Journal of Physiology-London最新文献

{"title":"Slow calcium removal contributes to impaired lusitropic response to β-adrenergic stimulation in HFpEF mice","authors":"Tamzin Zawadzki, Diana S. Usai, Sif G. Kaad, Katrine H. Rasmussen, Mie S. Larsen, Jens C. B. Jacobsen, Morten B. Thomsen","doi":"10.1113/JP291587","DOIUrl":"10.1113/JP291587","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>Heart failure with preserved ejection fraction (HFpEF) accounts for over half of heart failure cases, yet its underlying mechanisms remain incompletely understood and effective therapies are lacking. Diastolic dysfunction, a hallmark of HFpEF, may arise from impaired active myocardial relaxation, but the contribution of intracellular calcium (Ca<sup>2+</sup>) handling remains unclear. This study aimed to document impaired lusitropy and diastolic dysfunction in HFpEF, and to determine the contribution of altered ventricular Ca<sup>2+</sup> handling to slowed myocardial relaxation. HFpEF was induced by diet-driven obesity and hypertension. Cardiac function was assessed <i>in vivo</i> by echocardiography, <i>ex vivo</i> in preload-controlled isolated hearts and at the cellular level by Ca<sup>2+</sup> imaging of isolated ventricular myocytes. HFpEF mice developed diastolic dysfunction, hypertrophy, reduced cardiac output and exercise intolerance, yet ejection fraction was preserved. Impaired lusitropy was evident <i>in vivo</i>, <i>ex vivo</i> and at the cellular level, where basal cytosolic Ca<sup>2+</sup> handling was preserved, but the β-adrenergic-recruitable acceleration of Ca<sup>2+</sup> clearance was impaired. This attenuated lusitropic response to β-adrenergic stimulation in HFpEF myocytes was mirrored <i>in vivo</i> during echocardiography. Slowed myocardial relaxation is a consistent feature of HFpEF, evident at the organ, tissue and cellular levels. β-Adrenergic stimulation normally enhances lusitropy, but this response is blunted in HFpEF hearts both <i>in vivo</i> and in isolated cardiomyocytes. Impaired β-adrenergic amplification of Ca<sup>2+</sup> removal is associated with slowed ventricular relaxation, reduced cardiac output and exercise intolerance in HFpEF, identifying defective lusitropic reserve as a potential therapeutic target.\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>Heart failure with preserved ejection fraction (HFpEF) lacks effective therapies, in part because the disease mechanisms remain incompletely defined.</li>\u0000 \u0000 <li>Using a mouse model combining obesity and hypertension, we demonstrate diastolic dysfunction, reduced cardiac output and exercise intolerance despite preserved ejection fraction. Ventricular relaxation was impaired in HFpEF mice <i>in vivo</i> and <i>ex vivo</i>.</li>\u0000 \u0000 <li>β-Adrenergic lusitropic reserve was reduced in HFpEF mice during ultrasound echoc","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8345-8359"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP291587","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117787","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":"Can diet determine glucocorticoid efficacy? Metabolic control of mitochondrial homeostasis in dystrophic muscle","authors":"Anusha Liaqat, Salman Ahmad","doi":"10.1113/JP292108","DOIUrl":"10.1113/JP292108","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8317-8319"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963904","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":"The first brain at the centre: An enteric reframing of the nervous system","authors":"Tim Hibberd, Hayley Rhodes, Nick J. Spencer","doi":"10.1113/JP292328","DOIUrl":"10.1113/JP292328","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8303-8306"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149065576","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":"Effects of exercise followed by a low-carbohydrate diet on peak fat oxidation and mitochondrial coupling control and efficiency in healthy trained men","authors":"K. K. Lange, L. Becker, T. Rømer, M. Hassing, S. T. Høybye, N. Smailes, P. Pardo, B. Danisman, P. F. Andersen, S. Larsen, J. W. Helge","doi":"10.1113/JP291697","DOIUrl":"10.1113/JP291697","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>Whole-body fat oxidation correlates with mitochondrial oxidative capacity, emphasizing the role of mitochondrial function in systemic and skeletal muscle substrate utilization during exercise – a relationship that may be modulated by the prevailing fuel availability. Muscle glycogen is an important fuel during exercise due to its effects on substrate metabolism, but its influence on peak fat oxidation (PFO) and mitochondrial coupling control and efficiency (MCCE) remains unclear. The aim of the study was to investigate the influence of muscle glycogen content on PFO, the intensity eliciting PFO (Fat<sub>max</sub>) and MCCE. Ten trained men participated in a randomized crossover study comprising two interventions conducted over two consecutive days. Day 1 included anthropometric assessments, blood sampling, a muscle biopsy and a graded exercise test followed by a glycogen depletion protocol. The following day blood sampling, muscle biopsy and the graded exercise test were repeated. A diet high or low in carbohydrate was consumed between the days to manipulate glycogen levels. The experiment was repeated after 7–14 days. Muscle samples were analysed for glycogen and triacylglycerol content and MCCE. PFO increased after both interventions and was further enhanced by the combined exercise and low-carbohydrate intervention, where muscle glycogen was low. Fat<sub>max</sub> increased only following the combined exercise and low-carbohydrate intervention. MCCE was unaffected by the interventions. The study concludes that exercise-induced glycogen depletion together with a low-carbohydrate diet increases PFO and Fat<sub>max</sub> but does not influence MCCE. These findings have implications towards understanding and optimizing fat oxidation and as a potential read out of metabolic flexibility.\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>Whole-body fat oxidation is linked to mitochondrial capacity, yet the role of endogenous fuel availability in this relationship has not been studied.</li>\u0000 \u0000 <li>Muscle glycogen is a primary exercise fuel, but its specific influence on peak fat oxidation (PFO), the exercise intensity that elicits PFO (Fat<sub>max</sub>) and mitochondrial coupling control and efficiency (MCCE) is unclear.</li>\u0000 \u0000 <li>Ten trained men completed a randomized crossover study using glycogen depletion and dietary intervention to alter glycogen levels, with exercise tests and muscle biopsies performed ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8467-8483"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP291697","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149065662","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":"A century of Chinese physiology: The Chinese Association for Physiological Sciences as scientific infrastructure and a bridge to the world","authors":"Yun Wang, Xiao-Min Wang, Ming Fan, Tai Yao, Xiong-Li Yang","doi":"10.1113/JP292670","DOIUrl":"10.1113/JP292670","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8290-8294"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP292670","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117771","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":"Interplay between store-operated calcium entry and mitochondrial phosphate handling modulates force and fatigue during exercise","authors":"Emmet A. Francis, Juliette Hamid, Anusha Kumar, Padmini Rangamani","doi":"10.1113/JP289463","DOIUrl":"10.1113/JP289463","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>The dynamics of calcium ions (<span></span><math>\u0000 <semantics>\u0000 <msup>\u0000 <mtext>Ca</mtext>\u0000 <mrow>\u0000 <mn>2</mn>\u0000 <mo>+</mo>\u0000 </mrow>\u0000 </msup>\u0000 <annotation>$text{Ca}^{2+}$</annotation>\u0000 </semantics></math>) in skeletal muscles link electrochemical activation and contractile force generation. Recent experimental data suggest that store-operated <span></span><math>\u0000 <semantics>\u0000 <msup>\u0000 <mtext>Ca</mtext>\u0000 <mrow>\u0000 <mn>2</mn>\u0000 <mo>+</mo>\u0000 </mrow>\u0000 </msup>\u0000 <annotation>$text{Ca}^{2+}$</annotation>\u0000 </semantics></math> entry (SOCE), the process of extracellular <span></span><math>\u0000 <semantics>\u0000 <msup>\u0000 <mtext>Ca</mtext>\u0000 <mrow>\u0000 <mn>2</mn>\u0000 <mo>+</mo>\u0000 </mrow>\u0000 </msup>\u0000 <annotation>$text{Ca}^{2+}$</annotation>\u0000 </semantics></math> influx upon the depletion of <span></span><math>\u0000 <semantics>\u0000 <msup>\u0000 <mtext>Ca</mtext>\u0000 <mrow>\u0000 <mn>2</mn>\u0000 <mo>+</mo>\u0000 </mrow>\u0000 </msup>\u0000 <annotation>$text{Ca}^{2+}$</annotation>\u0000 </semantics></math> from the sarcoplasmic reticulum (SR), helps delay the onset of muscle fatigue during exercise. We hypothesize that SOCE regulates force generation during prolonged muscle activity by allowing for sustained <span></span><math>\u0000 <semantics>\u0000 <msup>\u0000 <mtext>Ca</mtext>\u0000 <mrow>\u0000 <mn>2</mn>\u0000 <mo>+</mo>\u0000 </mrow>\u0000 </msup>\u0000 <annotation>$text{Ca}^{2+}$</annotation>\u0000 </semantics></math> release from the SR. We test this hypothesis with a quantitative biophysical model that simulates the biochemical events of muscle contraction, from depolarization at the T-tubules to <span></span><math>\u0000 <semantics>\u0000 <msup>\u0000 <mtext>Ca</mtext>\u0000 <mrow>\u0000 ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8379-8427"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP289463","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138954","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":"Mitochondrial dynamics and repair differences in two mouse models of Friedreich's ataxia","authors":"Lili Salinas, Francisco Figueroa, Claire B. Montgomery-Bowie, Garrett P. Cox, Gino Cortopassi, Elena N. Dedkova","doi":"10.1113/JP291356","DOIUrl":"10.1113/JP291356","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>Friedreich's ataxia (FA) is an inherited disorder caused by reduced expression of the mitochondrial protein frataxin (FXN). Although defined as a neurodegenerative disease, cardiomyopathy is the leading cause of mortality. Cardiac manifestations of FA span from concentric hypertrophic cardiomyopathy with preserved systolic function and impaired diastolic relaxation, resembling heart failure with preserved ejection fraction (HFpEF), to systolic heart failure with reduced ejection fraction (HFrEF). The molecular mechanisms driving progression towards these cardiac phenotypes remain poorly understood. We examined mitochondrial content, dynamics and mitophagy in two FA mouse models: cardiac/skeletal muscle-specific MCK-Cre FXN knockout (FXN-cKO) mice, which develop HFrEF, and inducible FXN knockdown (FXNKD) mice, which develop HFpEF-like cardiomyopathy. FXN-cKO hearts exhibited increased mitochondrial transcription factor A expression, an elevated mitochondrial-to-nuclear DNA ratio and greater mitochondrial density by electron microscopy, consistent with enhanced mitochondrial biogenesis. In contrast, FXNKD hearts showed no changes in mitochondrial content or biogenesis markers. Mitochondrial dynamics were markedly altered in FXN-cKO hearts, with reduced mitofusin-2 and increased FIS1 expression, accompanied by smaller, fragmented mitochondria. FXNKD hearts exhibited preserved fission, modestly increased fusion and mild mitochondrial enlargement. Markers of mitophagy were increased in FXN-cKO hearts, but a reduced LC3-II/I ratio suggested impaired autophagosome maturation and defective mitochondrial clearance. No changes in mitophagy were observed in FXNKD hearts. These findings demonstrate that FA-associated HFrEF is characterized by increased mitochondrial biogenesis coupled with impaired mitochondrial quality control and fragmentation, whereas FA-associated HFpEF-like phenotype shows preserved mitochondrial architecture and turnover. Mitochondrial remodelling programmes may underlie divergent cardiac phenotypes in FA and represent therapeutic targets for disease modification.\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>Friedreich's ataxia (FA) cardiomyopathy develops as heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF)-like disease, but mechanisms leading to different cardiac phenotypes are unclear.</li>\u0000 \u0000 <li>We compared mitochondrial remodelling in FA mouse models with divergent","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8360-8378"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP291356","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138997","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":"Warburg redefined: Metabolites, mitochondria and macrophages in immune regulation.","authors":"Yukun Min, Órlaith C Henry, Luke A J O'Neill","doi":"10.1113/JP291073","DOIUrl":"https://doi.org/10.1113/JP291073","url":null,"abstract":"<p><p>Nearly 100 years ago, Otto Warburg observed that cancer cells preferentially use glycolysis even in the presence of oxygen, supporting rapid cell growth. Since then, the concept of the Warburg effect has expanded far beyond tumour bioenergetics and is now recognised as a key feature of immune cell activation. A notable example is in macrophages, which, following pro-inflammatory stimulation, undergo Warburg-like metabolic reprogramming, characterised by increased glycolysis. Recent studies have shown that accumulated metabolites such as lactate have a range of immunoregulatory functions that shape macrophage inflammatory responses. In addition, glycolytic enzymes have been found to exert non-canonical functions that directly regulate macrophage immune signalling. Mitochondria, once considered suppressed during Warburg reprogramming, also undergo profound changes, with the electron transport chain generating reactive oxygen species and metabolites such as succinate, fumarate and itaconate playing complex immunoregulatory roles, and mitochondrial dynamics actively shaping metabolism and immune responses. Together, these findings redefine the Warburg effect in macrophages as a coordinated metabolic and signalling process that integrates glycolysis, mitochondrial function and immunometabolite signalling to optimise context-dependent immune responses.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197700","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":"The ageing kidney remembers its nutritional beginnings","authors":"Kieran M. Short,&nbsp;John F. Bertram","doi":"10.1113/JP292399","DOIUrl":"10.1113/JP292399","url":null,"abstract":"&lt;p&gt;The developmental origins of chronic diseases, including hypertension and chronic kidney disease, are now widely accepted. Early epidemiological observations linking impaired fetal and infant growth with later cardiovascular disease helped to establish this concept. Subsequent experimental studies demonstrated that maternal protein restriction can have lasting effects on nephron endowment, blood pressure and renal haemodynamics (Lamana et al., &lt;span&gt;2021&lt;/span&gt;; Woods et al., &lt;span&gt;2001&lt;/span&gt;). Much of the evidence has therefore been framed in physiological and morphological terms. Although the cellular and molecular programmes governing nephrogenesis are increasingly well defined, considerably less is known about how nutritional adversity becomes embedded within the kidney and alters its response to ageing, although recent work has made significant progress in defining how a maternal low-protein diet perturbs nephron progenitor differentiation into nephrons during fetal development (Short et al., &lt;span&gt;2026&lt;/span&gt;). The study by Pires and colleagues in this issue of &lt;i&gt;The Journal of Physiology&lt;/i&gt; now extends this molecular perspective into ageing, revealing that the aged kidney retains a molecular memory of early protein restriction, marked by metabolic and redox remodelling alongside tubular injury and changes in the extracellular matrix.&lt;/p&gt;&lt;p&gt;Pires et al., (&lt;span&gt;2026&lt;/span&gt;) examined the effects of maternal protein restriction in rats by feeding dams either a 6% protein diet or a 17% protein control diet throughout gestation and lactation. The study focused on male offspring, and both cohorts received a normal diet post weaning. This design allowed late-life renal changes to be interpreted as a legacy of early nutritional exposure rather than ongoing protein deprivation. Their study combined renal histopathology, circulating biochemical measures, whole-kidney proteomics and computational pathway analyses. The aged kidneys displayed structural abnormalities and elevated circulating creatinine, consistent with renal impairment. Whole-kidney proteomics revealed broad remodelling of mitochondrial metabolism, redox regulation, small-molecule transport and cellular stress responses. At the same time, proteins associated with cytoskeletal organisation, vesicular transport, extracellular processes and immune regulation were reduced. Together, these findings suggest that maternal protein restriction does not leave a single molecular lesion. Rather, it produces persistent changes in how the kidney manages energy demand, cellular organisation and tissue maintenance during ageing. The study therefore extends developmental programming beyond the familiar end points of reduced nephron endowment and altered blood pressure, showing that early nutritional adversity remains detectable in the molecular physiology of the aged kidney.&lt;/p&gt;&lt;p&gt;A particular strength of the study is the convergence between pathology and proteomics. Tubular atrophy, congestion, ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8295-8296"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP292399","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018689","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":"A structure-based model that describes activation and inactivation of a sodium channel","authors":"D'Artagnan Greene,&nbsp;Sofia Perez,&nbsp;Yohannes Shiferaw","doi":"10.1113/JP291836","DOIUrl":"10.1113/JP291836","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;While the Hodgkin–Huxley formalism successfully describes sodium channel gating, the molecular origin of its nonlinear voltage dependence remains unclear. We developed a structure-based model of Na&lt;sub&gt;v&lt;/sub&gt;1.4 representing the four voltage-sensing domains, the isoleucine-phenylalanine-methionine (IFM) motif and the S6 gate as interacting binary variables, with activation parameters constrained by domain-specific fluorescence measurements. The fitted model reveals strongly heterogeneous voltage sensors whose interactions produce cooperative activation, suppressing channel opening at subthreshold voltages. Using timescale separation, we coarse-grain the 64-microstate system to obtain the Hodgkin–Huxley-like factorization &lt;i&gt;P&lt;/i&gt;&lt;sub&gt;o&lt;/sub&gt; = &lt;i&gt;m&lt;/i&gt; × &lt;i&gt;h&lt;/i&gt;, where &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;mi&gt;m&lt;/mi&gt;\u0000 &lt;annotation&gt;$m$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt; represents cooperative activation and &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;mi&gt;h&lt;/mi&gt;\u0000 &lt;annotation&gt;$h$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt; represents availability. The reduced theory shows that the voltage dependence of &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;mrow&gt;\u0000 &lt;msub&gt;\u0000 &lt;mi&gt;h&lt;/mi&gt;\u0000 &lt;mi&gt;∞&lt;/mi&gt;\u0000 &lt;/msub&gt;\u0000 &lt;mrow&gt;\u0000 &lt;mo&gt;(&lt;/mo&gt;\u0000 &lt;mi&gt;V&lt;/mi&gt;\u0000 &lt;mo&gt;)&lt;/mo&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;annotation&gt;${{h}_infty }( V )$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt; is inherited from the domain-IV voltage sensor. Because domain IV activates at more hyperpolarized voltages than the collective activation of domains I–III required for opening, availability declines before the channel reaches its main activation range. Coupling of domain IV to IFM engagement and S6 gate closure further controls the magnitude of this shift. Thus, the model identifies the molecular origin of the separation between activation and availability curves.\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;Sodium channels are proteins in nerve and muscle cells that open briefly to trigger electrical signals, then close. The 1952 Hodgkin–Huxley model captures this behaviour by treating the channel's four voltage sensors as independent.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;However, experiments show ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8450-8466"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149041817","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}