Journal of Physiology-London最新文献

{"title":"Multiple carbamylation events are required for differential modulation of Cx26 hemichannels and gap junctions by CO₂.","authors":"Sarbjit Nijjar, Deborah Brotherton, Jack Butler, Valentin-Mihai Dospinescu, Harry G Gannon, Victoria Linthwaite, Martin Cann, Alexander Cameron, Nicholas Dale","doi":"10.1113/JP285885","DOIUrl":"https://doi.org/10.1113/JP285885","url":null,"abstract":"<p><p>CO₂ directly modifies the gating of connexin26 (Cx26) gap junction channels and hemichannels. This gating depends upon Lys125, and the proposed mechanism involves carbamylation of Lys125 to allow formation of a salt bridge with Arg104 on the neighbouring subunit. We demonstrate via carbamate trapping and tandem mass spectrometry that five Lys residues within the cytoplasmic loop, including Lys125, are indeed carbamylated by CO₂. The cytoplasmic loop appears to provide a chemical microenvironment that facilitates carbamylation. Systematic mutation of these Lys residues to Arg shows that only carbamylation of Lys125 is essential for hemichannel opening. By contrast, carbamylation of Lys108 and Lys125 is essential for gap junction closure to CO₂. Chicken (Gallus gallus) Cx26 gap junction channels lack Lys108 and do not close to CO₂, as shown by both a dye transfer assay and a high-resolution cryogenic electron microscopy structure. The mutation Lys108Arg prevents CO₂-dependent gap junction channel closure in human Cx26. Our findings directly demonstrate carbamylation in connexins, provide further insight into the differential action of CO₂ on Cx26 hemichannels and gap junction channels, and increase support for the role of the N-terminus in gating the Cx26 channel. KEY POINTS: Direct evidence of carbamylation of multiple lysine residues in the cytoplasmic loop of Cx26. Concentration-dependent carbamylation at lysines 108, 122 and 125. Only carbamylation of lysine 125 is essential for hemichannel opening to CO₂. Carbamylation of lysine 108 along with lysine 125 is essential for CO₂-dependent gap junction channel closure.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191184","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":"CaMKII at the crossroads: calcium dysregulation, and post-translational modifications driving cell death.","authors":"Alicia Mattiazzi, Carolina Jaquenod De Giusti, Carlos A Valverde","doi":"10.1113/JP285941","DOIUrl":"https://doi.org/10.1113/JP285941","url":null,"abstract":"<p><p>The multifunctional Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) regulates numerous proteins involved in excitation-contraction-relaxation coupling and cardiac excitability. However, its overactivation induces severe Ca²⁺/handling alterations, playing a significant role in the pathogenesis of diseases such as hypertrophy, arrhythmias and cell death, which can ultimately lead to heart failure. Being a suitable target for various aberrant signals that characterize several diseases, such as Ca²⁺ overload, oxidative stress or excessive glycosylation, CaMKII shifts under these conditions from a physiological regulator to a pathological molecule. In this review, we explore the evolution of knowledge regarding the role of CaMKII activation on cell death across different pathological contexts, focusing on the converging mechanisms that transform the enzyme from an ally into a villain.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191214","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":"Evolutionary poker lacks a full deck when modelling the LTEE Cit⁺ phenotype.","authors":"Scott A Minnich, Carolyn J Hovde","doi":"10.1113/JP288355","DOIUrl":"https://doi.org/10.1113/JP288355","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191217","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":"A physiological pragmatic view of the philosophical debate on freedom to choose.","authors":"Shimon Marom","doi":"10.1113/JP288238","DOIUrl":"https://doi.org/10.1113/JP288238","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191210","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":"Physiological mechanisms of neuromuscular impairment in diabetes-related complications: Can physical exercise help prevent it?","authors":"Edoardo Lecce, Alessio Bellini, Giuseppe Greco, Fiorella Martire, Alessandro Scotto di Palumbo, Massimo Sacchetti, Ilenia Bazzucchi","doi":"10.1113/JP287589","DOIUrl":"https://doi.org/10.1113/JP287589","url":null,"abstract":"<p><p>Diabetes mellitus is a chronic disorder that progressively induces complications, compromising daily independence. Among these, diabetic neuropathy is particularly prevalent and contributes to substantial neuromuscular impairments in both types 1 and 2 diabetes. This condition leads to structural damage affecting both the central and peripheral nervous systems, resulting in a significant decline in sensorimotor functions. Alongside neuropathy, diabetic myopathy also contributes to muscle impairment and reduced motor performance, intensifying the neuromuscular decline. Diabetic neuropathy typically implicates neurogenic muscle atrophy, motoneuron loss and clustering of muscle fibres as a result of aberrant denervation-reinervation processes. These complications are associated with compromised neuromuscular junctions, where alterations occur in pre-synaptic vesicles, mitochondrial content and post-synaptic signalling. Neural damage is intensified by chronic hyperglycaemia and oxidative stress, exacerbating vascular dysfunction and reducing oxygen delivery. These complications imply a severe decline in neuromuscular performance, evidenced by reductions in maximal force and power output, rate of force development and muscle endurance. Furthermore, diabetes-related complications are compounded by age-related degenerative changes in long-term patients. Aerobic and resistance training offer promising approaches for managing blood glucose levels and neuromuscular function. Aerobic exercise promotes mitochondrial biogenesis and angiogenesis, supporting metabolic and cardiovascular health. Resistance training primarily enhances neural plasticity, muscle strength and hypertrophy, which are crucial factors for mitigating sarcopenia and preserving functional independence. This topical review examines current evidence on the physiological mechanisms underlying diabetic neuropathy and the potential impact of physical activity in counteracting this decline.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081887","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":"Inhibition of BK channels by GABAb receptors enhances intrinsic excitability of layer 2/3 vasoactive intestinal polypeptide-expressing interneurons in mouse neocortex.","authors":"Karolina Bogaj, Joanna Urban-Ciecko","doi":"10.1113/JP286439","DOIUrl":"https://doi.org/10.1113/JP286439","url":null,"abstract":"<p><p>GABAb receptors (GABAbRs) affect many signalling pathways, and hence the net effect of the activity of these receptors depends upon the specific ion channels that they are linked to, leading to different effects on specific neuronal populations. Typically, GABAbRs suppress neuronal activity in the cerebral cortex. Previously, we found that neocortical parvalbumin-expressing cells are strongly inhibited through GABAbRs, whereas somatostatin interneurons are immune to this modulation. Here, we employed in vitro whole-cell patch-clamp recordings to study whether GABAbRs modulate the activity of vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) in layer (L) 2/3 of the mouse primary somatosensory cortex. Utilizing machine learning algorithms (hierarchical clustering and principal component analysis), we revealed that one VIP-IN cluster (about 68% of all VIP-INs) was sensitive to GABAbR activation. Paradoxically, when recordings were performed in standard conditions with high extracellular Ca²⁺ level, GABAbRs indirectly inhibited the activity of large conductance voltage- and calcium-activated potassium (BK) channels and reduced GABAaR-mediated inhibition, leading to an increase in intrinsic excitability of these interneurons. However, a classical inhibitory effect of GABAbRs on L2/3 VIP-INs was observed in modified artificial cerebrospinal fluid with physiological (low) Ca²⁺ concentration. Our results are essential for a deeper understanding of mechanisms underlying the modulation of cortical networks. KEY POINTS: Layer 2/3 vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) in the mouse somatosensory cortex cluster into three electrophysiological types differentially sensitive to GABAb receptors (GABAbRs). The majority of VIP-INs (type 1, about 68% of all VIP-INs) are regulated through pre- and postsynaptic GABAbRs, while a subset of these interneurons (types 2 and 3) is controlled only presynaptically. The net effect of GABAbR activation on VIP-IN excitability depends on [Ca²⁺] in artificial cerebrospinal fluid. When [Ca²⁺] is high (2.5 mM), GABAbRs indirectly inhibit BK channels and reduce GABAaR inhibition leading to increased intrinsic excitability of type 1 VIP-INs. When [Ca²⁺] is low (1 mM), which is more physiological, BK channels do not regulate the intrinsic excitability of VIP-INs and thus postsynaptic GABAbRs canonically decrease the intrinsic excitability of type 1 VIP-INs.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124047","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 LINC complex in blood vessels: from physiology to pathological implications in arterioles.","authors":"Gonzalo Ferreira, Romina Cardozo, Luisina Chavarria, Axel Santander, Luis Sobrevia, Wakam Chang, Gregg Gundersen, Garth L Nicolson","doi":"10.1113/JP285906","DOIUrl":"https://doi.org/10.1113/JP285906","url":null,"abstract":"<p><p>The LINC (linker of nucleoskeleton and cytoskeleton) complex is a critical component of the cellular architecture that bridges the nucleoskeleton and cytoskeleton and mediates mechanotransduction to and from the nucleus. Though it plays important roles in all blood vessels, it is in arterioles that this complex plays a pivotal role in maintaining endothelial cell integrity, regulating vascular tone, forming new microvessels and modulating responses to mechanical and biochemical stimuli. It is also important in vascular smooth muscle cells and fibroblasts, where it possibly plays a role in the contractile to secretory phenotypic transformation during atherosclerosis and vascular ageing, and in fibroblasts' migration and inflammatory responses in the adventitia. Physiologically, the LINC complex contributes to the stability of arteriolar structure, adaptations to changes in blood flow and injury repair mechanisms. Pathologically, dysregulation or mutations in LINC complex components can lead to compromised endothelial function, vascular remodelling and exacerbation of cardiovascular diseases such as atherosclerosis (arteriolosclerosis). This review summarizes our current understanding of the roles of the LINC complex in cells from arterioles, highlighting its most important physiological functions, exploring its implications for vascular pathology and emphasizing some of its functional characteristics in endothelial cells. By elucidating the LINC complex's role in health and disease, we aim to provide insights that could improve future therapeutic strategies targeting LINC complex-related vascular disorders.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081888","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":"Increased muscle satellite cell content and preserved telomere length in response to combined exercise training in patients with FSHD.","authors":"Oscar Horwath, Diego Montiel-Rojas, Elodie Ponsot, Léonard Féasson, Fawzi Kadi","doi":"10.1113/JP287033","DOIUrl":"https://doi.org/10.1113/JP287033","url":null,"abstract":"<p><p>Facioscapulohumeral muscular dystrophy (FSHD) is an inherited muscle disease characterized by weakness and muscle wasting. In the absence of available treatments, exercise training has emerged as a potential strategy to attenuate muscle tissue deterioration. However, little is known about the impact of chronic exercise on degenerative events and regenerative capacity in FSHD muscle. Muscle biopsies were obtained from 16 FSHD patients before and after a 24 week training program combining aerobic-, strength- and high-intensity exercise (Control; n = 8, Training; n = 8). Histochemical and immunohistochemical approaches were applied to assess histopathological signs, markers of regeneration, inflammatory infiltrates and satellite cell content. Muscle telomere length was measured as an indicator of the remaining regenerative capacity. The proportion of muscle fibres expressing developmental myosins and centralized myonuclei was not exacerbated after the intervention. Similarly, no alterations were observed in the number of inflammatory infiltrates (CD68⁺ cells). Alongside muscle hypertrophy in slow (P = 0.022) and fast fibres (P = 0.022 and P = 0.008), satellite cell content increased specifically in fast fibres (+75 %, P = 0.015), indicating a functional satellite cell pool in FSHD muscle. Importantly, exercise training was not associated with a shortening of muscle telomere length, suggesting that muscle cell turnover was not accelerated despite an expansion of the satellite cell pool. Our findings suggest that combined exercise training elicits beneficial muscular adaptations without impairing important indicators of skeletal muscle regenerative capacity in patients with FSHD. KEY POINTS: A 24 week combined exercise training program is a safe and well-tolerated strategy to attenuate skeletal muscle deterioration in facioscapulohumeral muscular dystrophy (FSHD) patients. Markers of histopathology, muscle fibre regeneration and inflammatory infiltrates were not exacerbated following exercise training in FSHD muscle. Here, we show novel data that exercise training in FSHD patients induced muscle fibre hypertrophy and triggered an expansion of the satellite cell pool specifically in fast fibres. Exercise training in these patients is not associated with a shortening of muscle telomere length thereby indicating a preserved capacity for muscle regeneration.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076138","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":"Heart-derived factors and organ cross-talk in settings of health and disease: new knowledge and clinical opportunities for multimorbidity.","authors":"Melodi G Sen, Roger Chooi, Julie R McMullen","doi":"10.1113/JP287400","DOIUrl":"https://doi.org/10.1113/JP287400","url":null,"abstract":"<p><p>Cardiovascular disease affects millions of people worldwide and often presents with other conditions including metabolic, renal and neurological disorders. A variety of secreted factors from multiple organs/tissues (proteins, nucleic acids and lipids) have been implicated in facilitating organ cross-talk that may contribute to the development of multimorbidity. Secreted proteins have received the most attention, with the greatest body of research related to factors released from adipose tissue (adipokines), followed by skeletal muscle (myokines). To date, there have been fewer studies on proteins released from the heart (cardiokines) implicated with organ cross-talk. Early evidence for the secretion of cardiac-specific factors facilitating organ cross-talk came in the form of natriuretic peptides which are secreted via the classical endoplasmic reticulum-Golgi pathway. More recently, studies in cardiomyocyte-specific genetic mouse models have revealed cardiac-initiated organ cross-talk. Cardiomyocyte-specific modulation of microRNAs (miR-208a and miR-23-27-24 cluster) and proteins such as the mediator complex subunit 13 (MED13), G-protein-coupled receptor kinase 2 (GRK2), mutant α-myosin heavy-chain (αMHC), ubiquitin-like modifier-activating enzyme (ATG7), oestrogen receptor alpha (ERα) and fibroblast growth factor 21 (FGF21) have resulted in metabolic and renal phenotypes. These studies have implicated a variety of factors which can be secreted via the classical pathway or via non-classical mechanisms including the release of extracellular vesicles. Cross-talk between the heart and the brain has also been described (e.g. via miR-1 and an emerging concept, interoception: detection of internal neural signals). Here we summarize these studies taking into consideration that factors may be secreted in both settings of health and in disease.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069225","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 impact of plakophilin-2 deficiency on the atrial myocardium: electrophysiological insights and therapeutic implications.","authors":"Sasha Gladkikh, Jenny Cheng","doi":"10.1113/JP288315","DOIUrl":"https://doi.org/10.1113/JP288315","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069230","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}