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International Journal of Molecular... May 2024Cardiovascular diseases (CVDs), particularly heart failure, are major contributors to early mortality globally. Heart failure poses a significant public health problem,... (Review)
Review
Cardiovascular diseases (CVDs), particularly heart failure, are major contributors to early mortality globally. Heart failure poses a significant public health problem, with persistently poor long-term outcomes and an overall unsatisfactory prognosis for patients. Conventionally, treatments for heart failure have focused on lowering blood pressure; however, the development of more potent therapies targeting hemodynamic parameters presents challenges, including tolerability and safety risks, which could potentially restrict their clinical effectiveness. Adenosine has emerged as a key mediator in CVDs, acting as a retaliatory metabolite produced during cellular stress via ATP metabolism, and works as a signaling molecule regulating various physiological processes. Adenosine functions by interacting with different adenosine receptor (AR) subtypes expressed in cardiac cells, including AAR, AAR, AAR, and AAR. In addition to AAR, AAR has a multifaceted role in the cardiovascular system, since its activation contributes to reducing the damage to the heart in various pathological states, particularly ischemic heart disease, heart failure, and hypertension, although its role is not as well documented compared to other AR subtypes. Research on AAR signaling has focused on identifying the intricate molecular mechanisms involved in CVDs through various pathways, including G or G protein-dependent signaling, ATP-sensitive potassium channels, MAPKs, and G protein-independent signaling. Several AAR-specific agonists, such as piclidenoson and namodenoson, exert cardioprotective impacts during ischemia in the diverse animal models of heart disease. Thus, modulating AARs serves as a potential therapeutic approach, fueling considerable interest in developing compounds that target AARs as potential treatments for heart diseases.
Topics: Humans; Animals; Signal Transduction; Receptor, Adenosine A3; Heart Diseases; Adenosine A3 Receptor Agonists; Adenosine
PubMed: 38891948
DOI: 10.3390/ijms25115763 -
International Journal of Molecular... May 2024The sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin is increasingly used in the treatment of diabetes and heart failure. Dapagliflozin has been...
The sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin is increasingly used in the treatment of diabetes and heart failure. Dapagliflozin has been associated with reduced incidence of atrial fibrillation (AF) in clinical trials. We hypothesized that the favorable antiarrhythmic outcome of dapagliflozin use may be caused in part by previously unrecognized effects on atrial repolarizing potassium (K) channels. This study was designed to assess direct pharmacological effects of dapagliflozin on cloned ion channels K11.1, K1.5, K4.3, K2.1, K2.1, K3.1, and K17.1, contributing to , , , , and K currents. Human channels coded by , , , , , , and were heterologously expressed in oocytes, and currents were recorded using the voltage clamp technique. Dapagliflozin (100 µM) reduced K11.1 and K1.5 currents, whereas K2.1, K2.1, and K17.1 currents were enhanced. The drug did not significantly affect peak current amplitudes of K4.3 or K3.1 K channels. Biophysical characterization did not reveal significant effects of dapagliflozin on current-voltage relationships of study channels. In conclusion, dapagliflozin exhibits direct functional interactions with human atrial K channels underlying , , , and currents. Substantial activation of K2.1 and K17.1 currents could contribute to the beneficial antiarrhythmic outcome associated with the drug. Indirect or chronic effects remain to be investigated in vivo.
Topics: Humans; Glucosides; Sodium-Glucose Transporter 2 Inhibitors; Benzhydryl Compounds; Animals; Xenopus laevis; Potassium Channels; Oocytes; Sodium-Glucose Transporter 2
PubMed: 38891889
DOI: 10.3390/ijms25115701 -
Polymers May 2024This paper reports the successful development and application of an efficient method for quantifying Pb in aqueous samples using a smartphone-based colorimetric device...
This paper reports the successful development and application of an efficient method for quantifying Pb in aqueous samples using a smartphone-based colorimetric device with an imprinted polymer (IIP). The IIP was synthesized by modifying the previous study; using rhodizonate, 2-acrylamido-2-methylpropane sulfonic acid (AMPS), ,'-methylenebisacrylamide (MBA), and potassium persulfate (KPS). The polymers were then characterized. An absorption study was performed to determine the optimal conditions for the smartphone-based colorimetric device processing. The device consists of a black box (10 × 10 × 10 cm), which was designed to ensure repeatability of the image acquisition. The methodology involved the use of a smartphone camera to capture images of IIP previously exposed at Pb solutions with various concentrations, and color channel values were calculated (RGB, YMK HSVI). PLS multivariate regression was performed, and the optimum working range (0-10 mg L) was determined using seven principal components with a detection limit (LOD) of 0.215 mg L and R = 0.998. The applicability of a colorimetric sensor in real samples showed a coefficient of variation (% RSD) of less than 9%, and inductively coupled plasma mass spectrometry (ICP-MS) was applied as the reference method. These results confirmed that the quantitation smartphone-based colorimetric sensor is a suitable analytical tool for reliable on-site Pb monitoring.
PubMed: 38891469
DOI: 10.3390/polym16111523 -
Cells May 2024Pacemaking activity in substantia nigra dopaminergic neurons is generated by the coordinated activity of a variety of distinct somatodendritic voltage- and calcium-gated...
High-Resolution Proteomics Unravel a Native Functional Complex of Cav1.3, SK3, and Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in Midbrain Dopaminergic Neurons.
Pacemaking activity in substantia nigra dopaminergic neurons is generated by the coordinated activity of a variety of distinct somatodendritic voltage- and calcium-gated ion channels. We investigated whether these functional interactions could arise from a common localization in macromolecular complexes where physical proximity would allow for efficient interaction and co-regulations. For that purpose, we immunopurified six ion channel proteins involved in substantia nigra neuron autonomous firing to identify their molecular interactions. The ion channels chosen as bait were Cav1.2, Cav1.3, HCN2, HCN4, Kv4.3, and SK3 channel proteins, and the methods chosen to determine interactions were co-immunoprecipitation analyzed through immunoblot and mass spectrometry as well as proximity ligation assay. A macromolecular complex composed of Cav1.3, HCN, and SK3 channels was unraveled. In addition, novel potential interactions between SK3 channels and sclerosis tuberous complex (Tsc) proteins, inhibitors of mTOR, and between HCN4 channels and the pro-degenerative protein Sarm1 were uncovered. In order to demonstrate the presence of these molecular interactions in situ, we used proximity ligation assay (PLA) imaging on midbrain slices containing the substantia nigra, and we could ascertain the presence of these protein complexes specifically in substantia nigra dopaminergic neurons. Based on the complementary functional role of the ion channels in the macromolecular complex identified, these results suggest that such tight interactions could partly underly the robustness of pacemaking in dopaminergic neurons.
Topics: Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Proteomics; Dopaminergic Neurons; Animals; Small-Conductance Calcium-Activated Potassium Channels; Mesencephalon; Humans; Calcium Channels, L-Type; Mice; Substantia Nigra
PubMed: 38891076
DOI: 10.3390/cells13110944 -
The Journal of Headache and Pain Jun 2024Large conductance calcium-activated potassium (BK) channels have been implicated in the neurobiological underpinnings of migraine. Considering the clinical... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Large conductance calcium-activated potassium (BK) channels have been implicated in the neurobiological underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to examine whether MaxiPost (a BK channel opener) could induce migraine-like headache in persons with PPTH.
METHODS
This is a randomized double-blind, placebo-controlled, two-way crossover study from September 2023 to December 2023. Eligible participants were adults with PPTH after mild traumatic brain injury who reported having no personal history of migraine. The randomized participants received a single dose of either MaxiPost (0.05 mg/min) or placebo (isotonic saline) that was infused intravenously over 20 minutes. The two experiment sessions were scheduled at least one week apart to avoid potential carryover effects. The primary endpoint was the induction of migraine-like headache after MaxiPost as compared to placebo within 12 hours of drug administration. The secondary endpoint was the area under the curve (AUC) values for headache intensity scores between MaxiPost and placebo over the same 12-hour observation period.
RESULTS
Twenty-one adult participants (comprising 14 females and 7 males) with PPTH were enrolled and completed both experiment sessions. The proportion of participants who developed migraine-like headache was 11 (52%) of 21 participants after MaxiPost infusion, in contrast to four (19%) participants following placebo (P = .02). Furthermore, the median headache intensity scores, represented by AUC values, were higher following MaxiPost than after placebo (P < .001).
CONCLUSIONS
Our results indicate that BK channel opening can elicit migraine-like headache in persons with PPTH. Thus, pharmacologic blockade of BK channels might present a novel avenue for drug discovery. Additional investigations are nonetheless needed to confirm these insights and explore the therapeutic prospects of BK channel blockers in managing PPTH.
GOV IDENTIFIER
NCT05378074.
Topics: Humans; Female; Male; Adult; Double-Blind Method; Cross-Over Studies; Post-Traumatic Headache; Migraine Disorders; Middle Aged; Brain Concussion; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Young Adult; Large-Conductance Calcium-Activated Potassium Channels
PubMed: 38890563
DOI: 10.1186/s10194-024-01808-0 -
Nature Communications Jun 2024Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical...
Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating charges past the charge transfer center is accompanied by concomitant unwinding of the inner end of the S4 and S5 helices, disrupting the tight gating interface observed in the Closed state structure. This helix-coil transition at the intracellular gating interface accompanies a concerted iris-like dilation of the pore helices and underlies the reversed voltage dependence of HCN channels.
Topics: Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Humans; Cryoelectron Microscopy; Ion Channel Gating; Potassium Channels; Models, Molecular; Membrane Potentials
PubMed: 38890331
DOI: 10.1038/s41467-024-49599-x -
Biomedicine & Pharmacotherapy =... Jun 2024Endothelial dysfunction contributes to the pathogenesis of Takotsubo syndrome (TTS). However, the exact mechanism underlying endothelial dysfunction in the setting of...
Endothelial dysfunction contributes to the pathogenesis of Takotsubo syndrome (TTS). However, the exact mechanism underlying endothelial dysfunction in the setting of TTS has not been completely clarified. This study aims to investigate the roles of angiotensin II (Ang II) and intermediate-conductance Ca-activated K (SK4) channels in catecholamine-induced endothelial dysfunction. Human cardiac microvascular endothelial cells (HCMECs) were exposed to 100 µM epinephrine (Epi), mimicking the setting of TTS. Epi treatment increased the ET-1 concentration and reduced NO levels in HCMECs. Importantly, the effects of Epi were found to be mitigated in the presence of Ang II receptor blockers. Furthermore, Ang II mimicked Epi effects on ET-1 and NO production. Additionally, Ang II inhibited tube formation and increased cell apoptosis. The effects of Ang II could be reversed by an SK4 activator NS309 and mimicked by an SK4 channel blocker TRAM-34. Ang II also inhibited the SK4 channel current (I) without affecting its expression level. Ang II could depolarize the cell membrane potential. Ang II promoted ROS release and reduced protein kinase A (PKA) expression. A ROS blocker prevented Ang II effect on I. The PKA activator Sp-8-Br-cAMPS increased SK4 channel currents. Epinephrine enhanced the activity of ACE by activating the α1 receptor/Gq/PKC signal pathway, thereby promoting the secretion of Ang II. The study suggested that high-level catecholamine can increase Ang II release from endothelial cells by α1 receptors/Gq/PKC signal pathway. Ang II can inhibit SK4 channel current by increasing ROS generation and reducing PKA expression, thereby contributing to endothelial dysfunction.
PubMed: 38889637
DOI: 10.1016/j.biopha.2024.116928 -
Fly Dec 2024Adenosine-to-inosine (A-to-I) RNA editing recodes the genome and confers flexibility for the organisms to adapt to the environment. It is believed that RNA recoding...
Adenosine-to-inosine (A-to-I) RNA editing recodes the genome and confers flexibility for the organisms to adapt to the environment. It is believed that RNA recoding sites are well suited for facilitating adaptive evolution by increasing the proteomic diversity in a temporal-spatial manner. The function and essentiality of a few conserved recoding sites are recognized. However, the experimentally discovered functional sites only make up a small corner of the total sites, and there is still the need to expand the repertoire of such functional sites with bioinformatic approaches. In this study, we define a new category of RNA editing sites termed 'conserved editing with non-conserved recoding' and systematically identify such sites in editomes, figuring out their selection pressure and signals of adaptation at inter-species and intra-species levels. Surprisingly, conserved editing sites with non-conserved recoding are not suppressed and are even slightly overrepresented in . DNA mutations leading to such cases are also favoured during evolution, suggesting that the function of those recoding events in different species might be diverged, specialized, and maintained. Finally, structural prediction suggests that such recoding in potassium channel Shab might increase ion permeability and compensate the effect of low temperature. In conclusion, conserved editing with non-conserved recoding might be functional as well. Our study provides novel aspects in considering the adaptive evolution of RNA editing sites and meanwhile expands the candidates of functional recoding sites for future validation.
Topics: Animals; RNA Editing; Inosine; Drosophila; Adenosine; Drosophila melanogaster; Evolution, Molecular; Drosophila Proteins
PubMed: 38889318
DOI: 10.1080/19336934.2024.2367359 -
Microbiome Jun 2024Despite serious health and social consequences, effective intervention strategies for habitual alcohol binge drinking are lacking. The development of novel therapeutic...
BACKGROUND
Despite serious health and social consequences, effective intervention strategies for habitual alcohol binge drinking are lacking. The development of novel therapeutic and preventative approaches is highly desirable. Accumulating evidence in the past several years has established associations between the gut microbiome and microbial metabolites with drinking behavior, but druggable targets and their underlying mechanism of action are understudied.
RESULTS
Here, using a drink-in-the-dark mouse model, we identified a microbiome metabolite-based novel treatment (sodium valerate) that can reduce excessive alcohol drinking. Sodium valerate is a sodium salt of valeric acid short-chain fatty acid with a similar structure as γ-aminobutyric acid (GABA). Ten days of oral sodium valerate supplementation attenuates excessive alcohol drinking by 40%, reduces blood ethanol concentration by 53%, and improves anxiety-like or approach-avoidance behavior in male mice, without affecting overall food and water intake. Mechanistically, sodium valerate supplementation increases GABA levels across stool, blood, and amygdala. It also significantly increases H4 acetylation in the amygdala of mice. Transcriptomics analysis of the amygdala revealed that sodium valerate supplementation led to changes in gene expression associated with functional pathways including potassium voltage-gated channels, inflammation, glutamate degradation, L-DOPA degradation, and psychological behaviors. 16S microbiome profiling showed that sodium valerate supplementation shifts the gut microbiome composition and decreases microbiome-derived neuroactive compounds through GABA degradation in the gut microbiome.
CONCLUSION
Our findings suggest that sodium valerate holds promise as an innovative therapeutic avenue for the reduction of habitual binge drinking, potentially through multifaceted mechanisms. Video Abstract.
Topics: Animals; Male; Mice; Gastrointestinal Microbiome; gamma-Aminobutyric Acid; Fatty Acids, Volatile; Alcohol Drinking; Amygdala; Ethanol; Mice, Inbred C57BL; Disease Models, Animal; Binge Drinking; Pentanoic Acids
PubMed: 38886761
DOI: 10.1186/s40168-024-01829-6 -
Nature Communications Jun 2024The renal epithelium is sensitive to changes in blood potassium (K). We identify the basolateral K channel, Kir4.2, as a mediator of the proximal tubule response to K...
The renal epithelium is sensitive to changes in blood potassium (K). We identify the basolateral K channel, Kir4.2, as a mediator of the proximal tubule response to K deficiency. Mice lacking Kir4.2 have a compensated baseline phenotype whereby they increase their distal transport burden to maintain homeostasis. Upon dietary K depletion, knockout animals decompensate as evidenced by increased urinary K excretion and development of a proximal renal tubular acidosis. Potassium wasting is not proximal in origin but is caused by higher ENaC activity and depends upon increased distal sodium delivery. Three-dimensional imaging reveals Kir4.2 knockouts fail to undergo proximal tubule expansion, while the distal convoluted tubule response is exaggerated. AKT signaling mediates the dietary K response, which is blunted in Kir4.2 knockouts. Lastly, we demonstrate in isolated tubules that AKT phosphorylation in response to low K depends upon mTORC2 activation by secondary changes in Cl transport. Data support a proximal role for cell Cl which, as it does along the distal nephron, responds to K changes to activate kinase signaling.
Topics: Animals; Proto-Oncogene Proteins c-akt; Potassium Channels, Inwardly Rectifying; TOR Serine-Threonine Kinases; Signal Transduction; Mice, Knockout; Potassium; Kidney Tubules, Proximal; Mice; Mechanistic Target of Rapamycin Complex 2; Phosphorylation; Male; Chlorides; Mice, Inbred C57BL
PubMed: 38886379
DOI: 10.1038/s41467-024-49562-w