Cesar Millan-Pacheco, Iris N Serratos, Gerardo J Félix-Martínez, Gerardo Blancas-Flores, Alejandra Osorno, Rafael Godínez
{"title":"Cholesterol Concentration in Cell Membranes and its Impact on Receptor-Ligand Interaction: A Computational Study of ATP-Sensitive Potassium Channels and ATP Binding.","authors":"Cesar Millan-Pacheco, Iris N Serratos, Gerardo J Félix-Martínez, Gerardo Blancas-Flores, Alejandra Osorno, Rafael Godínez","doi":"10.1007/s00232-025-00345-4","DOIUrl":"https://doi.org/10.1007/s00232-025-00345-4","url":null,"abstract":"<p><p>This work describes a computer study that looks at how different amounts of cholesterol (0%, 25%, and 50%) in cell membranes change the relationship between ATP and the K<sub>ATP</sub> channel. This could explain why pancreatic beta-cells secrete insulin differently. We use computer simulations of molecular dynamics, calculations of binding free energy, and an integrated oscillator model to look at the electrical activity of beta-cells. There is a need for this kind of multiscale approach right now because cholesterol plays a part in metabolic syndrome and early type 2 diabetes. Our results showed that the increase in cholesterol concentration in the cell membrane affects the electrostatic interactions between ATP and the K<sub>ATP</sub> channel, especially with charged residues in the binding site. Cholesterol can influence the properties of a membrane, including its local charge distribution near the channel. This affects the electrostatic environment around the ATP-binding site, increasing the affinity of ATP for the channel as our results indicated from 0 to 25 and 50% cholesterol (- 141 to - 113 kJ/mol, respectively). Simulating this change in the affinity to ATP of the K<sub>ATP</sub> channels in a model of the electrical activity of the pancreatic beta-cell indicates that even a minimal increase could produce hyperinsulism. The study answers an important research question about how the structure of the membrane affects the function of K<sub>ATP</sub> and, in turn, insulin releases a common feature of metabolic syndrome and early stages of type 2 diabetes.</p>","PeriodicalId":50129,"journal":{"name":"Journal of Membrane Biology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bill H T Ho, Bradley A Spicer, Michelle A Dunstone
{"title":"Action of the Terminal Complement Pathway on Cell Membranes.","authors":"Bill H T Ho, Bradley A Spicer, Michelle A Dunstone","doi":"10.1007/s00232-025-00343-6","DOIUrl":"https://doi.org/10.1007/s00232-025-00343-6","url":null,"abstract":"<p><p>The complement pathway is one of the most ancient elements of the host's innate response and includes a set of protein effectors that rapidly react against pathogens. The late stages of the complement reaction are broadly categorised into two major outcomes. Firstly, C5a receptors, expressed on membranes of host cells, are activated by C5a to generate pro-inflammatory responses. Secondly, target cells are lysed by a hetero-oligomeric pore known as the membrane attack complex (MAC) that punctures the cellular membrane, causing ion and osmotic flux. Generally, several membrane-bound and soluble inhibitors protect the host membrane from complement damage. This includes inhibitors against the MAC, such as clusterin and CD59. This review addresses the most recent molecular and structural insights behind the activation and modulation of the integral membrane proteins, the C5a receptors (C5aR1 and C5aR2), as well as the regulation of MAC assembly. The second aspect of the review focuses on the molecular basis behind inflammatory diseases that are reflective of failure to regulate the terminal complement effectors. Although each arm is unique in its function, both pathways may share similar outcomes in these diseases. As such, the review outlines potential synergy and crosstalk between C5a receptor activation and MAC-mediated cellular responses.</p>","PeriodicalId":50129,"journal":{"name":"Journal of Membrane Biology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charles S Springer, Martin M Pike, Thomas M Barbara
{"title":"Metabolic Energy is Stored in a Homeostatic Trans-Membrane Water Barochemical Gradient.","authors":"Charles S Springer, Martin M Pike, Thomas M Barbara","doi":"10.1007/s00232-024-00332-1","DOIUrl":"https://doi.org/10.1007/s00232-024-00332-1","url":null,"abstract":"<p><p>Trans-membrane water transport and co-transport is ubiquitous in cell biology. Integrated over all the cell's H<sub>2</sub>O transporters and co-transporters, the rate of homeostatic, bidirectional trans-cytolemmal water \"exchange\" is synchronized with the metabolic rate of the crucial Na<sup>+</sup>,K<sup>+</sup>-ATPase (NKA) enzyme: the active trans-membrane water cycling (AWC) phenomenon. Is AWC futile, or is it consequential? Conservatively representative literature metabolomic and proteinomic results enable comprehensive free energy (ΔG) calculations for the many transport reactions with known water stoichiometries. Including established intracellular pressure (P<sub>i</sub>) magnitudes, these reveal an outward trans-membrane H<sub>2</sub>O barochemical ΔG gradient comparable to that of the well-known inward Na<sup>+</sup> electrochemical ΔG gradient. For most co-influxers, these two gradients are finely balanced to maintain intracellular metabolite concentration values near their consuming enzyme Michaelis constants. Our analyses include glucose, glutamate<sup>-</sup>, gamma-aminobutyric acid (GABA), and lactate<sup>-</sup> transporters. 2%-4% P<sub>i</sub> alterations can lead to disastrous metabolite concentrations. For the neurotransmitters glutamate<sup>-</sup> and GABA, very small astrocytic P<sub>i</sub> changes can allow/disallow synaptic transmission. Unlike the Na<sup>+</sup> and K<sup>+</sup> electrochemical steady-states, the H<sub>2</sub>O barochemical steady-state is in (or near) chemical equilibrium. The analyses show why the presence of aquaporins (AQPs) does not dissipate trans-membrane pressure gradients. A feedback loop inherent in the opposing Na<sup>+</sup> electrochemical and H<sub>2</sub>O barochemical gradients regulates AQP-catalyzed water flux as integral to AWC. A re-consideration of the underlying nature of P<sub>i</sub> is also necessary. AWC is not a futile cycle but is inherent to the cell's \"NKA system\"-a new, fundamental aspect of biology. Metabolic energy is stored in the trans-membrane water barochemical gradient.</p>","PeriodicalId":50129,"journal":{"name":"Journal of Membrane Biology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143505775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Schisandrin B Improves Mitochondrial Function and Inhibits HT22 Cell Apoptosis by Regulating Sirt3 Protein.","authors":"Fei Hu, Songlin Tong, Hongming Xu","doi":"10.1007/s00232-025-00340-9","DOIUrl":"https://doi.org/10.1007/s00232-025-00340-9","url":null,"abstract":"<p><p>Neurological diseases refer to pathological changes that occur in the brain, spinal cord, and peripheral nerves. Their etiologies are complex, treatment outcomes are poor, and prognoses are unfavorable. Therefore, how to improve the treatment efficacy of neurological diseases is an urgent problem to be addressed in current clinical practice. Schisandrin B, a commonly used traditional Chinese medicine in clinical settings, has anti-tumor, anti-inflammatory, and wound-healing promoting effects. However, there are relatively few studies on its application in the treatment of neurological diseases. In this study, HT22 nerve cells were cultured, and an injury model was constructed by applying H<sub>2</sub>O<sub>2</sub> stimulation to explore the protective effect of Schisandrin B on these cells. The research results showed that compared with the H<sub>2</sub>O<sub>2</sub> group, Schisandrin B could significantly increase the viability (30.872%) and migration ability (42.756%) of HT22 cells, and inhibit the apoptosis of HT22 cells (22.817%). Further exploration of the mechanism revealed that Schisandrin B regulated the mitochondrial dynamic balance and membrane potential level of HT22 cells by upregulating the expression of Sirt3 protein, enhanced the mitochondrial energy metabolism (with an increase of 53.411% in ATP production), and maintained the integrity of the quantity and structure of mitochondria, ultimately exerting a protective effect on HT22 cells.</p>","PeriodicalId":50129,"journal":{"name":"Journal of Membrane Biology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Virjinia Doltchinkova, Victoria Vitkova, Ognyan Petkov, Meglena Kitanova, Angelina Stoyanova-Ivanova, Siya Lozanova, Avgust Ivanov, Chavdar Roumenin
{"title":"Gamma-Aminobutyric Acid Action on Membrane and Electrical Properties of Synaptosomes and Model Lipid Bilayers.","authors":"Virjinia Doltchinkova, Victoria Vitkova, Ognyan Petkov, Meglena Kitanova, Angelina Stoyanova-Ivanova, Siya Lozanova, Avgust Ivanov, Chavdar Roumenin","doi":"10.1007/s00232-025-00339-2","DOIUrl":"https://doi.org/10.1007/s00232-025-00339-2","url":null,"abstract":"<p><p>Dysfunction of the main inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is the underlying reason behind many neurological disorders including Alzheimer's and Huntington's diseases, autism spectrum disorders, anxiety, depression, hypertension, and cardiovascular diseases, among others. Here, we address neurotransmitter-induced alterations of synaptosomal and model membrane electrical properties for elucidating membrane-related biophysical mechanisms of neurological disorders. We focus on membrane surface characteristics of the pinched off nerve endings synaptosomes, which for decades have been a powerful tool in neurobiology. Microelectrophoretic measurements of GABA-treated negatively charged synaptosomes from rat cerebral cortex reveal lower negative zeta potential as a result of reduced electrical charge on the membrane surface at (1-4 h) after isolation. Conversely, enhancement of the surface parameters of synaptosomes (17-22 h) post isolation is obtained due to additional negatively exposed groups on the surface of the vesicles. The electrical properties of bilayer lipid membranes are probed by electrochemical impedance spectroscopy, reporting as light increase of the membrane electrical capacitance in the presence of GABA, likely related to membrane thinning and dielectric permittivity alterations. The neurotransmitter inhibits sodium-potassium as well as the total ATPase activity and slightly enhances magnesium-ATPase of native synaptic membranes. At low (pM) GABA concentrations the activity of acetylcholinesterase (AChE) in synaptic membranes increases. AChE inhibition is reported at higher GABA concentrations. The relation between the surface electrical properties of cells and the enzymatic activity of brain ATPases and AChE, as examined here, are expected to be helpful in the elucidation of membrane-mediated molecular mechanisms relevant to neurological disorders and conditions.</p>","PeriodicalId":50129,"journal":{"name":"Journal of Membrane Biology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structural Dynamics of the Slide Helix of Inactive/Closed Conformation of KirBac1.1 in Micelles and Membranes: A Fluorescence Approach.","authors":"Arpan Bysack, Chandrima Jash, H Raghuraman","doi":"10.1007/s00232-024-00335-y","DOIUrl":"10.1007/s00232-024-00335-y","url":null,"abstract":"<p><p>Inward rectifying potassium (Kir) channels play a critical role in maintaining the resting membrane potential and cellular homeostasis. The high-resolution crystal structure of homotetrameric KirBac1.1 in detergent micelles provides a snapshot of the closed state. Similar to micelles, KirBac1.1 is reported to be in the inactive/closed conformation in POPC membranes. The slide helix of KirBac1.1 is an important structural motif that regulates channel gating. Despite the importance of slide helix in lipid-dependent gating, conflicting models have emerged for the location of slide helix and its structural dynamics in membrane mimetics is poorly understood. Here, we monitored the structural dynamics of the slide helix (residues 46-57) of KirBac1.1 in both DM micelles and POPC membranes utilizing various site-directed fluorescence approaches. We show, using ACMA-based liposome-flux assay, the cysteine mutants of the slide helix are not functional, ensuring the inactive/closed conformation in POPC membranes similar to wild-type channel. Time-resolved fluorescence and water accessibility measurements of NBD-labeled single-cysteine mutants of slide-helix residues suggest that the location of the slide helix at the interfacial region might be shallower in membranes compared to micelles. Interestingly, the slide helix of KirBac1.1 is more dynamic in the physiologically relevant membrane environment, which is accompanied by a differential hydration dynamics throughout the slide helix. Further, REES and lifetime distribution analyses suggest significant changes in conformational heterogeneity of the slide helix in membrane mimetics. Overall, our results give an insight into how membrane mimetics affect the organization and dynamics of slide helix of the closed state of KirBac1.1, and highlight the importance of lipid-protein interactions in membranes.</p>","PeriodicalId":50129,"journal":{"name":"Journal of Membrane Biology","volume":" ","pages":"97-112"},"PeriodicalIF":2.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anwaar S Chaudary, Yanglin Guo, Yuri N Utkin, Maryam Barancheshmeh, Ruben K Dagda, Edward S Gasanoff
{"title":"Sphingomyelin Inhibits Hydrolytic Activity of Heterodimeric PLA<sub>2</sub> in Model Myelin Membranes: Pharmacological Relevance.","authors":"Anwaar S Chaudary, Yanglin Guo, Yuri N Utkin, Maryam Barancheshmeh, Ruben K Dagda, Edward S Gasanoff","doi":"10.1007/s00232-024-00327-y","DOIUrl":"10.1007/s00232-024-00327-y","url":null,"abstract":"<p><p>In this work, the heterodimeric phospholipase A<sub>2</sub>, HDP-2, from viper venom was investigated for its hydrolytic activity in model myelin membranes as well as for its effects on intermembrane exchange of phospholipids (studied by phosphorescence quenching) and on phospholipid polymorphism (studied by <sup>1</sup>H-NMR spectroscopy) to understand the role of sphingomyelin (SM) in the demyelination of nerve fibers. By using well-validated in vitro approaches, we show that the presence of SM in model myelin membranes leads to a significant inhibition of the hydrolytic activity of HDP-2, decreased intermembrane phospholipid exchange, and reduced phospholipid polymorphism. Using AutoDock software, we show that the NH<sup>δ+</sup> group of the sphingosine backbone of SM binds to Tyr22(C=O<sub>pb</sub><sup>δ-</sup>) of HDP-2 via a hydrogen bond which keeps only the polar head of SM inside the HDP-2's active center and positions the sn-2 acyl ester bond away from the active center, thus making it unlikely to hydrolyze the alkyl chains at the sn-2 position. This observation strongly suggests that SM inhibits the catalytic activity of HDP-2 by blocking access to other phospholipids to the active center of the enzyme. Should this observation be verified in further studies, it would offer a tantalizing opportunity for developing effective pharmaceuticals to stop the demyelination of nerve fibers by aberrant PLA<sub>2</sub>s with overt activity - as observed in brain degenerative diseases - by inhibiting SM hydrolysis and/or facilitating SM synthesis in the myelin sheath membrane.</p>","PeriodicalId":50129,"journal":{"name":"Journal of Membrane Biology","volume":" ","pages":"29-46"},"PeriodicalIF":2.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Computational Insights on the Assembly of the Dengue Virus Membrane-Capsid-RNA Complex.","authors":"Dwaipayan Chaudhuri, Satyabrata Majumder, Joyeeta Datta, Kalyan Giri","doi":"10.1007/s00232-025-00337-4","DOIUrl":"10.1007/s00232-025-00337-4","url":null,"abstract":"<p><p>Dengue virus, an arbovirus from the genus Flavivirus in the family Flaviviridae, forms a nucleocapsid structure through interactions between its genome and multiple copies of the capsid protein. Experimental studies have confirmed the interaction between the viral capsid protein and lipid droplets, indicating a protein-lipid interaction. Cryo-EM studies show that in immature viruses, the nucleocapsid is located close to the viral membrane. This study uses multiple MD simulations to explore the orientation of the capsid protein relative to the lipid membrane, focusing on how the protein's hydrophobic pocket interacts with the membrane. We also investigated the interaction between the capsid protein and RNA, considering the effects of sequence length and identity. Finally, we construct a model of the lipid-protein-RNA complex, demonstrating that the capsid protein's hydrophobic pocket interacts with the membrane, while the positively charged H4 helix interacts with the negatively charged RNA. This research may identify crucial interactions for immature virus particle formation and provide insights for future therapeutic interventions.</p>","PeriodicalId":50129,"journal":{"name":"Journal of Membrane Biology","volume":" ","pages":"75-96"},"PeriodicalIF":2.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}