Acta Physiologica最新文献

{"title":"The Ancient Drug Salicylate Indirectly Targets Fructose-1,6-Bisphosphatase to Suppress Liver Glucose Production in Diet-Induced Obese Mice","authors":"Raid B. Nisr,&nbsp;Abdelmadjid Atrih,&nbsp;Erika J. Gutierrez Lara,&nbsp;Douglas Lamont,&nbsp;Katarzyna M. Luda,&nbsp;Rory J. McCrimmon,&nbsp;Kei Sakamoto,&nbsp;Graham Rena,&nbsp;Alison D. McNeilly","doi":"10.1111/apha.70058","DOIUrl":"https://doi.org/10.1111/apha.70058","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>The benefit of salicylate in the treatment of diabetes has been recognized for over a century; however, challenging side effects have prevented widespread use. A better understanding of the relevant enzyme targets mediating its anti-hyperglycaemic effect may lead to the development of novel therapies for diabetes. Here, we investigated the contribution of 5′-adenosine monophosphate (AMP)-dependent inhibition of fructose-1,6-bisphosphatase 1 (FBP1) to the anti-hyperglycaemic action of salicylate.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We studied AMP-insensitive FBP1 G27P knockin (KI) mice through a variety of cellular approaches, including proteomics, Seahorse metabolic analysis, glucose production, and other assays, in addition to a detailed assessment of metabolic responses in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with wild-type littermates, AMP-insensitive FBP1 KI mice were resistant to the effects of the drug on body weight, glucose tolerance, pyruvate disposal, liver lipid content and hepatic glucose production. Compared with wild-type, KI hepatocytes exhibited baseline differences in glycolytic, TCA cycle and fatty acid oxidation enzyme levels, potentially linking gluconeogenic dysregulation and its reversal to non-carbohydrate fuel management.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Collectively, our data highlight a novel mechanism of action for the effects of salicylate on glycaemia and weight gain, which depends on AMP-mediated allosteric inhibition of FBP1.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70058","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108820","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 Bioenergetics in Physiology","authors":"Martin Jastroch,&nbsp;Michaela Keuper","doi":"10.1111/apha.70056","DOIUrl":"https://doi.org/10.1111/apha.70056","url":null,"abstract":"&lt;p&gt;Physiology aims to understand the mechanisms that enable organisms to live in and adapt to their environment. These mechanisms range from the whole organism to the molecular level, but in all cases, energy has to be funneled into specific cellular functions. The central interfaces converting nutrients to cellular energy are small intracellular organelles, the mitochondria. Given the pivotal role of mitochondrial bioenergetics for powering physiology, a very active research field currently seeks to decipher how mitochondrial functions are integrated into cellular and organismic physiology, and how mitochondria contribute to ecological adaptation and human diseases.&lt;/p&gt;&lt;p&gt;&lt;i&gt;Acta Physiologica&lt;/i&gt; recently collated a special issue titled ‘Mitochondrial Bioenergetics in Physiology’, covering various aspects of mitochondrial adaptations in ectotherms, heat production in endotherms, the role of mitochondria in metabolic signaling during physiological challenges, and the function of mitochondrial transporters (Figure 1). The special issue reports on various aspects of mitochondrial involvement in health and disease, such as sarcopenia, pulmonary hypertension and cardioprotection, and factors regulating mitochondrial function, including microRNA and mitophagy, expanding our current understanding on mitochondrial physiology.&lt;/p&gt;&lt;p&gt;Despite their many cellular functions, mitochondria are best known for the oxidation of substrates to transport electrons along the respiratory chain, using the liberated energy to pump protons from the matrix over the mitochondrial inner membrane into the intermembrane space, thereby storing potential energy in a proton gradient that produces ATP. Although this mechanism is universal to all mitochondria, the efficiency and regulation differ tremendously between organisms, organs, and cell types, as they have to deal with different environmental and physiological challenges, requiring molecular integration into specific cellular functions to match energetic supply and demand.&lt;/p&gt;&lt;p&gt;The thermal environment of mitochondria can vary greatly in ectothermic organisms, where body temperature tracks the ambient temperature. Ectotherms represent beautiful model organisms to understand the effects of temperature on mitochondrial function and its relation to adaptation and physiological performance [&lt;span&gt;1&lt;/span&gt;]. The Crucian carp, for example, lives in Scandinavian lakes and experiences frequent fluctuations in temperature and oxygenation that require different handling of mitochondrial oxidative stress as compared to mitochondria of the mouse [&lt;span&gt;2&lt;/span&gt;]. Exposing fish to different temperatures over multiple generations uncovers that mitochondrial efficiency can adapt [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Mitochondria of endothermic birds and mammals are surrounded by a mostly warm environment, created by heat production of mitochondria themselves. We are still not sure how sufficient mitochondrial capacity evolved to sustain endothermy, bu","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085231","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":"Chronic High-Fat Diet Consumption Followed by Lipopolysaccharide Challenge Induces Persistent and Long-Lasting Microglial Priming, Mediates Synaptic Elimination via Complement C1q, and Leads to Behavioral Abnormalities in Male Wistar Rats","authors":"Titikorn Chunchai,&nbsp;Hiranya Pintana,&nbsp;Chanon Kunasol,&nbsp;Patcharapong Pantiya,&nbsp;Busarin Arunsak,&nbsp;Sasiwan Kerdphoo,&nbsp;Wichwara Nawara,&nbsp;Suriphan Donchada,&nbsp;Nattayaporn Apaijai,&nbsp;Jirapas Sripetchwandee,&nbsp;Chanisa Thonusin,&nbsp;Nipon Chattipakorn,&nbsp;Siriporn C. Chattipakorn","doi":"10.1111/apha.70060","DOIUrl":"https://doi.org/10.1111/apha.70060","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Microglia exhibit innate immune memory, altering their responses to subsequent challenges. Consumption of high-fat diet (HFD) triggers innate immune responses, but the characteristics of HFD-induced microglial priming remain unclear. We aim to investigate how HFD-induced microglial priming, followed by a lipopolysaccharide (LPS) challenge, affects brain functions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male Wistar rats were divided into control, unprimed, and primed groups. The primed groups received either a single LPS injection (0.5 mg/kg, intraperitoneally) or HFD consumption for 4–8 weeks. Following the priming phase, all rats (except controls) were subjected to an LPS challenge with a 4- or 8-week interval. After 24 h of LPS challenge, cognition, anxiety-, and depressive-like behaviors were assessed. The brain and hippocampus were collected for further analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Both LPS- and 4-week HFD-primed groups, followed by LPS challenge, exhibited increased peripheral and brain oxidative stress, impaired neurogenesis, disrupted neurotransmitter balance, and altered glycolysis and Krebs cycle substrates. These changes also caused microglial morphological alterations, elevated C1q levels, and synaptic loss, which were associated with anxiety- and depressive-like behaviors, indicating that 4-week HFD consumption has a similar immune priming ability to a single dose of LPS injection. Extending HFD priming to 8 weeks exacerbated microglial and brain inflammation, synaptic loss, and behavioral deficits. Furthermore, prolonging the interval between priming and LPS challenge worsened inflammation and cognitive decline, suggesting the persistent effects of microglial priming.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>HFD consumption persistently and time-dependently primes microglia similar to a single LPS injection, influencing immune responses and contributing to behavioral abnormalities.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085503","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":"Comparison of Phasic Store-Operated Calcium Entry in Rat Slow- and Fast-Twitch Muscle Fibers","authors":"Elena Lilliu,&nbsp;Rocky Choi,&nbsp;Karlheinz Hilber,&nbsp;Bradley Launikonis,&nbsp;Xaver Koenig","doi":"10.1111/apha.70059","DOIUrl":"https://doi.org/10.1111/apha.70059","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This study investigates the activation and regulation of phasic store-operated calcium entry (pSOCE) in fast- and slow-twitch skeletal muscle fibers. Specifically, we aimed to enhance the sensitivity of pSOCE detection in slow-twitch fibers by optimizing ionic conditions and to compare the physiological relevance of pSOCE between fiber types.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We employed mechanically skinned fast-twitch extensor digitorum longus (EDL) muscle fibers loaded with spectrally distinct Ca²⁺-sensitive dyes to simultaneously measure action potential-induced sarcoplasmic reticulum Ca²⁺ release and t-tubular system Ca²⁺ dynamics with millisecond resolution. Experimental conditions were optimized by reducing cytosolic Mg²⁺ and EGTA buffering to enhance Ca²⁺ release in slow-twitch soleus fibers. Confocal microscopy was used to track t-tubular system Ca²⁺ depletion and reuptake during electric field stimulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Skinned soleus fibers exhibited ~8-fold lower Ca²⁺ release per action potential compared to EDL fibers, yet pSOCE amplitudes were comparable. Reducing Mg²⁺ and EGTA levels increased Ca²⁺ release and left pSOCE kinetics in EDL fibers unaltered, but enabled pSOCE measurements in soleus fibers. While pSOCE in EDL fibers followed a linear dependence on the ambient Ca²⁺ concentration in the t-tubular system, such a relationship was violated in soleus fibers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings reveal a novel, fiber-type-specific difference in pSOCE regulation. When compared to EDL fibers, soleus fibers exhibited a higher sensitivity to SOCE activation despite releasing less Ca²⁺ from the sarcoplasmic reticulum upon an action potential. These differences may allow soleus fibers to sustain Ca²⁺ homeostasis more effectively, be more resilient against disruptions in Ca²⁺ handling, and entail protection against disease states.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085502","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":"Correction to “Neuronal Activity Modulates the Expression of Secretagogin, a Ca2+ Sensor Protein, During Mammalian Forebrain Development”","authors":"","doi":"10.1111/apha.70055","DOIUrl":"https://doi.org/10.1111/apha.70055","url":null,"abstract":"<p>Hanics J, Tretiakov EO, Romanov RA, et al. Neuronal activity modulates the expression of secretagogin, a Ca²⁺ sensor protein, during mammalian forebrain development. <i>Acta Physiol</i>. 2025;241:e70031. https://doi.org/10.1111/apha.70031.</p><p>In the originally published version of record, the funding statement was missing: Open access funding provided by Medizinische Universität Wien/KEMÖ.</p><p>The online version of this article has been corrected accordingly.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944791","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":"Carbamylation versus Carboxylation—A Clash Culminating in Vascular Calcification?","authors":"Jakob Voelkl,&nbsp;Mirjam Schuchardt","doi":"10.1111/apha.70054","DOIUrl":"https://doi.org/10.1111/apha.70054","url":null,"abstract":"&lt;p&gt;In their recent work in &lt;i&gt;Acta Physiologica&lt;/i&gt;, Kaesler et al. identify a novel mechanistic link between the uremic environment in chronic kidney disease (CKD) and vascular calcification [&lt;span&gt;1&lt;/span&gt;]. Medial vascular calcification (VC) is an inappropriate deposition of calcium-phosphate, mostly as hydroxyapatite, in the medial layer of the arteries [&lt;span&gt;2&lt;/span&gt;]. This VC increases with aging and is strongly accelerated by CKD [&lt;span&gt;2&lt;/span&gt;]. The intricate and multifaceted pathogenesis of VC is tightly linked to calcium–phosphate imbalance. When calcium and phosphate concentrations exceed their solubilities in the plasma, spontaneous complexation and formation of extraosseous minerals could occur that is physiologically balanced by a mineral buffering system [&lt;span&gt;3&lt;/span&gt;]. In CKD patients, bone demineralization and hyperphosphatemia strain the physiological mineral buffering system [&lt;span&gt;2&lt;/span&gt;]. Thereby, an increased formation of calcium–phosphate particles can occur, which in turn can induce pro-inflammatory cascades. The stimulation of this pro-inflammatory effect is further exacerbated by the accumulation of uremic toxins in the plasma of CKD patients [&lt;span&gt;4&lt;/span&gt;]. Vascular smooth muscle cells (VSMC) are particularly susceptible to calcium–phosphate particle stress and respond with phenotypic changes, including activation of inflammatory pathways, release of pro-calcific transmitters and extracellular vesicles as well as remodeling of the extracellular matrix. All these changes favor a local pro-calcific microenvironment [&lt;span&gt;2&lt;/span&gt;]. From this perspective, rectifying a deranged mineral buffering system in CKD holds great potential to prevent VC and reduce cardiovascular mortality.&lt;/p&gt;&lt;p&gt;Several factors of the mineral buffering system, such as pyrophosphate and fetuin-A, have been linked to an anticalcific function [&lt;span&gt;2, 3&lt;/span&gt;]. Additionally, a decisive role has been attributed to vitamin-K-dependent GLA proteins [&lt;span&gt;5&lt;/span&gt;]. Contrary to osteocalcin (bone GLA protein), matrix GLA protein (MGP) is a potent extraosseous calcification inhibitor. MGP is a ~12-kDa protein that was originally identified from bone matrix but is also highly expressed in soft tissues. Its critical role was identified in MPG-deficient mice that die from rupture of their calcified arteries before they reach an age of 2 months. Interestingly, the anticalcific effects of MGP might involve several mechanisms [&lt;span&gt;5&lt;/span&gt;]. MGP directly adsorbs hydroxyapatite crystals and is associated with inhibition of crystal growth but may also inhibit bone morphogenic protein 2, an important activator of pro-calcific effects in VSMCs [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;The function of MGP is regulated by posttranslational modifications, such as phosphorylation and carboxylation. Besides serine phosphorylation, the gamma-carboxylation of glutamate residues by gamma-glutamyl carboxylase (GGCX) and vitamin K as co-factor is important for the anti-calcific fun","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143930322","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":"Voltage-Gated Ca2+ Channels in Prefrontal Parvalbumin Neurons Are Essential for Stress-Induced Depression","authors":"Katrina Lin,&nbsp;Laurence Coutellier","doi":"10.1111/apha.70053","DOIUrl":"https://doi.org/10.1111/apha.70053","url":null,"abstract":"<p>Stress is a risk factor for neuropsychiatric disorders, including depression. While acute stress responses are typically protective and adaptive, prolonged or chronic stress can lead to lasting alterations in brain function that contribute to maladaptive behaviors. Among the brain regions affected by chronic stress, the prefrontal cortex (PFC) stands out due to its critical role in regulating affect, cognition, and top-down control of limbic circuits. Studies with rodent models show that chronic stress induces dendritic retraction, synaptic loss, and disruptions in excitatory/inhibitory (E/I) balance within the PFC [<span>1-3</span>]. These findings parallel neuroimaging studies in humans showing reduced PFC volume and hypoactivity in individuals with stress-related disorders, including major depressive disorder and post-traumatic stress disorder [<span>4, 5</span>]. While disruption of parvalbumin-expressing (PV+) inhibitory GABAergic neurons has been found to drive some of the effects of chronic stress on anxiety- and depressive-like behaviors in rodents [<span>2, 6, 7</span>], the molecular mechanisms linking stress-induced GABAergic dysfunction to long-term behavioral consequences have yet to be fully understood. In a recent issue of <i>Acta Physiologica</i>, Yabuki et al. [<span>8</span>] propose a novel understanding of the molecular mechanisms underlying chronic-stress induced depression using a rodent model.</p><p>The authors investigate the role of Cav3.1 T-type calcium channels, located on PV+ neurons in the medial PFC (mPFC), in stress-induced behavioral changes. Using Cav3.1 knockout mice, they demonstrate that deletion of the Cav3.1 channel prevents the development of depressive-like behaviors typically induced by acute stress paradigms such as the forced swim test (FST) and tail suspension test (TST). While these assays are conventionally used to assess acute stress responses, they are leveraged here to measure chronic stress-induced depressive-like behaviors. Stress-induced immobility was abolished in Cav3.1-deficient mice, indicating that Cav3.1 channels are necessary for inducing such depressive-like behavioral phenotypes.</p><p>To further probe the underlying neural mechanisms, the authors employed transcriptomic profiling of the mPFC, which revealed that chronic stress alters the expression of genes involved in E/I balance and synaptic signaling in wild-type mice, but not Cav3.1 knockout mice. These changes were particularly pronounced in genes associated with GABAergic transmission, implicating Cav3.1 in modulating the effects of chronic stress on inhibitory circuits in the mPFC.</p><p>Electrophysiological recordings demonstrated that chronic stress enhances the excitability of PV+ GABAergic neurons in the mPFC of wild-type mice, but not in Cav3.1-deficient mice, providing a mechanistic link between Cav3.1 channel activity, interneuron excitability, and behavioral output. Optogenetic activation of PV+ neurons in the mPFC wa","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926164","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":"SorCS2 Is Important for Astrocytic Function in Neurovascular Signaling","authors":"Christian Staehr,&nbsp;Hande Login,&nbsp;Elizaveta V. Melnikova,&nbsp;Magdalena Bakun,&nbsp;Ewelina Ziemlinska,&nbsp;Lilian Kisiswa,&nbsp;Simin Berenji Ardestani,&nbsp;Stella Solveig Nolte,&nbsp;Hans Christian Beck,&nbsp;Line Mathilde Brostrup Hansen,&nbsp;Dmitry Postnov,&nbsp;Alexei Verkhratsky,&nbsp;Anna R. Malik,&nbsp;Anders Nykjaer,&nbsp;Vladimir V. Matchkov","doi":"10.1111/apha.70052","DOIUrl":"https://doi.org/10.1111/apha.70052","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>The receptor SorCS2 is involved in the trafficking of membrane receptors and transporters. It has been implicated in brain disorders and has previously been reported to be indispensable for ionotropic glutamatergic neurotransmission in the hippocampus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>We aimed to study the role of SorCS2 in the control of astrocyte-neuron communication, critical for neurovascular coupling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Brain slices from P8 and 2-month-old wild-type and SorCS2 knockout (<i>Sorcs2</i>^{<i>−/−</i>}) mice were immunostained for SorCS2, GFAP, AQP4, IB4, and CD31. Neurovascular coupling was assessed in vivo using laser speckle contrast imaging and ex vivo in live brain slices loaded with calcium-sensitive dye. Bulk and cell surface fraction proteomics was analyzed on freshly isolated and cultured astrocytes, respectively, and validated with Western blot and qPCR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>SorCS2 was strongly expressed in astrocytes, primarily in their endfeet, of P8 mice; however, it was sparsely represented in 2-month-old mice. <i>Sorcs2</i>^{<i>−/−</i>} mice demonstrated reduced neurovascular coupling associated with a reduced astrocytic calcium response to neuronal excitation. No differences in vascularization or endothelium-dependent relaxation ex vivo between the 2-month-old groups were observed. Proteomics suggested changes in glutamatergic signaling and suppressed calcium signaling in <i>Sorcs2</i>^{<i>−/−</i>} brains from both P8 and 2-month-old mice. The increased abundance of glutamate metabotropic receptor 3 in <i>Sorcs2</i>^{<i>−/−</i>} astrocytes was validated by PCR and Western blot. In cultured <i>Sorcs2</i>^{<i>−/−</i>} astrocytes, AQP4 abundance was increased in the bulk lysate but reduced in the cell surface fraction, suggesting impaired trafficking.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The results suggest that SorCS2 expression is important for the development of neurovascular coupling, at least in part by modulating glutamatergic and calcium signaling in astrocytes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919656","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":"Sodium-Coupled Monocarboxylate Absorption in the Airway Epithelium Is Facilitated by the SLC5A8 Co-Transporter","authors":"Anita Guequen,&nbsp;Bárbara Tapia-Balladares,&nbsp;Tábata Apablaza,&nbsp;Daniela Guidone,&nbsp;Nátali Cárcamo-Lemus,&nbsp;Sandra Villanueva,&nbsp;Pamela Y. Sandoval,&nbsp;Luis J. V. Galietta,&nbsp;Carlos A. Flores","doi":"10.1111/apha.70051","DOIUrl":"https://doi.org/10.1111/apha.70051","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Amino acids, sugars, short-chain fatty acids (SCFA), vitamins, and other small molecules compose the extracellular metabolome on the airway lumen surface, but how the airway epithelium deals with these molecules has not been deeply studied. Due to the broad spectrum of metabolites transported by SLC5A8 and SLC5A12, we aim to determine if they are functionally expressed and participate in the absorption of Na⁺, short-chain fatty acids, and monocarboxylates in mouse and human airway epithelium.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Tracheas isolated from male or female mice and human bronchial epithelial cells (HBECs) were used for electrophysiological studies in the Ussing chamber and to detect members of the SLC16 family by RT-PCR and bulk RNAseq. Additionally, cell lines expressing the human and murine SLC5A8 transporter were employed for uptake studies using a fluorescent lactate probe.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We showed for the first time that human and murine airway epithelium express a functional SLC5A8 transporter, facilitating the absorption of glucose metabolites and SCFAs. The Na⁺-coupled monocarboxylate transport was not additive with ENaC-mediated Na⁺ absorption in mouse trachea. We observed that valproate acts as an inhibitor of the murine but not of the human SLC5A8 transporter.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our results demonstrate that several metabolites derived from bacterial and cellular metabolism can be transported from the airway lumen into the epithelial cells, participating in a homeostatic relation of the tissue with its environment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908914","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":"Cerebrospinal Fluid Enters Peripheral Organs by Spinal Nerves Supporting Brain–Body Volume Transmission","authors":"Baoman Li,&nbsp;Maosheng Xia,&nbsp;Tibor Harkany,&nbsp;Alexei Verkhratsky","doi":"10.1111/apha.70048","DOIUrl":"https://doi.org/10.1111/apha.70048","url":null,"abstract":"<p>The cerebrospinal fluid (CSF) provides many vital functions to the central nervous system (CNS). The CSF irrigates the CNS from within (through the ventricular system and the central canal of the spinal cord) and from without (through the sub-arachnoid space of the cranium and spine). As the brain and spinal cord therefore float within the CSF, the CNS is hydromechanically protected by the CSF, and the Archimedean principle of buoyancy means that the mass of the suspended brain is reduced from ~1.5 kg to mere 50 g. The CSF also acts as a hydraulic shock absorber that prevents the brain from hitting the skull and thus provides us the freedom of movement and acceleration. Simply put, the hydraulic shock absorption is the reason none of us incur debilitating concussions each time we take a step! Moreover, the CSF nourishes the CNS by providing a highway for nutrients and signaling molecules that are transported from the blood in the cerebral circulation to the CSF, and then to the interstitial fluid within the extracellular space of the nervous tissue. The CSF also provides haulage to a variety of waste products. In addition to these housekeeping functions, the CSF is a medium for long-range signaling within the CNS and between the CNS and the body, by carrying hormones, neurotransmitters, neuromodulators, signal-competent molecules, or extracellular vesicles over long distances.</p><p>The CSF production and flow are intimately associated with the ventricular system of the brain, the central canal of the spinal cord, and the sub-arachnoid space. The mammalian brain contains four ventricles: two lateral, localized quasi-symmetrically in each of the hemispheres, the third ventricle at the midline of the diencephalon, as well as the fourth ventricle of the hindbrain. The lateral ventricles are connected to the third ventricle through the foramen of Monro, while the third and fourth ventricles are linked with the cerebral aqueduct of Sylvius. The fourth ventricle is continuous with the central canal of the spinal cord and connected to the subarachnoid space through exits at the foraminae Magendie and Luschka [<span>1</span>]. The CSF is produced mainly by four choroid plexi (one per ventricle) although extrachoroid sites may also contribute [<span>2</span>]. Choroid plexi are lined with a monolayer of specialized “choroid” epithelium. This name is, however, incorrect: cells building the choroid plexi are <i>bona fide</i> ependymoglia: committed precursors of choroid cells are scions of a subpopulation of neuroepithelial precursors that emerge around embryonic Day 11 in mice, prior to the start of neurogenesis [<span>3</span>]. The cuboid choroid ependymocytes have several cilia and form a CSF-blood barrier reinforced by intercellular junctional complexes made of tight junctions, adherens junctions, and desmosomes [<span>4</span>].</p><p>The production of the CSF is supported by multiple plasmalemmal transporters that are selectively recruited at apic","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905116","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}