Journal of Physiology-London最新文献

{"title":"Acute oral digoxin in healthy adults hastens fatigue and increases plasma K+ during intense exercise, despite preserved skeletal muscle Na+,K+-ATPase","authors":"Tania Atanasovska, Trevor Farr, Robert Smith, Aaron C. Petersen, Andrew Garnham, Mitchell J. Andersen, Henry Krum, Chiew Wong, Michael J. McKenna","doi":"10.1113/JP287274","DOIUrl":"10.1113/JP287274","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>We investigated acute effects of the Na<sup>+</sup>,K<sup>+</sup>-ATPase (NKA) inhibitor, digoxin, on muscle NKA content and isoforms, arterial plasma [K<sup>+</sup>] ([K<sup>+</sup>]<sub>a</sub>) and fatigue with intense exercise. In a randomised, crossover, double-blind design, 10 healthy adults ingested 0.50 mg digoxin (DIG) or placebo (CON) 60 min before cycling for 1 min at 60% <span></span><math>\u0000 <semantics>\u0000 <msub>\u0000 <mover>\u0000 <mi>V</mi>\u0000 <mo>̇</mo>\u0000 </mover>\u0000 <mrow>\u0000 <msub>\u0000 <mi>O</mi>\u0000 <mn>2</mn>\u0000 </msub>\u0000 <mi>peak</mi>\u0000 </mrow>\u0000 </msub>\u0000 <annotation>${{dot{V}}_{{{{mathrm{O}}}_{mathrm{2}}}{mathrm{peak}}}}$</annotation>\u0000 </semantics></math> then at 95% <span></span><math>\u0000 <semantics>\u0000 <msub>\u0000 <mover>\u0000 <mi>V</mi>\u0000 <mo>̇</mo>\u0000 </mover>\u0000 <mrow>\u0000 <msub>\u0000 <mi>O</mi>\u0000 <mn>2</mn>\u0000 </msub>\u0000 <mi>peak</mi>\u0000 </mrow>\u0000 </msub>\u0000 <annotation>${{dot{V}}_{{{{mathrm{O}}}_{mathrm{2}}}{mathrm{peak}}}}$</annotation>\u0000 </semantics></math> until fatigue. Pre- and post-exercise muscle biopsies were analysed for [<sup>3</sup>H]-ouabain binding site content without (OB-F<sub>ab</sub>) and after incubation in digoxin antibody (OB+F<sub>ab</sub>) and NKA α<sub>1-2</sub> and β<sub>1-2</sub> isoform proteins. In DIG, pre-exercise serum [digoxin] reached 3.36 (0.80) nM [mean (SD)] and muscle NKA–digoxin occupancy was 8.2%. Muscle OB-F<sub>ab</sub> did not differ between trials, whereas OB+F<sub>ab</sub> was higher in DIG than CON (8.1%, treatment main effect, <i>P</i> = 0.001), whilst muscle NKA α<sub>1-2</sub> and β<sub>1-2</sub> abundances were unchanged by digoxin. Fatigue occurred earlier in DIG than CON [−7.7%, 2.90 (0.77) <i>vs</i>. 3.14 (0.86) min, respectively; <i>P</i> = 0.037]. [K<sup>+</sup>]<sub>a</sub> increased during exercise until 1 min post-exercise (<i>P</i> = 0.001), and fell below baseline at 3–10 (<i>P</i> = 0.001) and 20 min post-exercise (<i>P</i> = 0.022, time main effect). In DIG, [K<sup>+</sup>]<sub>a</sub> (<i>P</i> = 0.035, treatment effect) and [K<sup>+</sup>]<sub>a</sub> rise pre-fatigue were greater [1.64 (0.73) <i>vs</i>. 1.55 (0.73), <i>P</i> = 0.016], with lesser post-exercise [K<sup>+</sup>]<sub>a</sub> decline than CON [−2.5","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"6849-6869"},"PeriodicalIF":4.7,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-intensity interval exercise is more efficient than medium intensity exercise at inducing neurogenesis","authors":"Marvin Lambertus, Samuel Geiseler, Cecilie Morland","doi":"10.1113/JP287328","DOIUrl":"10.1113/JP287328","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>The neurogenic potential of the brain decreases during ageing, whereas the risk of neurodegenerative diseases and stroke rises. This creates a mismatch between the rate of neuron loss and the brain's capacity for replacement. Adult neurogenesis primarily occurs in the subgranular zone (SGZ) and the ventricular-subventricular zone (V-SVZ). Exercise enhances SGZ neurogenesis, and we previously showed that V-SVZ neurogenesis is induced by exercise via activation of the lactate receptor HCA<sub>1</sub>. Here, we investigated how high-intensity interval training (HIIT) and medium-intensity interval training (MIIT) affect neurogenesis in these niches. Wild-type (WT) and HCA<sub>1</sub> knockout (KO) mice were randomized to sedentary, HIIT or MIIT (<i>n</i> = 5–8 per group) for 3 weeks. In the SGZ, HIIT increased the density of doublecortin (DCX)-positive cells in WT mice by 85% (5.77±1.76 <i>vs</i>. 3.12±1.54 cells/100 µm, <i>P</i> = 0.013) and KO mice (67% increase; 7.91±2.92 <i>vs</i>. 4.73±1.63 cells/100 µm, <i>P</i> = 0.004). MIIT did not alter the density of DCX-positive cells in either genotype. HIIT increased the density of Ki-67-positive cells only in KO mice (<i>P</i> = 0.038), whereas no differences in nestin-positive cells were observed. In the V-SVZ, HIIT increased the density of DCX-positive cells in WT mice by 155% (117.79±39.72 <i>vs</i>. 46.25±19.96 cells/100 µm, <i>P </i>< 0.001) and MIIT increased the density of DCX-positive cells by 80% (83.26±39.48 <i>vs</i>. 46.25±19.96 cells/100µm, <i>P</i> = 0.027). No exercise-induced changes were observed in KO mice. Similar patterns were noted for Ki-67 positive and DCX/Ki-67 double-positive cells in the V-SVZ. These findings suggest that HIIT enhances neurogenesis more robustly than MIIT in both niches, with HCA<sub>1</sub> playing a crucial role in V-SVZ neurogenesis.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The neurogenic potential of the brain decreases with age, whereas the risk of neurodegenerative diseases and stroke increases, highlighting a mismatch between neuronal loss and replacement capacity.</li>\u0000 \u0000 <li>Exercise enhances neurogenesis in both the subgranular zone and the ventricular-subventricular zone.</li>\u0000 \u0000 <li>High-intensity interval exercise is more effective than medium-intensity interval exercise at promoting neurogenesis in both the subgranular zone and the ventricular-subventricular zone of wild-type mice.</li>\u0000 ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"7027-7042"},"PeriodicalIF":4.7,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287328","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calmodulin regulates TRPV5 intracellular trafficking and plasma membrane abundance","authors":"Malou Zuidscherwoude, Teodora Grigore, Brenda van de Langenberg, Guusje Witte, Jenny van der Wijst, Joost G. Hoenderop","doi":"10.1113/JP286182","DOIUrl":"10.1113/JP286182","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>As a member of the transient receptor potential (TRP) superfamily of ion channels, TRPV5 is a unique Ca<sup>2+</sup>-selective channel important for active reabsorption of Ca<sup>2+</sup> in the kidney. TRPV5-mediated Ca<sup>2+</sup> entry into the cell is controlled by a negative feedback mechanism, in which calmodulin (CaM) blocks the TRPV5 pore upon Ca<sup>2+</sup> binding. Combining microscopy techniques and biochemical assays, the present study uncovered an auxiliary role for CaM in the regulation of human (h)TRPV5 intracellular trafficking. Overexpressed hTRPV5 was mainly localised to the endoplasmic reticulum (ER) and associated with peripheral ER tubules. Limiting expression using the HEK293 TET-off system revealed that hTRPV5 trafficked through the endocytic recycling pathway. CaM co-localised with hTRPV5 at intracellular sites and overexpression of CaM slowed hTRPV5 exit from the ER. In accordance, CaM binding-disrupting truncations of the TRPV5 C-terminus (698X) or knockdown of endogenous CaM by small interfering RNA resulted in an increased fraction of TRPV5 that localised to the plasma membrane. hTRPV5 expressing cells had an increased intracellular Ca<sup>2+</sup> concentration upon knockdown of CaM. The protein abundance of the Ca<sup>2+</sup> impermeable hTRPV5-D542 mutant is also regulated by CaM, which suggests that the mode of action is independent of disrupted intracellular calcium concentrations. In conclusion, our study reveals a novel role for CaM in Ca<sup>2+</sup>-dependent TRPV5 regulation, modulating TRPV5 intracellular trafficking.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The renal Ca<sup>2+</sup> channel TRPV5 is a crucial player in maintenance of the body's Ca<sup>2+</sup> homeostasis.</li>\u0000 \u0000 <li>Ca<sup>2+</sup> transport through TRPV5 is controlled by single channel activity, as well as TRPV5 plasma membrane abundance.</li>\u0000 \u0000 <li>Calmodulin (CaM) co-localised with TRPV5 at intracellular sites and retained TRPV5 in the endoplasmic reticulum.</li>\u0000 \u0000 <li>Disrupted CaM–TRPV5 binding or knockdown of endogenous CaM by small interfering RNA (siRNA) resulted in an increased TRPV5 plasma membrane abundance.</li>\u0000 \u0000 <li>Knockdown of endogenous CaM by siRNA resulted in increased intracellular Ca<sup>2+</sup> concentrations. The regulation of TRPV5 trafficking by CaM is independent of the effect of","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"6871-6888"},"PeriodicalIF":4.7,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP286182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incretin hormones and obesity.","authors":"Constanza Alcaino, Frank Reimann, Fiona M Gribble","doi":"10.1113/JP286293","DOIUrl":"https://doi.org/10.1113/JP286293","url":null,"abstract":"<p><p>The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play critical roles in co-ordinating postprandial metabolism, including modulation of insulin secretion and food intake. They are secreted from enteroendocrine cells in the intestinal epithelium following food ingestion, and act at multiple target sites including pancreatic islets and the brain. With the recent development of agonists targeting GLP-1 and GIP receptors for the treatment of type 2 diabetes and obesity, and the ongoing development of new incretin-based drugs with improved efficacy, there is great interest in understanding the physiology and pharmacology of these hormones.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maladaptive cardiomyocyte calcium handling in adult offspring of hypoxic pregnancy: protection by antenatal maternal melatonin","authors":"Mitchell C. Lock,&nbsp;Olga V. Patey,&nbsp;Kerri L. M. Smith,&nbsp;Youguo Niu,&nbsp;Ben Jaggs,&nbsp;Andrew W. Trafford,&nbsp;Dino A. Giussani,&nbsp;Gina L. J. Galli","doi":"10.1113/JP287325","DOIUrl":"10.1113/JP287325","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Chronic fetal hypoxia is one of the most common complications of pregnancy and can programme cardiac abnormalities in adult offspring including ventricular remodelling, diastolic dysfunction and sympathetic dominance. However, the underlying mechanisms at the level of the cardiomyocyte are unknown, preventing the identification of targets for therapeutic intervention. Therefore, we aimed to link echocardiographic data with cardiomyocyte function to reveal cellular mechanism for cardiac dysfunction in rat offspring from hypoxic pregnancy. Further, we investigated the potential of maternal treatment with melatonin as antenatal antioxidant therapy. Wistar rats were randomly allocated into normoxic (21% O&lt;sub&gt;2&lt;/sub&gt;) or hypoxic (13% O&lt;sub&gt;2&lt;/sub&gt;) pregnancy with or without melatonin treatment (5 µg/ml; normoxic melatonin in the maternal drinking water from gestational day 6 to 20 (term = 22 days). After delivery, male and female offspring were maintained to adulthood (16 weeks). Cardiomyocytes were isolated from the left and right ventricles, and calcium (Ca&lt;sup&gt;2+&lt;/sup&gt;) handling was investigated in field-stimulated myocytes. Systolic and diastolic function was negatively impacted in male and female offspring of hypoxic pregnancy demonstrating biventricular systolic and diastolic dysfunction and compensatory increases in cardiac output. Ca&lt;sup&gt;2+&lt;/sup&gt; transients from isolated cardiomyocytes in offspring of both sexes in hypoxic pregnancy displayed diastolic dysfunction with a reduced rate of [Ca&lt;sup&gt;2+&lt;/sup&gt;]&lt;sub&gt;i&lt;/sub&gt; recovery. Cardiac and cardiomyocyte dysfunction in male and female adult offspring was ameliorated by maternal antenatal treatment with melatonin in hypoxic pregnancy. Therefore, cardiomyocyte Ca&lt;sup&gt;2+&lt;/sup&gt; mishandling provides a cellular mechanism explaining functional deficits in hearts of male and female offspring in pregnancies complicated by chronic fetal hypoxia.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;This study identified significant changes in Ca&lt;sup&gt;2+&lt;/sup&gt; handling within cardiomyocytes isolated from offspring of hypoxic pregnancy including reduced systolic Ca&lt;sup&gt;2+&lt;/sup&gt; transients, impaired diastolic recovery of [Ca&lt;sup&gt;2+&lt;/sup&gt;]&lt;sub&gt;i&lt;/sub&gt; and a greater increase in systolic [Ca&lt;sup&gt;2+&lt;/sup&gt;]&lt;sub&gt;i&lt;/sub&gt; amplitude to β-adrenergic stimulation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;These changes in cardiomyocyte Ca&lt;sup&gt;2+&lt;/sup&gt; handling help to explain dysregulation of biventricular systolic and diastolic dysfunction determined by","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"6683-6703"},"PeriodicalIF":4.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287325","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated responses of the SIP syncytium generate a major motility pattern in the colon","authors":"Sang Don Koh,&nbsp;Ji Yeon Lee,&nbsp;Seung-Bum Ryoo,&nbsp;Bernard T. Drumm,&nbsp;Hyun Jin Kim,&nbsp;Sal A. Baker,&nbsp;Kenton M. Sanders","doi":"10.1113/JP287315","DOIUrl":"10.1113/JP287315","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;The peristaltic reflex has been a central concept in gastrointestinal motility; however, evidence was published recently suggesting that post-stimulus responses that follow inhibitory neural responses provide the main propulsive force in colonic motility. This new concept was based on experiments on proximal colon where enteric inhibitory neural inputs are mainly nitrergic. However, the nature of inhibitory neural inputs changes from proximal to distal colon where purinergic inhibitory regulation dominates. In spite of the transition from nitrergic to purinergic regulation, post-stimulus responses and propulsive contractions were both blocked by antagonists of a conductance (ANO1) exclusive to interstitial cells of Cajal (ICC). How purinergic neurotransmission, transduced by PDGFRα&lt;sup&gt;+&lt;/sup&gt; cells, can influence ANO1 in ICC is unknown. We compared neural responses in proximal and distal colon. Post-stimulus responses were blocked by inhibition of nitrergic neurotransmission in proximal colon, but P2Y1 receptor antagonists were more effective in distal colon. Ca&lt;sup&gt;2+&lt;/sup&gt; entry through voltage-dependent channels (Ca&lt;sub&gt;V&lt;/sub&gt;3) enhances Ca&lt;sup&gt;2+&lt;/sup&gt; release in ICC. Thus, we reasoned that hyperpolarization caused by purinergic responses in PDGFRα&lt;sup&gt;+&lt;/sup&gt; cells, which are electrically coupled to ICC, might decrease inactivation of Ca&lt;sub&gt;V&lt;/sub&gt;3 channels and activate Ca&lt;sup&gt;2+&lt;/sup&gt; entry into ICC via anode-break upon cessation of inhibitory responses. Post-stimulus responses in distal colon were blocked by MRS2500 (P2Y1 receptor antagonist), apamin (SK channel antagonist) and NNC55-0396 (Ca&lt;sub&gt;V&lt;/sub&gt;3 antagonist). These compounds also blocked propagating contractions in mid and distal colon. These data provide the first clear demonstration that integration of functions in the smooth muscle–ICC–PDGFRα&lt;sup&gt;+&lt;/sup&gt; cell (SIP) syncytium generates a major motility behaviour.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Propagating propulsive contractions initiated by the enteric nervous system are a major motility behaviour in the colon. A major component of contractions, necessary for propulsive contractions, occurs at cessation of enteric inhibitory neurotransmission (post-stimulus response) and is generated by interstitial cells of Cajal (ICC), which are electrically coupled to smooth muscle cells.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The nature of enteric inhibitory neurotransmission shifts from proximal colon, where it is predominantly due to nitric oxide, to distal colon, where it is predominantly due to purine neurot","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"6659-6682"},"PeriodicalIF":4.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brief response to Terrar","authors":"David A. Eisner,&nbsp;David J. Greensmith,&nbsp;Andrew W. Trafford","doi":"10.1113/JP288008","DOIUrl":"10.1113/JP288008","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"7111"},"PeriodicalIF":4.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP288008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPV4 couples with NCX1 to mediate glucose-dependent glucagon-like peptide-1 release and improve glucose homeostasis","authors":"Xiongying Chen,&nbsp;Fenglan Chu,&nbsp;Sijin Sunchen,&nbsp;Junhui Li,&nbsp;Mengting Zhang,&nbsp;Feng Xu,&nbsp;Hui Dong","doi":"10.1113/JP287092","DOIUrl":"10.1113/JP287092","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>Although glucose, as a secretagogue of intestinal hormone, can stimulate glucagon-like peptide 1 (GLP-1) release, it has not been fully elucidated how glucose triggers GLP-1 release from enteroendocrine cells (EECs). Here, we investigated the regulatory mechanisms of glucose-induced Ca²⁺-dependent GLP-1 release from EECs. STC-1 cells that possess many features of native intestinal EECs were used. The expression of TRPV4 channels and Na⁺/Ca²⁺ exchanger 1 (NCX1) in STC-1 was analysed by immunocytochemistry. Calcium and sodium imaging, and patch clamp were applied, and GLP-1 was detected using quantitative PCR, western blot and enzyme-linked immunosorbent assays. Glucose markedly induced Na⁺ and Ca²⁺ signalling in STC-1 cells. The glucose-induced Ca²⁺ signalling was significantly attenuated by selective blockers of the voltage-gated Ca²⁺ channels (VGCC), ryanodine receptors and Ins<i>P</i>₃ receptors. Most importantly, glucose-induced Ca²⁺ signalling was significantly attenuated by the selective blockers of TRPV4 and NCX1. Moreover, the physical and functional couplings of TRPV4 and NCX1 were demonstrated in STC-1 cells, and they promoted glucose-mediated Ca²⁺ signalling to upregulate expression and release of GLP-1 via Ca²⁺-sensitive PKCα. Finally, the selective TRPV4 activator improved glucose tolerance in an oral glucose tolerance test in mice, but the selective blockers of TRPV4 and NCX1 attenuated glucose-induced intestinal GLP-1 release. We demonstrate a coupling of TRPV4 and NCX1 in EECs to regulate glucose-stimulated intestinal GLP-1 release via a novel TRPV4/NCX1/Ca²⁺/PKCα axis. Targeting this axis may provide new therapeutic potentials for glycometabolic diseases.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Glucagon-like peptide 1 (GLP-1) secreted primarily from intestinal L cells in response to meals plays a critical role in maintaining glucose homeostasis.</li>\u0000 \u0000 <li>Physical and functional couplings of TRPV4 and NCX1 are pivotal in glucose-stimulated GLP-1 release via a novel TRPV4/NCX1/Ca²⁺/PKCα axis.</li>\u0000 \u0000 <li>Since this axis is involved in glucose homeostasis, our findings may provide new potential drug targets for prevention/treatment of glycometabolic diseases.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"6827-6847"},"PeriodicalIF":4.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RyR cooperativity and mobile buffers: functional clues to the resolution of the cardiac calcium wave problem?","authors":"Michael A. Colman","doi":"10.1113/JP287762","DOIUrl":"10.1113/JP287762","url":null,"abstract":"&lt;p&gt;Spontaneous calcium (Ca&lt;sup&gt;2+&lt;/sup&gt;) sparks and propagating Ca&lt;sup&gt;2+&lt;/sup&gt; waves have been closely linked to the cellular mechanisms underlying cardiac arrhythmias. The resulting spontaneous Ca&lt;sup&gt;2+&lt;/sup&gt; transients can activate the sodium–calcium exchanger, generating an inward current that may lead to early or delayed afterdepolarisations that can serve as both triggers and substrate for arrhythmogenesis (Liu et al., &lt;span&gt;2015&lt;/span&gt;). Understanding these phenomena is therefore crucial for elucidation of the mechanisms of arrhythmia.&lt;/p&gt;&lt;p&gt;Spontaneous Ca&lt;sup&gt;2+&lt;/sup&gt; sparks occur in restricted subspaces that mediate Ca&lt;sup&gt;2+&lt;/sup&gt;-induced-Ca&lt;sup&gt;2+&lt;/sup&gt;-release (CICR) and arise from the spontaneous opening of clusters of ryanodine receptors (RyRs), the channels responsible for Ca&lt;sup&gt;2+&lt;/sup&gt; release. Diffusion of Ca&lt;sup&gt;2+&lt;/sup&gt; between neighbouring clusters provides a mechanism for the nucleation and propagation of spontaneous Ca&lt;sup&gt;2+&lt;/sup&gt; waves throughout the cell. This ‘fire-diffuse-fire’ mechanism posits a reasonable and simple explanation for the propagation of Ca&lt;sup&gt;2+&lt;/sup&gt; waves. Given this, one could very well then ask: wherein lies the problem?&lt;/p&gt;&lt;p&gt;The issue at the heart of the Ca&lt;sup&gt;2+&lt;/sup&gt; wave problem is that our contemporary computational models of spatial Ca&lt;sup&gt;2+&lt;/sup&gt; handling at the whole-cell scale, based on our best functional and structural knowledge, struggle to reproduce sustained, propagating Ca&lt;sup&gt;2+&lt;/sup&gt; waves under physiological conditions. This suggests that something is missing from our theoretical understanding.&lt;/p&gt;&lt;p&gt;For a Ca&lt;sup&gt;2+&lt;/sup&gt; spark to propagate between clusters, the local concentration elevation at the neighbouring cluster must be sufficient to induce CICR. Yet, it is necessarily not much higher than diastolic levels due to buffering and the impact of diffusion in three dimensions; RyR model parameters that induce CICR at these concentrations often lead to excessive spontaneous sparks and arrhythmogenesis. Models have therefore had to make compromises to solve this problem (Colman et al., &lt;span&gt;2022&lt;/span&gt;), either incorporating ‘natural’ spatial coupling but relying on large Ca&lt;sup&gt;2+&lt;/sup&gt; transients (&gt;4 µM) to propagate Ca&lt;sup&gt;2+&lt;/sup&gt; waves, or by ‘artificially’ strengthening the spatial coupling through the inclusion of coupled Ca&lt;sup&gt;2+&lt;/sup&gt; subspaces, with the benefit of maintaining physiological Ca&lt;sup&gt;2+&lt;/sup&gt; transients (∼0.5–1 µM). It seems, at least, almost impossible for detailed models to fulfil both normal CICR and sustained Ca&lt;sup&gt;2+&lt;/sup&gt; waves without relying on these coupled subspaces, which lack structural evidence.&lt;/p&gt;&lt;p&gt;It is likely no coincidence that diseased myocytes that are very prone to sustained Ca&lt;sup&gt;2+&lt;/sup&gt; waves have been observed with severe structural remodelling, such as a loss of the transverse and axial tubule system, fragmentation of the arrangement of RyRs within clusters and rearrangement of inter-cluster spacing, and remodelling of o","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"6637-6638"},"PeriodicalIF":4.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287762","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of ryanodine receptor cooperativity in Ca2+-wave-mediated triggered activity in cardiomyocytes","authors":"Mingwang Zhong,&nbsp;Alain Karma","doi":"10.1113/JP286145","DOIUrl":"10.1113/JP286145","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Ca&lt;sup&gt;2+&lt;/sup&gt; waves are known to trigger delayed after-depolarizations that can cause malignant cardiac arrhythmias. However, modelling Ca&lt;sup&gt;2+&lt;/sup&gt; waves using physiologically realistic models has remained a major challenge. Existing models with low Ca&lt;sup&gt;2+&lt;/sup&gt; sensitivity of ryanodine receptors (RyRs) necessitate large release currents, leading to an unrealistically large Ca&lt;sup&gt;2+&lt;/sup&gt; transient amplitude incompatible with the experimental observations. Consequently, current physiologically detailed models of delayed after-depolarizations resort to unrealistic cell architectures to produce Ca&lt;sup&gt;2+&lt;/sup&gt; waves with a normal Ca&lt;sup&gt;2+&lt;/sup&gt; transient amplitude. Here, we address these challenges by incorporating RyR cooperativity into a physiologically detailed model with a realistic cell architecture. We represent RyR cooperativity phenomenologically through a Hill coefficient within the sigmoid function of RyR open probability. Simulations in permeabilized myocytes with high Ca&lt;sup&gt;2+&lt;/sup&gt; sensitivity reveal that a sufficiently large Hill coefficient is required for Ca&lt;sup&gt;2+&lt;/sup&gt; wave propagation via the fire–diffuse–fire mechanism. In intact myocytes, propagating Ca&lt;sup&gt;2+&lt;/sup&gt; waves can occur only within an intermediate Hill coefficient range. Within this range, the spark rate is neither too low, enabling Ca&lt;sup&gt;2+&lt;/sup&gt; wave propagation, nor too high, allowing for the maintenance of a high sarcoplasmic reticulum load during diastole of the action potential. Moreover, this model successfully replicates other experimentally observed manifestations of Ca&lt;sup&gt;2+&lt;/sup&gt;-wave-mediated triggered activity, including phase 2 and phase 3 early after-depolarizations and high-frequency voltage–Ca&lt;sup&gt;2+&lt;/sup&gt; oscillations. These oscillations feature an elevated take-off potential with depolarization mediated by the L-type Ca&lt;sup&gt;2+&lt;/sup&gt; current. The model also sheds light on the roles of luminal gating of RyRs and the mobile buffer ATP in the genesis of these arrhythmogenic phenomena.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Existing mathematical models of Ca&lt;sup&gt;2+&lt;/sup&gt; waves use an excessively large Ca&lt;sup&gt;2+&lt;/sup&gt;-release current or unrealistic diffusive coupling between release units.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Our physiologically realistic model, using a Hill coefficient in the ryanodine receptor (RyR) gating function to represent RyR cooperativity, addresses these limitations and generates organized Ca&lt;sup&gt;2+&lt;/sup&gt; waves at Hill coefficients ranging from ∼5 to 10, as opposed to the traditional value of 2","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"6745-6787"},"PeriodicalIF":4.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}