Acta Physiologica最新文献

{"title":"Transient receptor potential melastatin 7 cation channel, magnesium and cell metabolism in vascular health and disease","authors":"Belma Melda Abidin,&nbsp;Francisco J. Rios,&nbsp;Augusto C. Montezano,&nbsp;Rhian M. Touyz","doi":"10.1111/apha.14282","DOIUrl":"10.1111/apha.14282","url":null,"abstract":"<p>Preserving the balance of metabolic processes in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), is crucial for optimal vascular function and integrity. ECs are metabolically active and depend on aerobic glycolysis to efficiently produce energy for their essential functions, which include regulating vascular tone. Impaired EC metabolism is linked to endothelial damage, increased permeability and inflammation. Metabolic alterations in VSMCs also contribute to vascular dysfunction in atherosclerosis and hypertension. Magnesium (Mg²⁺) is the second most abundant intracellular divalent cation and influences molecular processes that regulate vascular function, including vasodilation, vasoconstriction, and release of vasoactive substances. Mg²⁺ is critically involved in maintaining cellular homeostasis and metabolism since it is an essential cofactor for ATP, nucleic acids and hundreds of enzymes involved in metabolic processes. Low Mg²⁺ levels have been linked to endothelial dysfunction, increased vascular tone, vascular inflammation and arterial remodeling. Growing evidence indicates an important role for the transient receptor potential melastatin-subfamily member 7 (TRPM7) cation channel in the regulation of Mg²⁺ homeostasis in EC and VSMCs. In the vasculature, TRPM7 deficiency leads to impaired endothelial function, increased vascular contraction, phenotypic switching of VSMCs, inflammation and fibrosis, processes that characterize the vascular phenotype in hypertension. Here we provide a comprehensive overview on TRPM7/Mg²⁺ in the regulation of vascular function and how it influences EC and VSMC metabolism such as glucose and energy homeostasis, redox regulation, phosphoinositide signaling, and mineral metabolism. The putative role of TRPM7/Mg²⁺ and altered cellular metabolism in vascular dysfunction and hypertension is also discussed.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055751","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":"Cardiomyocyte engineering: The meeting point of transcription factors, signaling networks, metabolism and function","authors":"Oksana O. Piven,&nbsp;Raminta Vaičiulevičiūtė,&nbsp;Eiva Bernotiene,&nbsp;Pawel Dobrzyn","doi":"10.1111/apha.14271","DOIUrl":"10.1111/apha.14271","url":null,"abstract":"<p>Direct cardiac reprogramming or transdifferentiation is a relatively new and promising area in regenerative therapy, cardiovascular disease modeling, and drug discovery. Effective reprogramming of fibroblasts is limited by their plasticity, that is, their ability to reprogram, and depends on solving several levels of tasks: inducing cardiomyocyte-like cells and obtaining functionally and metabolically mature cardiomyocytes. Currently, in addition to the use of more classical approaches such as overexpression of exogenous transcription factors, activation of endogenous cardiac transcription factors via controlled nucleases, such as CRISPR, represents another interesting way to obtain cardiomyocytes. Therefore, special attention is given to the potential of synthetic biology, in particular the CRISPR system, for the targeted conversion of only certain subpopulations of fibroblasts into cardiomyocytes. However, obtaining functionally and metabolically mature cardiomyocytes remains a challenge despite the range of recently developed approaches. In this review, we summarized current knowledge on the function and diversity of human cardiac fibroblasts and alternative cell sources for in vitro human cardiomyocyte models. We examined in detail the transcription factors that initiate cardiomyogenic reprogramming and their interactions. Additionally, we critically analyzed the strategies used for the metabolic and physiological maturation of induced cardiomyocytes.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14271","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968890","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":"Proteinuria and tubular cells: Plasticity and toxicity","authors":"Anna Faivre,&nbsp;Thomas Verissimo,&nbsp;Sophie de Seigneux","doi":"10.1111/apha.14263","DOIUrl":"10.1111/apha.14263","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Proteinuria is the most robust predictive factors for the progression of chronic kidney disease (CKD), and interventions targeting proteinuria reduction have shown to be the most effective nephroprotective treatments to date. While glomerular dysfunction is the primary source of proteinuria, its consequences extend beyond the glomerulus and have a profound impact on tubular epithelial cells. Indeed, proteinuria induces notable phenotypic changes in tubular epithelial cells and plays a crucial role in driving CKD progression. This comprehensive review aims to elucidate the mechanisms involved in the tubular handling of proteins and explore the potential effects of proteinuria on the function of tubular epithelial cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This paper is a narrative review. Litterature review was performed on PubMed from its inception until 2024, focusing on the effects of proteinuria on tubular cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The review highlights the toxic effects of plasma proteins on tubular epithelial cells through signal transduction pathways, as well as endoplasmic reticulum stress activation, oxidative stress, and metabolic alterations. Additionally, it provides an updated understanding of the dynamic phenotypic changes occurring within the nephron in response to proteinuria.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>By examining the intricate interplay between proteinuria and tubular epithelial cells, this review sheds light on key factors contributing to CKD progression and unveils potential targets for therapeutic interventions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963370","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 pleiotropic effects of PCSK9 in cardiovascular diseases beyond cholesterol metabolism","authors":"Gang Liu,&nbsp;Xiatian Yu,&nbsp;Chaochu Cui,&nbsp;Xiao Li,&nbsp;Tianyun Wang,&nbsp;Philip T. Palade,&nbsp;Jawahar L. Mehta,&nbsp;Xianwei Wang","doi":"10.1111/apha.14272","DOIUrl":"10.1111/apha.14272","url":null,"abstract":"<p>Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality globally, with elevated low-density lipoprotein cholesterol (LDL-C) levels being a major risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in regulating LDL-C levels by promoting the degradation of hepatic low-density lipoprotein receptors (LDLR) responsible for clearing LDL-C from the circulation. PCSK9 inhibitors are novel lipid-modifying agents that have demonstrated remarkable efficacy in reducing plasma LDL-C levels and decreasing the incidence of CVD. However, the broader clinical impacts of PCSK9 functions beyond cholesterol metabolism, including both desired and undesired effects from therapeutic PCSK9 inhibition, underscore the urgent necessity to elucidate the underlying mechanisms. Recent studies have shown that local PCSK9 in the vascular system can interact with other receptors such as CD36, LRP-1, and ABCA1. This provides new evidence supporting the potential contribution of PCSK9 to CVD through LDLR-independent signaling pathways. Therefore, this review aimed to outline the diverse effects of PCSK9 on CVD and discuss the underlying mechanisms in non-cholesterol-related processes, which will provide a rational basis for its long-term pharmacological inhibition in the clinic.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963387","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":"Deuterated water (2H2O) can be used to quantify hemoglobin synthesis and red blood cell lifespan in humans","authors":"Hilkka Kontro,&nbsp;Chris McGlory,&nbsp;Martin J. MacInnis","doi":"10.1111/apha.14259","DOIUrl":"10.1111/apha.14259","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862618","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":"Of manuscripts and memories: Passing the pen to Tobias","authors":"Pontus B. Persson","doi":"10.1111/apha.14255","DOIUrl":"10.1111/apha.14255","url":null,"abstract":"&lt;p&gt;Imagine awarding authors one of the highest honors in scientific publishing, only to receive an insult in response. Picture writing to inform them they've won the US$100000 &lt;i&gt;Acta Physiologica&lt;/i&gt; Award, and instead of gratitude, getting a fiery phone call. Initially, the author thought it was a prank. But once the truth sunk in, it was amusing to witness the quick change in tone—scrambling to recover and secure the award.&lt;/p&gt;&lt;p&gt;Reflecting on 12 years as Editor-in-Chief of &lt;i&gt;Acta Physiologica&lt;/i&gt;, the predominant feeling is one of the deep gratitude and pride. The long journey transformed the journal, elevating its readership, recognition, and scientific impact to new heights. This success is due to the unwavering dedication of our authors, the expertise of our reviewers, the editorial team's rigor, and the enthusiasm of our readers. Together, we've shaped &lt;i&gt;Acta Physiologica&lt;/i&gt; into an internationally respected journal that pushes the field of physiology ever forward.&lt;/p&gt;&lt;p&gt;Today, the editorial team and I are thrilled to welcome Professor Tobias Wang as the new Editor-in-Chief. A distinguished physiologist from Aarhus University, Tobias brings a remarkable depth of experience and an impressive record of achievements. His pioneering work in respiratory and comparative physiology, along with his insights into thermoregulation, make the foremost voice in the field, as seen in his acclaimed articles and television appearances. Having collaborated with Tobias on our editorial team, it's clear he has the vision and drive to lead &lt;i&gt;Acta Physiologica&lt;/i&gt; to even greater success. He is the force behind our journal's latest developments.&lt;/p&gt;&lt;p&gt;We are all in great debt to our previous expert editors Joakim Ek, Lena Eliasson, Karl-Heinz Herzig, Tadashi Isa, Sari Lauri, Bridgit Lumb, Mikko Nikinmaa, Mia Phillipson, and Ursula Seidler. Naturally, the true Chief Editor of this term, Carola Neubert is unforgotten. Inside the eye of the tornado, she makes order out of chaos and will stay onboard with Tobias.&lt;/p&gt;&lt;p&gt;Excuse me Peter (Peter Bie) for being such a pain in the neck at times. You are the one I thank most for providing me with the honor of becoming &lt;i&gt;Acta Physiologica&lt;/i&gt;'s Chief Editor and you are the one that bailed me out when my visions got out of hand. Besides that, you were the first expert editor for kidney physiology during my term and a great friend.&lt;/p&gt;&lt;p&gt;Together, these extraordinary scientists have shaped &lt;i&gt;Acta Physiologica&lt;/i&gt; to reflect the very best of physiology across its diverse fields. Alongside our broader community of readers and contributors, they have transformed the journal over the past decade.&lt;/p&gt;&lt;p&gt;As the official journal of the Scandinavian Physiological Society (SPS), &lt;i&gt;Acta Physiologica&lt;/i&gt; fulfills a unique mission. The SPS, a charitable nonprofit, reinvests journal profits back into the physiological community—funding travel grants, symposia, awards, and more. Being part of a journal that prioritizes the growth","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14255","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851617","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":"Targeting histone deacetylase 6 (HDAC6) in Duchenne muscular dystrophy: New insights into therapeutic potential","authors":"Alexis Osseni,&nbsp;Laurent Schaeffer","doi":"10.1111/apha.14256","DOIUrl":"10.1111/apha.14256","url":null,"abstract":"&lt;p&gt;Rodney and colleagues provide compelling evidence for the therapeutic potential of selective histone deacetylase 6 (HDAC6) inhibition in &lt;i&gt;mdx&lt;/i&gt; mice, a widely used model of Duchenne muscular dystrophy (DMD).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Their study reveals that HDAC6 inhibition promotes enhanced autophagy through increased tubulin acetylation, offering new hope for treatment strategies targeting this critical enzyme. This research sheds light on the potential of HDAC6 inhibitors to address some of the key pathological features of DMD.&lt;/p&gt;&lt;p&gt;Duchenne muscular dystrophy is a severe, progressive neuromuscular disorder caused by mutations in the dystrophin gene on the X chromosome.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Affecting approximately 1 in 3500 male births, DMD leads to the absence of dystrophin, a structural protein that connects muscle fibers to the extracellular matrix. Without dystrophin, muscle cells are vulnerable to damage and progressive degeneration. DMD typically presents in early childhood, with delayed motor milestones, muscle weakness, and difficulty standing. As the disease progresses, children develop a characteristic waddling gait, difficulty climbing stairs, and progressive muscle loss, ultimately leading to wheelchair dependence by age 12. Complications such as skeletal deformities, breathing difficulties, and cardiomyopathy arise, and most patients do not survive beyond their 30s due to respiratory and cardiac failure.&lt;/p&gt;&lt;p&gt;Despite two decades of research, no cure for DMD exists, and current treatments remain limited to glucocorticoid therapy. Although innovative genetic approaches, such as exon skipping, gene editing with CRISPR/Cas9, and viral vector-mediated dystrophin delivery, show promise, challenges like inconsistent efficacy, off-target effects, and incomplete dystrophin restoration in muscle tissues—especially in the heart—have slowed progress. As a result, a more comprehensive treatment strategy, combining genetic and pharmacological approaches, is likely necessary to address the multifaceted nature of DMD.&lt;/p&gt;&lt;p&gt;Over the past 20 years, HDAC inhibitors have shown promise in pre-clinical DMD models. Givinostat, a pan-HDAC inhibitor, was recently FDA-approved for its ability to slow disease progression in ambulatory boys with DMD.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; However, pan-HDAC inhibitors can have undesirable side effects, including genotoxicity and impaired DNA repair. To mitigate these risks, more selective HDAC inhibitors have been developed, with HDAC6 emerging as a particularly attractive target. HDAC6-specific inhibitors have been shown to have several advantages over pan-HDAC inhibitors, including a lack of severe side effects. For instance, &lt;i&gt;HDAC6 knockout&lt;/i&gt; mice do not exhibit significant pathological features, suggesting that selective inhibition of HDAC6 may be safe and beneficial.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In animal models, HDAC6 inhibition has demonstrated therapeutic effects in a range of disorders, includi","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14256","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826726","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 potential link between enteric glia and the pathophysiology of diet-induced obesity and related metabolic diseases","authors":"Onesmo B. Balemba,&nbsp;Brian D. Gulbransen","doi":"10.1111/apha.14258","DOIUrl":"10.1111/apha.14258","url":null,"abstract":"&lt;p&gt;Enteric glia are a large population of peripheral neuroglia that accompany neurons in the enteric nervous system. These cells have diverse functions and engage in bidirectional communication with various cell types, including enteric neurons, immune cells, and possibly the gut microbiota.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Enteric glia play important roles in maintaining gastrointestinal (GI) homeostasis, and it is thought that alterations in their functions could be pivotal in the development of GI disorders. For instance, gains or losses in glial functions contribute to abnormal gut barrier function, inflammation, immune activation, and motor control. Understanding mechanisms by which enteric glia serve as “guardians” of the mucosal barrier has been an area of considerable interest; however, their involvement in mucosal barrier dysfunction is still debated.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Inflammation caused by altered diet–gut microbiome–host interactions is considered an important driver of increased epithelial permeability in the development of obesity; yet the underlying mechanisms remain poorly understood.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; A recent study by D'Antongiovanni et al.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; in Acta Physiologica Volume 240 addressed this issue by exploring potential contributions of enteric glia in gut barrier dysfunction driven by ingesting a Western (high-fat) diet. This study specifically focused on potential roles of inflammasome activation in glia as a potential contributor to diet-induced inflammation. The investigators approached this question using wild-type C57BL/6J and NLRP3-KO&lt;sup&gt;−/−&lt;/sup&gt; mice fed a 60-kcal high-fat diet (HFD) or standard diet for 8 weeks and studied mucosal integrity by histology, immunolabeling, and western blot. Potential reactive gliosis processes and inflammasome activation were assessed by immunolabeling for glial fibrillary acidic protein (GFAP) and co-labeling for inflammasome components.&lt;/p&gt;&lt;p&gt;The data show that mice consuming a HFD for 8 weeks increased body weight, altered colon mucus composition by decreasing acidic mucins, disrupted epithelial barrier integrity, increased GFAP-positive glial cells (gliosis), and triggered NLRP3 inflammasome activation. Surprisingly, HFD-NLRP3&lt;sup&gt;−/−&lt;/sup&gt; mice failed to gain weight on the HFD and did not exhibit signs of enteric gliosis or altered mucus composition and epithelial barrier integrity. Based on these results, the authors suggested that inflammasome activation is involved in causing obesity, impairing the mucosal barrier, and activating gliosis. To test this concept more directly, the investigators turned to in vitro coculture experiments with a rat-transformed cell line used to model enteric glia (CRL-2690) and a rat intestinal epithelial cell (IEC) line. Challenging cultures with a combination of lipopolysaccharide (LPS) and palmitate was then used to broadly test whether dietary saturated fatty acids and endotoxins disrupt the epithelial barrier ","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14258","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783358","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":"Did you know: Kangaroos are resistant to ventricular arrhythmia","authors":"Kirstine Calloe,&nbsp;Stefan M Sattler,&nbsp;Julie Norup Hertel,&nbsp;Carsten Grøndahl,&nbsp;Stamatios Alan Tahas,&nbsp;Morten B. Thomsen","doi":"10.1111/apha.14257","DOIUrl":"10.1111/apha.14257","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779025","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":"Chloride fluxes and GABA release sustain inhibition in the CNS: The role for Bestrophin 1 anion channels","authors":"Alexei Verkhratsky,&nbsp;Verena Untiet,&nbsp;Vladimir V. Matchkov","doi":"10.1111/apha.14254","DOIUrl":"10.1111/apha.14254","url":null,"abstract":"&lt;p&gt;In the current issue of &lt;i&gt;Acta Physiologica&lt;/i&gt;, Di Papma et al.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; revealed a widespread brain expression of Ca&lt;sup&gt;2+&lt;/sup&gt;-dependent anion (chloride) channel Bestrophin 1 (Best1) in both neurones and neuroglia. Chloride ions (Cl&lt;sup&gt;−&lt;/sup&gt;) are indispensable for ionotropic inhibition of neurons in the central nervous system (CNS). This inhibition is mainly mediated by GABA&lt;sub&gt;A&lt;/sub&gt; and glycine pentameric receptors, the ligand-gated anion channels. Thus, controlling Cl&lt;sup&gt;−&lt;/sup&gt; homeostasis is paramount for balancing inhibition and excitation in the nervous circuits, which is critical for CNS function. An aberrant inhibition in the nervous circuits leads to many neurological and neuropsychiatric diseases, including epilepsy and mood disorders.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Homeostasis of Cl&lt;sup&gt;−&lt;/sup&gt; in the CNS is functionally segregated between neurones and astrocytes. In the mature brain, neurones keep cytoplasmic Cl&lt;sup&gt;−&lt;/sup&gt; concentration ([Cl&lt;sup&gt;−&lt;/sup&gt;]&lt;sub&gt;&lt;i&gt;i&lt;/i&gt;&lt;/sub&gt;) low at around ~5–10 mM, while astrocytes maintain high [Cl&lt;sup&gt;−&lt;/sup&gt;]&lt;sub&gt;&lt;i&gt;i&lt;/i&gt;&lt;/sub&gt; in the range of 30–60 mM.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; This disparity defines the functional outcome of the opening of anion channels: in neurones an opening of anion channels mediates Cl&lt;sup&gt;−&lt;/sup&gt; influx (which results in hyperpolarization which inhibits neuronal activity), whereas in astrocytes these channels mediate depolarising Cl&lt;sup&gt;−&lt;/sup&gt; efflux. Such an opposite arrangement of the [Cl&lt;sup&gt;−&lt;/sup&gt;]&lt;sub&gt;&lt;i&gt;i&lt;/i&gt;&lt;/sub&gt; homeostasis is critical for maintaining synaptic and extrasynaptic neuronal inhibition. That is, Cl&lt;sup&gt;−&lt;/sup&gt; influx into neurones may deplete Cl&lt;sup&gt;−&lt;/sup&gt; from the extracellular space but Cl&lt;sup&gt;-&lt;/sup&gt; is replenished by a continuous supply of Cl&lt;sup&gt;−&lt;/sup&gt; ions from astrocytes.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; This coordinated Cl&lt;sup&gt;−&lt;/sup&gt; movement between cells and extracellular space is greatly facilitated by a close synaptic association of neuronal and astrocytic compartments, which form a multipartite synapse and a synaptic cradle.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; At the inhibitory synapses, the postsynaptic neuronal specialization, as well as astrocytic perisynaptic leaflets, possess GABA&lt;sub&gt;A&lt;/sub&gt; receptors.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Hence, presynaptic GABA release opens anion channels in both neuronal and astrocytic membranes. Considering that extracellular Cl&lt;sup&gt;−&lt;/sup&gt; concentration can be less than the presumed 120 mM,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; astrocytic Cl&lt;sup&gt;−&lt;/sup&gt; supply is critical for sustaining inhibitory synaptic transmission. Indeed, optogenetic manipulations with astrocytic [Cl&lt;sup&gt;−&lt;/sup&gt;]&lt;sub&gt;&lt;i&gt;i&lt;/i&gt;&lt;/sub&gt; substantially affect neuronal inhibition.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Another key player in Cl&lt;sup&gt;−&lt;/sup&gt; homeostasis in the brain tissue is represented by Ca&lt;sup&gt;2+&lt;/sup&gt;-activated Cl&lt;sup&gt;−&lt;/sup&gt; channels that link together cells excitation, expressed as an intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; raise, an","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14254","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714896","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}