Function (Oxford, England)最新文献

{"title":"IK Channel Confers Fine-tuning of Rod Bipolar Cell Excitation and Synaptic Transmission in the Retina.","authors":"Yong Soo Park, Ki-Wug Sung, In-Beom Kim","doi":"10.1093/function/zqae054","DOIUrl":"https://doi.org/10.1093/function/zqae054","url":null,"abstract":"<p><p>During retinal visual processing, rod bipolar cells (RBC) transfer scotopic signals from rods to AII amacrine cells as second-order neurons. Elucidation of the RBC's excitation/inhibition is essential for understanding the visual signal transmission. Excitation mechanisms via mGluR6 and voltage-gated Ca2+ channels in the RBCs and GABAergic inhibitory synaptic inputs have been studied in previous studies. However, its intrinsic inhibitory mechanisms like K+ and Cl- channels remain unclear. We focused on RBC's prominent K+ current, which exhibits voltage and Ca2+ dependence. We isolated and confirmed the expression of intermediate-conductance Ca2+-activated K+ channels (IK) in RBCs using the patch-clamp method with IK inhibitors (clotrimazole and TRAM34) and immunohistochemistry. The regulation of the IK channel primarily relies on Ca2+ influx via low-threshold Ca2+ channels during RBC's excitation. Additionally, IK mediates late repolarization and suppresses excessive oscillation of the membrane potential in the RBCs, enabling fast and transient synaptic transmission to AII amacrine cells. Our findings highlight the unique role of the IK channel in RBCs, suggesting that it plays a critical role in the scotopic pathway by fine-tuning RBC activity.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STIMulating salivary glands.","authors":"Karla M Marquez Nogueras, Ivana Y Kuo","doi":"10.1093/function/zqae055","DOIUrl":"https://doi.org/10.1093/function/zqae055","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The core circadian clock factor, Bmal1, transduces sex-specific differences in both rhythmic and non-rhythmic gene expression in the mouse heart.","authors":"Xiping Zhang, Spencer B Procopio, Haocheng Ding, Maya G Semel, Elizabeth A Schroder, Mark R Viggars, Tanya S Seward, Ping Du, Kevin Wu, Sidney R Johnson, Abhilash Prabhat, David J Schneider, Isabel G Stumpf, Ezekiel R Rozmus, Zhiguang Huo, Brian P Delisle, Karyn A Esser","doi":"10.1093/function/zqae053","DOIUrl":"https://doi.org/10.1093/function/zqae053","url":null,"abstract":"<p><p>It has been well established that cardiovascular diseases exhibit significant differences between sexes in both preclinical models and humans. In addition, there is growing recognition that disrupted circadian rhythms can contribute to the onset and progression of cardiovascular diseases. However, little is known about sex differences between the cardiac circadian clock and circadian transcriptomes in mice. Here, we show that the core clock genes are expressed in common in both sexes, but the cardiac circadian transcriptome is very sex specific. Hearts from female mice expressed significantly more rhythmically expressed genes (REGs) than male hearts, and the temporal distribution of REGs was distinctly different between sexes. To test the contribution of the circadian clock in sex-specific gene expression in the heart, we knocked out the core circadian clock factor Bmal1 in adult cardiomyocytes. The sex differences in the circadian transcriptomes were significantly diminished with cardiomyocyte-specific loss of Bmal1. Surprisingly, loss of cardiomyocyte Bmal1 also resulted in a roughly 8-fold reduction in the number of all differentially expressed genes (DEGs) between male and female hearts. We highlight sex-specific changes in several cardiac-specific transcription factors, including Gata4, Nkx2-5 and Tbx5. While there is still much to learn, we conclude that cardiomyocyte-specific Bmal1 is vital in conferring sex-specific gene expression in the adult mouse heart.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular and Functional Characterization of the Peritoneal Mesothelium, a Barrier for Solute Transport.","authors":"Marinovic Iva, Bartosova Maria, Levai Eszter, Herzog Rebecca, Saleem Arslan, Du Zhiwei, Zhang Conghui, Sacnun Juan Manuel, Pitaraki Eleanna, Sinis Sotirios, Damgov Ivan, Krunic Damir, Lajqi Trim, Al-Saeedi Mohammed, Szabo J Attila, Hausmann Michael, Pap Domonkos, Kratochwill Klaus, Krug Susanne, G Zarogiannis Sotirios, Schmitt Claus Peter","doi":"10.1093/function/zqae051","DOIUrl":"https://doi.org/10.1093/function/zqae051","url":null,"abstract":"<p><p>Peritoneal dialysis (PD) is an increasingly needed, life-maintaining kidney replacement therapy; efficient solute transport is critical for patient outcome. While the role of peritoneal perfusion on solute transport in PD has been described, the role of cellular barriers is uncertain, the mesothelium has been considered irrelevant. We calculated peritoneal blood microvascular endothelial (BESA) to mesothelial surface area (MSA) ratio in human peritonea in health, chronic kidney disease, and on PD, and performed molecular transport related gene profiling and single molecule localization microscopy in two mesothelial (MC) and two endothelial cell lines (EC). Molecular-weight dependent transport was studied in-vitro, ex-vivo and in mice. Peritoneal BESA is 1-3-fold higher than MSA across age groups, and increases with PD, while the mesothelium is preserved during the first two years of PD. Tight junction, transmembrane and transcytotic transporter expression are cell-type specifically expressed. At nanoscale, tight junction anchoring protein Zonula occludens-1 is more abundant and more continuously expressed along the MC than the EC. Ionic conductance is 3-fold lower across the MC than human microvascular EC, as is the permeability for creatinine, 4- and 10-kDa, but not for 70-kDa dextran. MC removal from sheep peritoneum abolishes ionic barrier function. Short term intraperitoneal LPS exposure in mice selectively affects peritoneal mesothelial integrity and increases transperitoneal solute transport. We provide molecular correlates and consistent functional evidence for the mesothelium as a barrier for peritoneal solute transport, i.e., essential information on peritoneal transport modelling, and for interventions to improve PD efficiency and biocompatibility, and beyond.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased Anion Exchanger-1 (Band 3) on the Red Blood Cell Membrane Accelerates Scavenge of Nitric Oxide Metabolites and Predisposes Hypertension Risks.","authors":"Li-Yang Chen, Pin-Lung Chen, Si-Tse Jiang, Hui-Lin Lee, Yen-Yu Liu, Alysa Chueh, Jing-Heng Lin, Caleb G Chen, Chung-Lieh Hung, Kate Hsu","doi":"10.1093/function/zqae052","DOIUrl":"https://doi.org/10.1093/function/zqae052","url":null,"abstract":"<p><p>The erythrocyte membrane is highly specialized with ∼one million anion exchanger-1 (AE1) per cell for rapid membrane permeation of HCO3-(aq), as most blood CO2(g) is carried in this hydrated anionic form. People with the GP.Mur blood type have more AE1 on their erythrocyte membrane, and they excrete CO2(g) more efficiently. Unexpectedly, GP.Mur/increased AE1 is also associated with higher blood pressure (BP). To solve this, we knocked human GYP.Mur gene into C57BL/6J mice at 3'UTR of GYPA to generate GPMur knock-in (KI) mice. Knock-in of human GYP.Mur increased murine AE1 expression on the red blood cells (RBC). GPMur KI mice were naturally hypertensive, with normal kidney functions and lipid profiles. Blood NO3- (the stable NO reservoir) was significantly lower in the GPMur mice. GPMur knock-in also accelerated AE1-mediated NO2- influx into the RBCs and intraerythrocytic NO2-/NO processing. From tests with different categories of antihypertensives, hypertension in GPMur mice responded best to direct arterial vasodilator hydralazine, suggesting that vasodilator deficiency is the leading cause of \"GPMur/AE1-triggered hypertension\". In conclusion, we showed that GPMur/increased AE1 predisposed hypertension risks. Mechanistically, higher AE1 expression increased RBC membrane permeability for NO2- and consequently accelerated erythroid NO2-/NO metabolism; this is associated with lower NO bioavailability and higher BP. As hypertension affects a quarter of the world population and GP.Mur is a common Southeast Asian (SEA) blood type, this work may serve as a primer for \"GPMur (biomarker)-based\" therapeutic development for hypertension.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The P2Y6 Receptor as a Potential Keystone in Essential Hypertension.","authors":"Nuria Daghbouche-Rubio, Inés Álvarez-Miguel, Victor Alejandro Flores, Jorge Rojo-Mencía, Manuel Navedo, Madeleine Nieves-Citrón, Pilar Cidad, M Teresa Pérez-García, José R López-López","doi":"10.1093/function/zqae045","DOIUrl":"10.1093/function/zqae045","url":null,"abstract":"<p><p>Essential hypertension (HT) is a highly prevalent cardiovascular disease of unclear physiopathology. Pharmacological studies suggest that purinergic P2Y6 receptors (P2ry6) play important roles in cardiovascular function and may contribute to angiotensin II (AgtII) pathophysiological effects. Here, we tested the hypothesis that functional coupling between P2ry6 and AgtII receptors mediates altered vascular reactivity in HT. For this, a multipronged approach was implemented using mesenteric vascular smooth muscle cells (VSMCs) and arteries from Blood Pressure Normal (BPN) and Blood Pressure High (BPH) mice. Differential transcriptome profiling of mesenteric artery VSMCs identified P2ry6 purinergic receptor mRNA as one of the top upregulated transcripts in BPH. P2Y receptor activation elicited distinct vascular responses in mesenteric arteries from BPN and BPH mice. Accordingly, 10 µm UTP produced a contraction close to half-maximal activation in BPH arteries but no response in BPN vessels. AgtII-induced contraction was also higher in BPH mice despite having lower AgtII receptor type-1 (Agtr1) expression and was sensitive to P2ry6 modulators. Proximity ligation assay and super-resolution microscopy showed closer localization of Agtr1 and P2ry6 at/near the membrane of BPH mice. This proximal association was reduced in BPN mice, suggesting a functional role for Agtr1-P2ry6 complexes in the hypertensive phenotype. Intriguingly, BPN mice were resistant to AgtII-induced HT and showed reduced P2ry6 expression in VSMCs. Altogether, results suggest that increased functional coupling between P2ry6 and Agtr1 may contribute to enhanced vascular reactivity during HT. In this regard, blocking P2ry6 could be a potential pharmacological strategy to treat HT.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333860","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":"PARticularly Forceful: PAR1 Drives Glomerular Mesangial Cell Contractility.","authors":"Amanda P Waller, Kaushik Muralidharan, Bryce A Kerlin","doi":"10.1093/function/zqae044","DOIUrl":"10.1093/function/zqae044","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302566","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":"Impaired Neurocirculatory Control in Chronic Kidney Disease: New Evidence for Blunted Sympathetic Baroreflex and Reduced Sympathetic Transduction.","authors":"Jeann L Sabino-Carvalho, Elsa Mekonnen, Matias Zanuzzi, Sabrina Li, Xiangqin Cui, Jeanie Park","doi":"10.1093/function/zqae036","DOIUrl":"10.1093/function/zqae036","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is characterized by over-activation of the sympathetic nervous system (SNS) that increases cardiovascular risk. Whether sympathetic baroreflex sensitivity (sBRS) is impaired or intact in CKD remains under-studied and controversial. Furthermore, the downstream effect of SNS activation on blood pressure transduction has not been previously examined in CKD. We tested the hypothesis that sBRS is attenuated, while sympathetic transduction is augmented in CKD. In 18 sedentary patients with CKD stages III-IV (eGFR: 40±14 mL/min) and 13 age-matched controls (eGFR: 95±10 mL/min), beat-to-beat blood pressure (BP; finger photoplethysmography), heart rate (electrocardiography) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded at rest for 10-min. Weighted linear regression analysis between MSNA burst incidence and diastolic BP was used to determine the spontaneous sBRS. Sympathetic-BP transduction was quantified using signal averaging, whereby the BP response to each MSNA burst was tracked over 15 cardiac cycles and averaged to derive the peak change in BP. Compared with controls, CKD patients had an attenuated sBRS [CKD: -1.34 ± 0.59 versus CON: -2.91 ± 1.09 bursts (100 heartbeats)-1 mmHg-1; P = 0.001]. |sBRS| was significantly associated with eGFR (r = 0.69, P < 0.001). CKD patients had attenuated sympathetic-BP transduction compared to controls (0.75 ± 0.7 vs. 1.60 ± 0.8 mmHg; P = 0.010). Resting MSNA was negatively associated with sympathetic transduction (r = -0.57, P = 0.002). CKD patients exhibit impaired sBRS that may contribute to SNS overactivation and cardiovascular risk in this patient population. In addition, CKD patients had an attenuated sympathetic transduction that may counteract the vascular effects of SNS overactivation.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging the Gap: How Endothelial-Adipocyte Cx43 Mediated Gap Junctions Could Revolutionize Adiposity Regulation.","authors":"Teresa Vezza, Víctor M Víctor","doi":"10.1093/function/zqae046","DOIUrl":"10.1093/function/zqae046","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333859","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":"Sulfonylurea Receptor Pharmacology Alters the Performance of Two Central Pattern Generating Circuits in Cancer borealis.","authors":"Sonal Kedia, Naziru M Awal, Jackie Seddon, Eve Marder","doi":"10.1093/function/zqae043","DOIUrl":"10.1093/function/zqae043","url":null,"abstract":"<p><p>Neuronal activity and energy supply must maintain a fine balance for neuronal fitness. Various channels of communication between the two could impact network output in different ways. Sulfonylurea receptors (SURs) are a modification of ATP-binding cassette proteins that confer ATP-dependent gating on their associated ion channels. They are widely expressed and link metabolic states directly to neuronal activity. The role they play varies in different circuits, both enabling bursting and inhibiting activity in pathological conditions. The crab, Cancer borealis, has central pattern generators (CPGs) that fire in rhythmic bursts nearly constantly and it is unknown how energy availability influences these networks. The pyloric network of the stomatogastric ganglion and the cardiac ganglion (CG) control rhythmic contractions of the foregut and heart, respectively. Known SUR agonists and antagonists produce opposite effects in the two CPGs. Pyloric rhythm activity completely stops in the presence of a SUR agonist, and activity increases in SUR blockers. This results from a decrease in the excitability of pyloric dilator neurons, which are a part of the pacemaker kernel. The neurons of the CG, paradoxically, increase firing within bursts in SUR agonists, and bursting slows in SUR antagonists. Analyses of the agonist-affected conductance properties present biophysical effects that do not trivially match those of mammalian SUR-dependent conductances. We suggest that SUR-associated conductances allow different neurons to respond to energy states in different ways through a common mechanism.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302568","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}