The vestibular nerve is comprised of neuron sub-groups with diverse functions related to their intrinsic biophysical properties. This diversity is partly due to...
The vestibular nerve is comprised of neuron sub-groups with diverse functions related to their intrinsic biophysical properties. This diversity is partly due to differences in the types and numbers of low-voltage-gated potassium channels found in the neurons' membranes. Expression for some low-voltage gated ion channels like KCNQ4 is upregulated during early post-natal development; suggesting that ion channel composition and neuronal diversity may be shaped by hair cell activity. This idea is consistent with recent work showing that glutamatergic input from hair cells is necessary for the normal diversification auditory neurons. To test if biophysical diversity is similarly dependent on glutamatergic input in vestibular neurons, we examined the maturation of the vestibular epithelium and ganglion neurons in mice whose hair cell synapses lack glutamate. Despite lacking glutamatergic input, the knockout mice showed no notable balance deficits and crossed challenging balance beams with little difficulty. Immunolabeling of the vestibular epithelia showed normal development as indicated by an identifiable striolar zone with calyceal terminals labeled by molecular marker calretinin, and normal expression of KCNQ4 by the end of the second post-natal week. We found similar numbers of Type I and Type II hair cells in the knockout and wildtype animals, regardless of epithelial zone. Thus, the presumably quiescent Type II hair cells are not cleared from the epithelium. Patch-clamp recordings showed that biophysical diversity of vestibular ganglion neurons in the mice is comparable to that found in wildtype controls, with a similar range firing patterns at both immature and juvenile ages. However, our results suggest a subtle biophysical alteration to the largest ganglion cells (putative somata of central zone afferents); those in the knockout had smaller net conductance and were more excitable than those in the wild type. Thus, unlike in the auditory nerve, glutamatergic signaling is unnecessary for producing biophysical diversity in vestibular ganglion neurons. And yet, because the input signals from vestibular hair cells are complex and not solely reliant on quantal release of glutamate, whether diversity of vestibular ganglion neurons is simply hardwired or regulated by a more complex set of input signals remains to be determined.
PubMed: 38915604
DOI: 10.1101/2024.06.12.597464 -
BioRxiv : the Preprint Server For... Jun 2024Ion channels are essential for proper morphogenesis of the craniofacial skeleton. However, the molecular mechanisms underlying this phenomenon are unknown. Loss of the...
UNLABELLED
Ion channels are essential for proper morphogenesis of the craniofacial skeleton. However, the molecular mechanisms underlying this phenomenon are unknown. Loss of the potassium channel disrupts Bone Morphogenetic Protein (BMP) signaling within the developing palate. BMP signaling is essential for the correct development of several skeletal structures, including the palate, though little is known about the mechanisms that govern BMP secretion. We introduce a tool to image the release of bone morphogenetic protein 4 (BMP4) from mammalian cells. Using this tool, we show that depolarization induces BMP4 release from mouse embryonic palate mesenchyme cells in a calcium-dependent manner. We show native transient changes in intracellular calcium occur in cranial neural crest cells, the cells from which embryonic palate mesenchyme derives. Waves of transient changes in intracellular calcium suggest that these cells are electrically coupled and may temporally coordinate BMP release. These transient changes in intracellular calcium persist in palate mesenchyme cells from embryonic day (E) 9.5 to 13.5 mice. Disruption of significantly decreases the amplitude of calcium transients and the ability of cells to secrete BMP. Together, these data suggest that temporal control of developmental cues is regulated by ion channels, depolarization, and changes in intracellular calcium for mammalian craniofacial morphogenesis.
SUMMARY
We show that embryonic palate mesenchyme cells undergo transient changes in intracellular calcium. Depolarization of these cells induces BMP4 release suggesting that ion channels are a node in BMP4 signaling.
PubMed: 38915514
DOI: 10.1101/2024.06.11.598333 -
Hypertension Research : Official... Jun 2024Hesperetin is one of the prominent flavonoids found in citrus fruit. Several research studies have reported that hesperetin can promote vasodilation in vascular tissue...
Hesperetin is one of the prominent flavonoids found in citrus fruit. Several research studies have reported that hesperetin can promote vasodilation in vascular tissue by increasing the level of nitric oxide and cyclic nucleotides. However, these may not be the only pathway for hesperetin to exert its vasodilatory effect. In addition to vasodilation, hesperetin has been found to carry an antihypertensive effect through intraperitoneal injection, although no study has comprehensively investigated the antihypertensive effect of hesperetin through oral administration. Therefore, this study aimed to determine the possible mechanism pathways involved in hesperetin-induced vasodilation and investigated its antihypertensive effects on hypertensive rats' model via oral administration. The ex vivo experimental findings showed that the NO/sGC/cGMP signalling pathway was involved in hesperetin-mediated vasodilation. Moreover, hesperetin activated the AC/cAMP/PKA pathway through PGI and activated the β-adrenergic receptor. Hesperetin can act as a voltage-gated potassium channel (K) and ATP-sensitive potassium channel (K) opener. The intracellular calcium in vascular smooth muscle was reduced by hesperetin through blocking the voltage-operated calcium channels (VOCC) and inositol triphosphate receptor (IPR). In the in vivo assessment, hesperetin shows a significant decrease in Spontaneously Hypertensive rats' blood pressure following 21 days of oral treatment. The sub-chronic toxicity assessment demonstrated that hesperetin exhibited no deleterious effects on the body weights, clinical biochemistry and haematological profile of Sprague-Dawley rats. This study implies that hesperetin holds promise as a potential medication for hypertension treatment, devoid of undesirable side effects.
PubMed: 38914702
DOI: 10.1038/s41440-024-01652-4