Function (Oxford, England)最新文献

{"title":"Genetic Ablation of Prorenin Receptor in the Rostral Ventrolateral Medulla Influences Blood Pressure and Hydromineral Balance in Deoxycorticosterone-Salt Hypertension.","authors":"Natalia M Mathieu, Eva M Fekete, Patricia C Muskus, Daniel T Brozoski, Ko-Ting Lu, Kelsey K Wackman, Javier Gomez, Shi Fang, John J Reho, Connie C Grobe, Ibrahim Vazirabad, Gary C Mouradian, Matthew R Hodges, Jeffrey L Segar, Justin L Grobe, Curt D Sigmund, Pablo Nakagawa","doi":"10.1093/function/zqad043","DOIUrl":"10.1093/function/zqad043","url":null,"abstract":"<p><p>Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin-angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral medulla (RVLM). Overactivation of bulbospinal neurons in the RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRR^RVLM-Null mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRR^RVLM-Null females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRR^RVLM-Null subsequently showed exacerbated DOCA-salt-induced pressor responses during the \"maintenance\" phase with a maximal peak at 13 d on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems. Graphical abstract.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad043"},"PeriodicalIF":5.1,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10206983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breaking New Ground: The Crucial Role of Animal Research in the Advancement of Rhabdomyolysis-Induced AKI Treatment and Prevention.","authors":"Marharyta Semenikhina, Joshua H Lipschutz, Oleg Palygin","doi":"10.1093/function/zqad039","DOIUrl":"10.1093/function/zqad039","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad039"},"PeriodicalIF":0.0,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10006225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Modeling of Substrate-Dependent Mitochondrial Respiration and Bioenergetics in the Heart and Kidney Cortex and Outer Medulla.","authors":"Shima Sadri,&nbsp;Xiao Zhang,&nbsp;Said H Audi,&nbsp;Allen W Cowley,&nbsp;Ranjan K Dash","doi":"10.1093/function/zqad038","DOIUrl":"10.1093/function/zqad038","url":null,"abstract":"<p><p>Integrated computational modeling provides a mechanistic and quantitative framework to characterize alterations in mitochondrial respiration and bioenergetics in response to different metabolic substrates <i>in-silico</i>. These alterations play critical roles in the pathogenesis of diseases affecting metabolically active organs such as heart and kidney. Therefore, the present study aimed to develop and validate thermodynamically constrained integrated computational models of mitochondrial respiration and bioenergetics in the heart and kidney cortex and outer medulla (OM). The models incorporated the kinetics of major biochemical reactions and transport processes as well as regulatory mechanisms in the mitochondria of these tissues. Intrinsic model parameters such as Michaelis-Menten constants were fixed at previously estimated values, while extrinsic model parameters such as maximal reaction and transport velocities were estimated separately for each tissue. This was achieved by fitting the model solutions to our recently published respirometry data measured in isolated rat heart and kidney cortex and OM mitochondria utilizing various NADH- and FADH₂-linked metabolic substrates. The models were validated by predicting additional respirometry and bioenergetics data, which were not used for estimating the extrinsic model parameters. The models were able to predict tissue-specific and substrate-dependent mitochondrial emergent metabolic system properties such as redox states, enzyme and transporter fluxes, metabolite concentrations, membrane potential, and respiratory control index under diverse physiological and pathological conditions. The models were also able to quantitatively characterize differential regulations of NADH- and FADH₂-linked metabolic pathways, which contribute differently toward regulations of oxidative phosphorylation and ATP synthesis in the heart and kidney cortex and OM mitochondria.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad038"},"PeriodicalIF":0.0,"publicationDate":"2023-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10006232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Driver Mutations of Pancreatic Cancer Affect Ca²⁺ Signaling and ATP Production.","authors":"Kinga B Stopa, Filip Łoziński, Agnieszka A Kusiak, Jacek Litewka, Daria Krzysztofik, Sylwester Mosiołek, Jan Morys, Paweł E Ferdek, Monika A Jakubowska","doi":"10.1093/function/zqad035","DOIUrl":"10.1093/function/zqad035","url":null,"abstract":"<p><p>Glandular pancreatic epithelia of the acinar or ductal phenotype may seem terminally differentiated, but they are characterized by remarkable cell plasticity. Stress-induced trans-differentiation of these cells has been implicated in the mechanisms of carcinogenesis. Current consensus links pancreatic ductal adenocarcinoma with onco-transformation of ductal epithelia, but under the presence of driver mutations in <i>Kras</i> and <i>Trp53</i>, also with trans-differentiation of pancreatic acini. However, we do not know when, in the course of cancer progression, physiological functions are lost by mutant acinar cells, nor can we assess their capacity for the production of pancreatic juice components. Here, we investigated whether two mutations-Kras^G12D and Trp53^R172H-present simultaneously in acinar cells of KPC mice (model of oncogenesis) influence cytosolic Ca²⁺ signals. Since Ca²⁺ signals control the cellular handling of digestive hydrolases, any changes that affect intracellular signaling events and cell bioenergetics might have an impact on the physiology of the pancreas. Our results showed that physiological doses of acetylcholine evoked less regular Ca²⁺ oscillations in KPC acinar cells compared to the control, whereas responses to supramaximal concentrations were markedly reduced. Menadione elicited Ca²⁺ signals of different frequencies in KPC cells compared to control cells. Finally, Ca²⁺ extrusion rates were significantly inhibited in KPC cells, likely due to the lower basal respiration and ATP production. Cumulatively, these findings suggest that driver mutations affect the signaling capacity of pancreatic acinar cells even before the changes in the epithelial cell morphology become apparent.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad035"},"PeriodicalIF":0.0,"publicationDate":"2023-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10006228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure and Function of RhoBTB1 Required for Substrate Specificity and Cullin-3 Ubiquitination.","authors":"Gaurav Kumar,&nbsp;Shi Fang,&nbsp;Daria Golosova,&nbsp;Ko-Ting Lu,&nbsp;Daniel T Brozoski,&nbsp;Ibrahim Vazirabad,&nbsp;Curt D Sigmund","doi":"10.1093/function/zqad034","DOIUrl":"10.1093/function/zqad034","url":null,"abstract":"<p><p>We identified Rho-related BTB domain containing 1 (RhoBTB1) as a key regulator of phosphodiesterase 5 (PDE5) activity, and through PDE5, a regulator of vascular tone. We identified the binding interface for PDE5 on RhoBTB1 by truncating full-length RhoBTB1 into its component domains. Co-immunoprecipitation analyses revealed that the C-terminal half of RhoBTB1 containing its two BTB domains and the C-terminal domain (B1B2C) is the minimal region required for PDE5 recruitment and subsequent proteasomal degradation via Cullin-3 (CUL3). The C-terminal domain was essential in recruiting PDE5 as constructs lacking this region could not participate in PDE5 binding or proteasomal degradation. We also identified Pro³⁵³ and Ser³⁶³ as key amino acid residues in the B1B2C region involved in CUL3 binding to RhoBTB1. Mutation of either of these residues exhibited impaired CUL3 binding and PDE5 degradation, although the binding to PDE5 was preserved. Finally, we employed ascorbate peroxidase 2 (APEX2) proximity labeling using a B1B2C-APEX2 fusion protein as bait to capture unknown RhoBTB1 binding partners. Among several B1B2C-binding proteins identified and validated, we focused on SET domain containing 2 (SETD2). SETD2 and RhoBTB1 directly interacted, and the level of SETD2 increased in response to pharmacological inhibition of the proteasome or Cullin complex, CUL3 deletion, and RhoBTB1-inhibition with siRNA. This suggests that SETD2 is regulated by the RhoBTB1-CUL3 axis. Future studies will determine whether SETD2 plays a role in cardiovascular function.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad034"},"PeriodicalIF":0.0,"publicationDate":"2023-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10400406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal Epidermal Growth Factor Promotes Neonatal Claudin-2 Dependent Increases in Small Intestinal Calcium Permeability.","authors":"Megan R Beggs,&nbsp;Kennedi Young,&nbsp;Allen Plain,&nbsp;Debbie D O'Neill,&nbsp;Ahsan Raza,&nbsp;Veit Flockerzi,&nbsp;Henrik Dimke,&nbsp;R Todd Alexander","doi":"10.1093/function/zqad033","DOIUrl":"10.1093/function/zqad033","url":null,"abstract":"<p><p>A higher concentration of calcium in breast milk than blood favors paracellular calcium absorption enabling growth during postnatal development. We aimed to determine whether suckling animals have greater intestinal calcium permeability to maximize absorption and to identify the underlying molecular mechanism. We examined intestinal claudin expression at different ages in mice and in human intestinal epithelial (Caco-2) cells in response to hormones or human milk. We also measured intestinal calcium permeability in wildtype, <i>Cldn2</i> and <i>Cldn12</i> KO mice and Caco-2 cells in response to hormones or human milk. Bone mineralization in mice was assessed by μCT. Calcium permeability across the jejunum and ileum of mice were 2-fold greater at 2 wk than 2 mo postnatal age. At 2 wk, <i>Cldn2</i> and <i>Cldn12</i> expression were greater, but only <i>Cldn2</i> KO mice had decreased calcium permeability compared to wildtype. This translated to decreased bone volume, cross-sectional thickness, and tissue mineral density of femurs. Weaning from breast milk led to a 50% decrease in <i>Cldn2</i> expression in the jejunum and ileum. Epidermal growth factor (EGF) in breast milk specifically increased only CLDN2 expression and calcium permeability in Caco-2 cells. These data support intestinal permeability to calcium, conferred by claudin-2, being greater in suckling mice and being driven by EGF in breast milk. Loss of the CLDN2 pathway leads to suboptimal bone mineralization at 2 wk of life. Overall, EGF-mediated control of intestinal claudin-2 expression contributes to maximal intestinal calcium absorption in suckling animals.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad033"},"PeriodicalIF":0.0,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1e/06/zqad033.PMC10413934.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10006231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Responses of Normal Rat Kidneys to a High Salt Intake.","authors":"Satoshi Shimada, Brian R Hoffmann, Chun Yang, Theresa Kurth, Andrew S Greene, Mingyu Liang, Ranjan K Dash, Allen W Cowley","doi":"10.1093/function/zqad031","DOIUrl":"10.1093/function/zqad031","url":null,"abstract":"<p><p>In this study, novel methods were developed, which allowed continuous (24/7) measurement of arterial blood pressure and renal blood flow in freely moving rats and the intermittent collection of arterial and renal venous blood to estimate kidney metabolic fluxes of O₂ and metabolites. Specifically, the study determined the effects of a high salt (HS; 4.0% NaCl) diet upon whole kidney O₂ consumption and arterial and renal venous plasma metabolomic profiles of normal Sprague-Dawley rats. A separate group of rats was studied to determine changes in the cortex and outer medulla tissue metabolomic and mRNAseq profiles before and following the switch from a 0.4% to 4.0% NaCl diet. In addition, targeted mRNA expression analysis of cortical segments was performed. Significant changes in the metabolomic and transcriptomic profiles occurred with feeding of the HS diet. A progressive increase of kidney O₂ consumption was found despite a reduction in expression of most of the mRNA encoding enzymes of TCA cycle. A novel finding was the increased expression of glycolysis-related genes in Cx and isolated proximal tubular segments in response to an HS diet, consistent with increased release of pyruvate and lactate from the kidney to the renal venous blood. Data suggests that aerobic glycolysis (eg, Warburg effect) may contribute to energy production under these circumstances. The study provides evidence that kidney metabolism responds to an HS diet enabling enhanced energy production while protecting from oxidative stress and injury. Metabolomic and transcriptomic analysis of kidneys of Sprague-Dawley rats fed a high salt diet.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad031"},"PeriodicalIF":0.0,"publicationDate":"2023-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10134598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOE4, Age, and Sex Regulate Respiratory Plasticity Elicited by Acute Intermittent Hypercapnic-Hypoxia.","authors":"Jayakrishnan Nair, Joseph F Welch, Alexandria B Marciante, Tingting Hou, Qing Lu, Emily J Fox, Gordon S Mitchell","doi":"10.1093/function/zqad026","DOIUrl":"10.1093/function/zqad026","url":null,"abstract":"<p><strong>Rationale: </strong>Acute intermittent hypoxia (AIH) shows promise for enhancing motor recovery in chronic spinal cord injuries and neurodegenerative diseases. However, human trials of AIH have reported significant variability in individual responses.</p><p><strong>Objectives: </strong>Identify individual factors (eg, genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH).</p><p><strong>Methods: </strong>In 17 healthy individuals (age = 27 ± 5 yr), associations between individual factors and changes in the magnitude of AIHH (15, 1-min O2 = 9.5%, CO2 = 5% episodes) induced changes in diaphragm motor-evoked potential (MEP) amplitude and inspiratory mouth occlusion pressures (P0.1) were evaluated. Single nucleotide polymorphisms (SNPs) in genes linked with mechanisms of AIH induced phrenic motor plasticity (<i>BDNF, HTR2A, TPH2, MAOA, NTRK2</i>) and neuronal plasticity (apolipoprotein E, <i>APOE</i>) were tested. Variations in AIHH induced plasticity with age and sex were also analyzed. Additional experiments in humanized (h)<i>ApoE</i> knock-in rats were performed to test causality.</p><p><strong>Results: </strong>AIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for <i>APOE4</i> (i.e., <i>APOE3</i>/<i>4</i>) compared to individuals with other <i>APOE</i> genotypes (<i>P</i> = 0.048) and the other tested SNPs. Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (<i>P</i> = 0.004). Additionally, age was inversely related with change in P0.1 (<i>P</i> = 0.007). In h<i>ApoE4</i> knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than h<i>ApoE3</i> controls (<i>P</i> < 0.05).</p><p><strong>Conclusions: </strong><i>APOE4</i> genotype, sex, and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults.</p><p><strong>Addition to knowledge base: </strong>AIH is a novel rehabilitation strategy to induce functional recovery of respiratory and non-respiratory motor systems in people with chronic spinal cord injury and/or neurodegenerative disease. Figure 5 Since most AIH trials report considerable inter-individual variability in AIH outcomes, we investigated factors that potentially undermine the response to an optimized AIH protocol, AIHH, in healthy humans. We demonstrate that genetics (particularly the lipid transporter, <i>APOE</i>), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad026"},"PeriodicalIF":0.0,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/78/79/zqad026.PMC10413930.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10019366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skeletal Muscle Consequences of Phosphatidylethanolamine Synthesis Deficiency.","authors":"Sophie Grapentine,&nbsp;Rathnesh K Singh,&nbsp;Marica Bakovic","doi":"10.1093/function/zqad020","DOIUrl":"10.1093/function/zqad020","url":null,"abstract":"<p><p>The maintenance of phospholipid homeostasis is increasingly being implicated in metabolic health. Phosphatidylethanolamine (PE) is the most abundant phospholipid on the inner leaflet of cellular membranes, and we have previously shown that mice with a heterozygous ablation of the PE synthesizing enzyme, Pcyt2 (<i>Pcyt2^+/-</i>), develop obesity, insulin resistance, and NASH. Skeletal muscle is a major determinant of systemic energy metabolism, making it a key player in metabolic disease development. Both the total PE levels and the ratio of PE to other membrane lipids in skeletal muscle are implicated in insulin resistance; however, the underlying mechanisms and the role of Pcyt2 regulation in this association remain unclear. Here, we show how reduced phospholipid synthesis due to Pcyt2 deficiency causes <i>Pcyt2^+/-</i> skeletal muscle dysfunction and metabolic abnormalities. <i>Pcyt2^+/-</i> skeletal muscle exhibits damage and degeneration, with skeletal muscle cell vacuolization, disordered sarcomeres, mitochondria ultrastructure irregularities and paucity, inflammation, and fibrosis. There is intramuscular adipose tissue accumulation, and major disturbances in lipid metabolism with impaired FA mobilization and oxidation, elevated lipogenesis, and long-chain fatty acyl-CoA, diacylglycerol, and triacylglycerol accumulation. <i>Pcyt2^+/-</i> skeletal muscle exhibits perturbed glucose metabolism with elevated glycogen content, impaired insulin signaling, and reduced glucose uptake. Together, this study lends insight into the critical role of PE homeostasis in skeletal muscle metabolism and health with broad implications on metabolic disease development.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 4","pages":"zqad020"},"PeriodicalIF":0.0,"publicationDate":"2023-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0c/ed/zqad020.PMC10278983.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Control of Small-conductance Calcium-activated Potassium Channel Diffusion by Actin in Different Neuronal Subcompartments.","authors":"Shiju Gu, Anastasios V Tzingounis, George Lykotrafitis","doi":"10.1093/function/zqad018","DOIUrl":"10.1093/function/zqad018","url":null,"abstract":"<p><p>Small-conductance calcium-activated potassium (SK) channels show a ubiquitous distribution on neurons, in both somatodendritic and axonal regions. SK channels are associated with neuronal activity regulating action potential frequency, dendritic excitability, and synaptic plasticity. Although the physiology of SK channels and the mechanisms that control their surface expression levels have been investigated extensively, little is known about what controls SK channel diffusion in the neuronal plasma membrane. This aspect is important, as the diffusion of SK channels at the surface may control their localization and proximity to calcium channels, hence increasing the likelihood of SK channel activation by calcium. In this study, we successfully investigated the diffusion of SK channels labeled with quantum dots on human embryonic kidney cells and dissociated hippocampal neurons by combining a single-particle tracking method with total internal reflection fluorescence microscopy. We observed that actin filaments interfere with SK mobility, decreasing their diffusion coefficient. We also found that during neuronal maturation, SK channel diffusion was gradually inhibited in somatodendritic compartments. Importantly, we observed that axon barriers formed at approximately days <i>in vitro</i> 6 and restricted the diffusion of SK channels on the axon initial segment (AIS). However, after neuron maturation, SK channels on the AIS were strongly immobilized, even after disruption of the actin network, suggesting that crowding may cause this effect. Altogether, our work provides insight into how SK channels diffuse on the neuronal plasma membrane and how actin and membrane crowding impacts SK channel diffusion.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 3","pages":"zqad018"},"PeriodicalIF":5.1,"publicationDate":"2023-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/70/69/zqad018.PMC10165553.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9691399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}