Function (Oxford, England)最新文献

{"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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333860","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":"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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302566","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":"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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333859","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":"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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302568","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":"Intrinsic Skeletal Muscle Function and Contraction-Stimulated Glucose Uptake Do Not Vary by Time-of-Day in Mice.","authors":"Liam S Fitzgerald, Shannon N Bremner, Samuel R Ward, Yoshitake Cho, Simon Schenk","doi":"10.1093/function/zqae035","DOIUrl":"10.1093/function/zqae035","url":null,"abstract":"<p><p>A growing body of data suggests that skeletal muscle contractile function and glucose metabolism vary by time-of-day, with chronobiological effects on intrinsic skeletal muscle properties being proposed as the underlying mediator. However, no studies have directly investigated intrinsic contractile function or glucose metabolism in skeletal muscle over a 24 h circadian cycle. To address this, we assessed intrinsic contractile function and endurance, as well as contraction-stimulated glucose uptake, in isolated extensor digitorum longus and soleus from mice at 4 times-of-day (zeitgeber times 1, 7, 13, 19). Significantly, though both muscles demonstrated circadian-related changes in gene expression, there were no differences between the 4 time points in intrinsic contractile function, endurance, and contraction-stimulated glucose uptake, regardless of sex. Overall, these results suggest that time-of-day variation in exercise performance and the glycemia-reducing benefits of exercise are not due to chronobiological effects on intrinsic muscle function or contraction-stimulated glucose uptake.</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":"141972405","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":"Regulation of Kv1.2 Redox-Sensitive Gating by the Transmembrane Lectin LMAN2.","authors":"Shawn M Lamothe, Damayantee Das, Anson A Wong, Yubin Hao, Aislinn D Maguire, Bradley J Kerr, Victoria A Baronas, Harley T Kurata","doi":"10.1093/function/zqae041","DOIUrl":"10.1093/function/zqae041","url":null,"abstract":"<p><p>Voltage gated potassium (Kv)1.2 channels influence excitability and action potential propagation in the nervous system. Unlike closely related Kv1 channels, Kv1.2 exhibits highly variable voltage-dependence of gating, attributed to regulation by unidentified extrinsic factors. Variability of Kv1.2 gating is strongly influenced by the extracellular redox potential, and we demonstrate that Kv1.2 currents in dorsal root ganglion sensory neurons exhibit similar variability and redox sensitivity as observed when the channel is heterologously expressed in cell lines. We used a functional screening approach to test the effects of candidate regulatory proteins on Kv1.2 gating, using patch clamp electrophysiology. Among 52 candidate genes tested, we observed that co-expression with the transmembrane lectin LMAN2 led to a pronounced gating shift of Kv1.2 activation to depolarized voltages in CHO and L(tk-) cell lines, accompanied by deceleration of activation kinetics. Overexpression of LMAN2 promoted a slow gating mode of Kv1.2 that mimics the functional outcomes of extracellular reducing conditions, and enhanced sensitivity to extracellular reducing agents. In contrast, shRNA-mediated knockdown of endogenous LMAN2 in cell lines reduced Kv1.2 redox sensitivity and gating variability. Kv1.2 sensitivity to LMAN2 is abolished by mutation of neighboring residues F251 and T252 in the intracellular S2-S3 linker, and these also abolish redox-dependent gating changes, suggesting that LMAN2 influences the same pathway as redox for Kv1.2 modulation. In conclusion, we identified LMAN2 as a candidate regulatory protein that influences redox-dependent modulation of Kv1.2, and clarified the structural elements of the channel that are required for sensitivity.</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":"142302567","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":"Exploring Circadian Changes in Muscle Physiology: Methodological Considerations.","authors":"Mark R Viggars, Karyn A Esser","doi":"10.1093/function/zqae038","DOIUrl":"10.1093/function/zqae038","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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127513","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":"Malaria and Hypertension: What Is the Direction of Association?","authors":"Aparna Tiwari, Auley De, Abhinav Sinha","doi":"10.1093/function/zqae037","DOIUrl":"10.1093/function/zqae037","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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115681","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":"A Skeletal Muscle-Mediated Anticontractile Response on Vascular Tone: Unraveling the Lactate-AMPK-NOS1 Pathway in Femoral Arteries.","authors":"Milene T Fontes, Tiago J Costa, Ricardo B de Paula, Fênix A Araújo, Paula R Barros, Paul Townsend, Landon Butler, Kandy T Velazquez, Fiona Hollis, Gisele F Bomfim, Joshua T Butcher, Cameron G McCarthy, Camilla F Wenceslau","doi":"10.1093/function/zqae042","DOIUrl":"10.1093/function/zqae042","url":null,"abstract":"<p><p>The regulation of vascular tone by perivascular tissues is a complex interplay of various paracrine factors. Here, we investigate the anti-contractile effect of skeletal muscle surrounding the femoral and carotid arteries and its underlying mechanisms. Using male and female Wistar rats, we demonstrated that serotonin, phenylephrine, and U-46619 induced a concentration-dependent vasoconstrictor response in femoral artery rings. Interestingly, this response was diminished in the presence of surrounding femoral skeletal muscle, irrespective of sex. No anti-contractile effect was observed when the carotid artery was exposed to its surrounding skeletal muscle. The observed effect in the femoral artery persisted even in the absence of endothelium and when the muscle was detached from the artery. Furthermore, the skeletal muscle surrounding the femoral artery was able to promote an anti-contractile effect in three other vascular beds (basilar, mesenteric, and carotid arteries). Using inhibitors of lactate dehydrogenase and the 1/4 monocarboxylate transporter, we confirmed the involvement of lactate, as both inhibitors were able to abolish the anti-contractile effect. However, lactate did not directly promote vasodilation; rather, it exerted its effect by activating 5' AMP-activated protein kinase (AMPK) and neuronal nitric oxide synthase (NOS1) in the skeletal muscle. Accordingly, Nω-propyl l-arginine, a specific inhibitor of NOS1, prevented the anti-contractile effect, as well as lactate-induced phosphorylation of NOS1 at the stimulatory serine site (1417) in primary skeletal muscle cells. Phosphorylation of NOS1 was reduced in the presence of Bay-3827, a selective AMPK inhibitor. In conclusion, femoral artery-associated skeletal muscle is a potent paracrine and endocrine organ that influences vascular tone in both sexes. Mechanistically, the anti-contractile effect involves muscle fiber type and/or its anatomical location but not the type of artery or its related vascular endothelium. Finally, the femoral artery anti-contractile effect is mediated by the lactate-AMPK-phospho-NOS1Ser1417-NO signaling axis.</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":"142302564","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}