Function (Oxford, England)最新文献

{"title":"Topical ATP Application in the Peripheral Swallowing-Related Regions Facilitates Triggering of the Swallowing Reflex Involving P2X3 Receptors.","authors":"Mohammad Zakir Hossain, Hiroshi Ando, Rita Rani Roy, Junichi Kitagawa","doi":"10.1093/function/zqaf010","DOIUrl":"10.1093/function/zqaf010","url":null,"abstract":"<p><p>The swallowing reflex is a critical component of the digestive process, triggered when food or liquids pass from the oral cavity to the oesophagus. Although adenosine triphosphate (ATP) is involved in various physiological processes, its potential to trigger the swallowing reflex has not been fully explored. This study investigated the ability of ATP to induce the swallowing reflex and examined the involvement of the purinoreceptor P2X3 in this process. We observed that the topical application of exogenous ATP to the superior laryngeal nerve (SLN)-innervated swallowing-related regions dose-dependently facilitated the triggering of the swallowing reflex. P2X3 receptors were predominantly localized on nerve fibres within these regions, including intraepithelial and subepithelial nerves and those associated with taste-bud-like structures. In the nodose-petrosal-jugular ganglionic complex, approximately 40% of retrogradely traced SLN-afferent neurons expressed P2X3, with 59% being medium-sized, 30% small, and 11% large. Prior topical application of a P2X3 antagonist in SLN-innervated, swallowing-related regions significantly reduced the number of ATP-induced swallowing reflexes. Furthermore, topical application of a P2X3 receptor agonist more selective than ATP facilitated reflex triggering in a dose-dependent manner. These findings suggest that exogenous ATP facilitates the triggering of the swallowing reflex through the activation of P2X3 receptors. This activation excites afferent neurons that supply peripheral swallowing-related regions, stimulating the swallowing central pattern generator to facilitate the reflex. The current findings suggest the therapeutic potential of ATP or P2X3 agonists for dysphagia treatment and provide valuable physiological insights into the involvement of purinergic signaling in triggering the swallowing reflex.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568983","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":"High-Salt Diet Increases Suprachiasmatic Neuronal Excitability Through Endothelin Receptor Type B Signaling.","authors":"Jodi R Paul, Megan K Rhoads, Anna Elam, David M Pollock, Karen L Gamble","doi":"10.1093/function/zqaf014","DOIUrl":"10.1093/function/zqaf014","url":null,"abstract":"<p><p>Circadian rhythms are 24-h oscillations in behavioral and biological processes such as blood pressure and sodium excretion. Endothelin B (ETB) receptor has been connected to the molecular clock in peripheral tissues and plays a key role in the regulation of sodium excretion, especially in response to a high-salt diet. However, little is known about the role of ETB in the primary circadian pacemaker in the brain, the suprachiasmatic nucleus (SCN), despite recent reports showing its enrichment in SCN astrocytes. In this study, we tested the hypothesis that high-salt diet (4.0% NaCl) impacts the circadian system via the ETB receptor at the behavioral, molecular, and physiological levels in C57BL/6 mice. Two weeks of high-salt diet feeding changed the organization of nighttime wheel-running activity, as well as increased the SCN expression of ETB mRNA determined by fluorescence in situ hybridization at night. Neuronal excitability determined using loose-patch electrophysiology was also elevated at night. This high-salt diet-induced increase in SCN activity was ameliorated by ex vivo bath application of an ETB antagonist and could be mimicked with acute treatment of endothelin-3. Finally, we found that the excitatory effects of endothelin-3 were blocked with co-application of an N-methyl-D-aspartate (NMDA) receptor antagonist, suggesting that glutamate mediates endothelin-induced neuronal excitability in the SCN. Together, our data demonstrate the presence of functional ETB receptors in SCN astrocytes and point to a novel role for endothelin signaling in mediating neuronal responses to a dietary sodium intake.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568980","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 Exerts Partial Diet-dependent Effects on Energy Expenditure and Skeletal Muscle Mitochondrial Pathways in a Preclinical Model.","authors":"Chelsea N Johnson, Colton R Lysaker, Elaine C Gast, Colin S McCoin, Riley E Kemna, Kelly N Z Fuller, Benjamin A Kugler, Edziu Franczak, Vivien Csikos, Julie Allen, Casey S John, MaryJane A Wolf, Matthew E Morris, John P Thyfault, Heather M Wilkins, Paige C Geiger, Jill K Morris","doi":"10.1093/function/zqaf017","DOIUrl":"10.1093/function/zqaf017","url":null,"abstract":"<p><p>Apolipoprotein E4 (APOE4) is the greatest genetic risk factor for Alzheimer's (AD) and is linked to whole-body metabolic dysfunction. However, it is unclear how APOE4 interacts with modifiable factors like diet to impact tissues central to regulating whole-body metabolism. We examined APOE4- and Western diet-driven effects in skeletal muscle using APOE3 (control) and APOE4 targeted replacement mice on a C57BL/6NTac background fed a high-fat diet (HFD, 45% kcal fat) or low-fat diet (LFD, 10% kcal fat) for 4 months (n = 7-8 per genotype/diet/sex combination). We assessed body composition and whole-body outcomes linked to skeletal muscle function including respiratory exchange ratio (RER) and resting energy expenditure (REE). In skeletal muscle, we evaluated the proteome and mitochondrial respiration. In males only, APOE4 drove greater gains in fat mass and lower gains in lean mass on both diets. APOE4 did not affect daily RER but was associated with elevated REE in males and lower REE in HFD females after covarying for body composition. Skeletal muscle proteomics showed APOE4 exerts several diet- and sex-specific effects on mitochondrial pathways, including elevations in branched-chain amino catabolism in HFD males and reductions in oxidative phosphorylation in LFD females. This did not translate to differences in skeletal muscle mitochondrial respiration, suggesting that compensatory mechanisms may sustain mitochondrial function at this age. Our work indicates that genetic risk may mediate early life effects on skeletal muscle mitochondria and energy expenditure that are partially dependent on diet. This has important implications for mitigating ad risk in APOE4 carriers.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712443","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":"Depletion of Mitochondrial Cyclophilin D in Endothelial and Smooth Muscle Cells Attenuates Vascular Dysfunction and Hypertension.","authors":"Anna Dikalova, Mingfang Ao, Louise Lantier, Sergey Gutor, Sergey Dikalov","doi":"10.1093/function/zqaf006","DOIUrl":"10.1093/function/zqaf006","url":null,"abstract":"<p><p>Hypertension is a major risk factor of cardiovascular disease affecting nearly half of adult population. It is associated with mitochondrial dysfunction and understanding these mechanisms is important to develop new therapies. Cyclophilin D (CypD) promotes mitochondrial swelling and dysfunction. The objective of this study is to test if CypD depletion attenuates vascular dysfunction and hypertension using endothelial and smooth muscle-specific CypD knockout mice in angiotensin II model of vascular dysfunction and hypertension. Our results show that depletion of endothelial CypD prevents angiotensin II-induced impairment of endothelial-dependent vasorelaxation, preserves endothelial nitric oxide and mitochondrial respiration, attenuates hypertension, vascular oxidative stress and vascular metabolic glycolytic-switch. Depletion of smooth muscle CypD slightly reduces angiotensin II-induced hypertension, protects vascular nitric oxide and vasorelaxation, decreases vascular superoxide, diminishes angiotensin II-induced vascular glycolysis, hypertrophy and fibrosis. These data suggest \"metabolic\" and \"redox\" crosstalk between endothelial and smooth muscle cells. Endothelial CypD depletion reduces not only endothelial glycolysis but also attenuates smooth muscle cell glycolytic switch. Smooth muscle CypD depletion reduced not only smooth muscle glycolysis, but it also attenuated endothelial glycolysis. Vascular oxidative stress was inhibited both in EcCypDKO and SmcCypDKO mice, therefore, cell-specific CypD depletion had \"global\" antioxidant effect in vasculature. Our results support a novel function of mitochondrial CypD in regulation of superoxide and metabolism in vascular smooth muscle and endothelial cells which affect endothelial barrier and smooth muscle vascular functions. We suggest that blocking vascular CypD reduces vascular oxidative stress, improves vascular metabolism and vascular function which may be beneficial in cardiovascular disease.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371188","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":"Mapping Organism-wide Single Cell mRNA Expression Linked to Extracellular Vesicle Biogenesis, Secretion, and Cargo.","authors":"Thomas J LaRocca, Daniel S Lark","doi":"10.1093/function/zqaf005","DOIUrl":"10.1093/function/zqaf005","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are functional lipid-bound nanoparticles trafficked between cells and found in every biofluid. It is widely claimed that EVs can be secreted by every cell, but the quantity and composition of these EVs can differ greatly among cell types and tissues. Defining this heterogeneity has broad implications for EV-based communication in health and disease. Recent discoveries have linked single-cell EV secretion to the expression of genes encoding EV machinery and cargo. To gain insight at single-cell resolution across an entire organism, we compared the abundance, variance, and co-expression of 67 genes involved in EV biogenesis and secretion, or carried as cargo, across >44 000 cells obtained from 117 cell populations in the Tabula Muris. Our analysis provides both novel holistic and cell population-specific insight into EV biology. The highest overall expression of EV genes occurs in secretory cells of the pancreas and perhaps more surprisingly, multiple non-neuronal cell populations of the brain. We find that the most abundant EV genes encode the most abundant EV cargo proteins (tetraspanins and syndecans), but these genes are highly differentially expressed across functionally distinct cell populations. Expression variance identifies dynamic and constitutively expressed EV genes while co-expression analysis reveals novel insights into cell population-specific coordination of expression. Results of our analysis illustrate the diverse transcriptional regulation of EV genes which could be useful for predicting how individual cell populations might communicate via EVs to influence health and disease.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043883","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":"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":"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}