Function (Oxford, England)最新文献

{"title":"STIMulating Salivary Glands.","authors":"Karla M Márquez-Nogueras, Ivana Y Kuo","doi":"10.1093/function/zqae055","DOIUrl":"10.1093/function/zqae055","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857105","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":"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":"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":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883839","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":"The Core Circadian Clock Factor, Bmal1, Transduces Sex-specific Differences in Both Rhythmic and Nonrhythmic 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":"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 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":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807748","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":"BMAL1 is a Critical Regulator of Sex-Specific Gene Expression in the Heart.","authors":"Pieterjan Dierickx","doi":"10.1093/function/zqaf004","DOIUrl":"10.1093/function/zqaf004","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025529","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":"Increased Anion Exchanger-1 (Band 3) on the Red Blood Cell Membrane Accelerates Scavenging 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":"10.1093/function/zqae052","url":null,"abstract":"<p><p>The erythrocyte membrane is highly specialized with ∼1 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 the human GYP.Mur gene into C57BL/6J mice at 3'-UTR of GYPA to generate GPMur knock-in (KI) mice. KI 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 nitric oxide (NO) reservoir] was significantly lower in the GPMur mice. GPMur KI 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":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830955","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":"Molecular and Functional Characterization of the Peritoneal Mesothelium, a Barrier for Solute Transport.","authors":"Iva Marinovic, Maria Bartosova, Eszter Levai, Rebecca Herzog, Arslan Saleem, Zhiwei Du, Conghui Zhang, Juan Manuel Sacnun, Eleanna Pitaraki, Sotirios Sinis, Ivan Damgov, Damir Krunic, Trim Lajqi, Mohammed Al-Saeedi, J Attila Szabo, Michael Hausmann, Domonkos Pap, Klaus Kratochwill, Susanne M Krug, Sotirios G Zarogiannis, Claus Peter Schmitt","doi":"10.1093/function/zqae051","DOIUrl":"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 surface area (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 2 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, ie, essential information on peritoneal transport modeling, 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":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807650","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":"Thick Ascending Limb Specific Inactivation of Myh9 and Myh10 Myosin Motors Results in Progressive Kidney Disease and Drives Sex-specific Cellular Adaptation in the Distal Nephron and Collecting Duct.","authors":"Karla L Otterpohl, Brook W Busselman, Jenna L Zimmerman, Malini Mukherjee, Claire Evans, Kelly Graber, Vedant P Thakkar, Jermaine G Johnston, Arooba Ilyas, Michelle L Gumz, Douglas C Eaton, Jeff M Sands, Kameswaran Surendran, Indra Chandrasekar","doi":"10.1093/function/zqae048","DOIUrl":"10.1093/function/zqae048","url":null,"abstract":"<p><p>Our previous work established a role for myosin motor proteins MYH9 and MYH10 in trafficking of thick ascending limb (TAL) cargoes uromodulin and Na+-K+-2Cl- cotransporter NKCC2. We have generated a TAL-specific Myh9&10 conditional knockout (Myh9&10 TAL-cKO) mouse model to determine the cell autonomous roles for MYH9&10 in TAL cargo trafficking and to understand the consequence of TAL dysfunction in adult kidney. Myh9&10 TAL-cKO mice develop progressive kidney disease with pathological tubular injury confirmed by histological changes, tubular injury markers, upregulated endoplasmic reticulum (ER) stress/unfolded protein response, and higher blood urea nitrogen and serum creatinine. However, male mice survive twice as long as female mice. We have determined this sexual dimorphism in morbidity is due to adaptation of the distal nephron and collecting duct in response to TAL dysfunction and lower NKCC2 expression. We demonstrate that this triggers a compensatory mechanism involving sex-specific cellular adaptation within the distal nephron and collecting duct to boost sodium reabsorption. While both sexes overcompensate by activating epithelial sodium channel (ENaC) expression in medullary collecting ducts resulting in hypernatremia, this is initially subdued in male Myh9&10 TAL-cKO mice through higher sodium chloride cotransporter (NCC) expression within the distal nephron. Our results indicate that compromised TAL function ultimately results in maladaptation of medullary collecting duct cells which acquire cortical-like properties including ENaC expression. This work further confirms a cell autonomous role for MYH9&10 in maintenance of NKCC2 expression in the TAL and uncover distal nephron and collecting duct adaptive mechanisms which respond to TAL dysfunction.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585153","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":"Systemic Glucose Homeostasis Requires Pancreatic but Not Neuronal ATP-sensitive Potassium Channels.","authors":"Athena H Li, Wen-Sheng Tsai, Wen-Hao Tsai, Shi-Bing Yang","doi":"10.1093/function/zqaf002","DOIUrl":"10.1093/function/zqaf002","url":null,"abstract":"<p><p>The adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits, are essential for glucose homeostasis. While the role of pancreatic KATP channels in regulating insulin secretion is well-documented, the specific contributions of neuronal KATP channels remain unclear due to challenges in precisely targeting neuronal subpopulations. In this study, we utilized a Kir6.2 conditional knockout mouse model to distinguish the roles of KATP channels in different cell types. Our findings demonstrate that deletion of neuronal KATP channels does not impair glucose homeostasis, as glucose-sensing neurons retained their responsiveness despite the absence of functional KATP channels. In contrast, the deletion of KATP channels in pancreatic β cells led to significant hyperglycemia and glucose intolerance, indicating unstable blood glucose levels under varying physiological conditions. Importantly, we showed that restoring KATP channel function exclusively in pancreatic β cells within a global Kir6.2 knockout background effectively reversed glucose regulation defects. This underscores the critical role of pancreatic KATP channels in maintaining systemic glucose homeostasis. Our results challenge the previous hypothesis that neuronal KATP channels are essential for glucose regulation, suggesting that their primary function may be neuroprotective rather than homeostatic. These findings highlight pancreatic KATP channels as key regulators of glucose balance and potential therapeutic targets for correcting glucose dysregulation.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985581","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":"Signal Transduction Pathway Mediating Carotid Body Dependent Sympathetic Activation and Hypertension by Chronic Intermittent Hypoxia.","authors":"Ying-Jie Peng, Jayasri Nanduri, Ning Wang, Xiaoyu Su, Matthew Hildreth, Nanduri R Prabhakar","doi":"10.1093/function/zqaf003","DOIUrl":"10.1093/function/zqaf003","url":null,"abstract":"<p><p>Patients with obstructive sleep apnea (OSA) experience chronic intermittent hypoxia (CIH). OSA patients and CIH-treated rodents exhibit overactive sympathetic nervous system and hypertension, mediated through hyperactive carotid body (CB) chemoreflex. Activation of olfactory receptor 78 (Olfr78) by hydrogen sulfide (H2S) is implicated in CB activation and sympathetic nerve responses to CIH, but the downstream signaling pathways remain unknown. Given that odorant receptor signaling is coupled to adenylyl cyclase 3 (Adcy3), we hypothesized that Adcy3-dependent cyclic adenosine monophosphate (cAMP) contributes to CB and sympathetic responses to CIH. Our findings show that CIH increases cAMP levels in the CB, a response absent in Adcy3, Cth (encoding CSE), and Olfr78 null mice. CBs from Cth and Olfr78 mutant mice lacked a persulfidation response to CIH, indicating that Adcy3 activation requires Olfr78 activation by H2S in CIH. CIH also enhanced glomus cell Ca2+ influx, an effect absent in Cnga2 (encoding cyclic nucleotide-gated channel alpha2 subunit) and Adcy3 mutants, suggesting that CIH-induced cAMP mediates enhanced Ca2+ responses through cyclic nucleotide-gated channels. Furthermore, Adcy3 null mice did not exhibit either CB activation or sympathetic activation by CIH. These results demonstrate that Adcy3-dependent cAMP is a downstream signaling pathway to H2S/Olfr78, mediating CIH-induced CB activation, sympathetic activity and hypertension.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025466","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":"Loss of STIM1 and STIM2 in Salivary Glands Disrupts ANO1 Function but Does Not Induce Sjogren's Disease.","authors":"Ga-Yeon Son, Anna Zou, Amanda Wahl, Kai Ting Huang, Saruul Zorgit, Manikandan Vinu, Fang Zhou, Larry Wagner, Youssef Idaghdour, David I Yule, Stefan Feske, Rodrigo S Lacruz","doi":"10.1093/function/zqae047","DOIUrl":"10.1093/function/zqae047","url":null,"abstract":"<p><p>Ca2+ signaling via the store-operated Ca2+ entry (SOCE) mediated by STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel is important in saliva fluid secretion and has been associated with Sjogren's disease (SjD). However, there are no studies addressing STIM1/2 dysfunction in salivary glands or SjD in animal models. We report that mice lacking Stim1 and Stim2 [Stim1/2K14Cre(+)] in salivary glands exhibited reduced Ca2+ levels and hyposalivate. SOCE was functionally required for the activation of the Ca2+ activated Cl- channel ANO1. Ageing Stim1/2K14Cre(+) mice showed no evidence of lymphocytic infiltration or increased levels of autoantibodies characteristic of SjD, possibly associated with a downregulation of toll-like receptor 8 (Tlr8) expression. Salivary gland biopsies of SjD patients showed increased expression of STIM1 and TLR7/8. Our study shows that SOCE activates ANO1 function and fluid secretion in salivary glands and highlights a potential link between SOCE and TLR signaling in SjD.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549288","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}