Function (Oxford, England)最新文献

{"title":"Comparing Transgenic Production to Supplementation of ω-3 PUFA Reveals Distinct But Overlapping Mechanisms Underlying Protection Against Metabolic and Hepatic Disorders.","authors":"Noëmie Daniel,&nbsp;Mélanie Le Barz,&nbsp;Patricia L Mitchell,&nbsp;Thibault V Varin,&nbsp;Isabelle Bourdeau Julien,&nbsp;Dominique Farabos,&nbsp;Geneviève Pilon,&nbsp;Josée Gauthier,&nbsp;Carole Garofalo,&nbsp;Jing X Kang,&nbsp;Jocelyn Trottier,&nbsp;Olivier Barbier,&nbsp;Denis Roy,&nbsp;Benoit Chassaing,&nbsp;Emile Levy,&nbsp;Frédéric Raymond,&nbsp;Antonin Lamaziere,&nbsp;Nicolas Flamand,&nbsp;Cristoforo Silvestri,&nbsp;Christian Jobin,&nbsp;Vincenzo Di Marzo,&nbsp;André Marette","doi":"10.1093/function/zqac069","DOIUrl":"https://doi.org/10.1093/function/zqac069","url":null,"abstract":"<p><p>We compared endogenous ω-3 PUFA production to supplementation for improving obesity-related metabolic dysfunction. Fat-1 transgenic mice, who endogenously convert exogenous ω-6 to ω-3 PUFA, and wild-type littermates were fed a high-fat diet and a daily dose of either ω-3 or ω-6 PUFA-rich oil for 12 wk. The endogenous ω-3 PUFA production improved glucose intolerance and insulin resistance but not hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased hepatic levels of ω-3 PUFA-containing 2-monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids with ω-3 PUFA supplementation being more efficacious. Reduced hepatic lipid accumulation associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both models induced a significant fecal enrichment of the beneficial <i>Allobaculum</i> genus, mice supplemented with ω-3 PUFA displayed additional changes in the gut microbiota functions with a significant reduction of fecal levels of the proinflammatory molecules lipopolysaccharide and flagellin. Multiple-factor analysis identify that the metabolic improvements induced by ω-3 PUFAs were accompanied by a reduced production of the proinflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. While endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 2","pages":"zqac069"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9446287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining the Specialized Functions of cAMP Signals in an Organelle Formerly Deemed to Have No Function: The Primary Cilium.","authors":"Aldebaran M Hofer","doi":"10.1093/function/zqad007","DOIUrl":"https://doi.org/10.1093/function/zqad007","url":null,"abstract":"The primary cilium is a decidedly “cute” organelle that first attracted the attention of electron microscopists in the early 1960s (Figure 1). A few prescient scientists of the last century recognized that the cilium was more than just an ultrastructural curiosity. But this was not the prevailing view; in fact, cell biology textbooks published only three decades ago discounted the cilium as a “vestigial” structure of “unknown function.” Interest in this diminutive organelle began to seriously build around 20 yr ago with the discovery of its central role in several disease states. These included autosomal dominant polycystic kidney disease (ADPKD), and inherited “ciliopathies” such as Bardet– Biedl syndrome. The ciliary localization of signaling pathways such as hedgehog and its connection to glioblastoma accelerated further interest.1 Now, in 2023, the primary cilium has been launched from relative obscurity to the focus of exuberant scientific inquiry. Discoveries of new connections between ciliary biology and cellular functions (autophagy, neuronal migration, and necroptosis, to name a few) seem to emerge daily. Loss of proper function is implicated in an ever-expanding list of human diseases and conditions that include obesity and appetite control, cancer, cognitive decline, and diabetes.1 Among the most titillating of observations to come to light in the past years (for some of us, at least), was that cilia are enriched with a specific subset of G-protein coupled receptors (GPCRs) that are typically linked to cAMP signaling through Galpha(s) or Galpha(i).2 Another early observation regarded the very exclusive sequestration of adenylyl cyclase 3 (AC3) in neuronal cilia, and its link to obesity and depression. Other AC isoforms (eg, AC5 and AC6) are now known to localize to cilia in different cell types, along with phosphodiesterases and betaarrestins. The main effector of the cAMP signal, protein kinase A (PKA), is tethered within the organelle by A-kinase anchoring proteins (AKAPs), ready to phosphorylate a host of potential and confirmed ciliary PKA targets. Direct measurements by our lab using targeted cAMP biosensors showed that stimulation of GPCRs confined exclusively in the cilium produced local cAMP signals. (Interestingly, this response was greatly amplified during activation of the hedgehog pathway.)3 Taken together, it appears everything is in place to operate a self-contained cAMP signaling circuit in the cilium. But what special purpose does it serve, especially considering that small molecules like cyclic nucleotides move freely between cytosol and cilium? Recent studies now implicate ciliary GPCRs coupled to cAMP production in the control of several physiological functions. For example, Hilgendorf et al. reported that white adipose tissue expansion and differentiation required FFAR4, a ciliary GPCR that could be stimulated by omega-3 fatty acids to locally produce cAMP.4 FFAR4 stimulation was shown to converge on the chromatin r","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 2","pages":"zqad007"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/89/d4/zqad007.PMC9972343.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10346793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ion Channel Lateral Diffusion Reveals the Maturation Process of the Neuronal Actin Cytoskeleton.","authors":"Luis A Pardo","doi":"10.1093/function/zqad029","DOIUrl":"https://doi.org/10.1093/function/zqad029","url":null,"abstract":"mall-conductance calcium-acti v ated potassium (SK) channels r e v olta ge-inde pendent K + channels that acti v ate in r esponse o a rise in cytoplasmic Ca 2 + 1 . In neurons, they are, therefore, b le to r educe Ca 2 + entr y in spines and dendrites, limiting proonged depolarization. SK channels can also be found in the oma and in axons, where they likely contribute to spike freuency adaptation. Gu and colleagues used single-particle tr ac kng 2 of SK channels in different areas of pyramidal hippocamal neurons in cultures of different ages. The diffusion coefcient of SK channels was determined along the maturation rocess of the neuronal culture using biotinylated apamin and tr e ptavidin-conjugated quantum dots to label the channels in ombination with total internal reflection microscopy. At the ame time, actin cytoskeleton integrity was manipulated pharacologically to investigate its impact on the diffusion velocity f SK channels. The approach allowed tracking the diffusion of he channel in different compartments, which served as a proxy o determine the stability of actin cytoskeletal structures. Since ta b le actin filaments limited the distribution of SK channels, it as possib le to infer how structured the actin cytoskeleton was long the maturation pr ocess. Importantl y, the submembrane ctin cytoskeleton is incr easingl y r egarded as a crucial factor for odulating the activity of ion channels and transporters at the lasma membrane (see Morache vska ya and Sudarikova 3 ). Neuronal function critically depends on the cytoar c hitecture f the neuron. The cytoskeleton plays a critical role in mainaining the proper neural computation that goes far beyond er e mechanical sta bility and shape maintenance. Specialized tructures crucial for neurotransmission, such as the node of anvier, the axon initial segment (AIS), or synaptic terminals, are","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 4","pages":"zqad029"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Muscle-Specific Cellular and Molecular Adaptations to Late-Life Voluntary Concurrent Exercise.","authors":"","doi":"10.1093/function/zqad036","DOIUrl":"https://doi.org/10.1093/function/zqad036","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/function/zqac027.].</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad036"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/25/3d/zqad036.PMC10413927.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9991179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-injury Inhibition of Endothelin-1 Dependent Renal Vasoregulation Mitigates Rhabdomyolysis-Induced Acute Kidney Injury.","authors":"Jeremiah M Afolabi,&nbsp;Praghalathan Kanthakumar,&nbsp;Jada D Williams,&nbsp;Ravi Kumar,&nbsp;Hitesh Soni,&nbsp;Adebowale Adebiyi","doi":"10.1093/function/zqad022","DOIUrl":"https://doi.org/10.1093/function/zqad022","url":null,"abstract":"<p><p>In patients with rhabdomyolysis, the overwhelming release of myoglobin into the circulation is the primary cause of kidney injury. Myoglobin causes direct kidney injury as well as severe renal vasoconstriction. An increase in renal vascular resistance (RVR) results in renal blood flow (RBF) and glomerular filtration rate (GFR) reduction, tubular injury, and acute kidney injury (AKI). The mechanisms that underlie rhabdomyolysis-induced AKI are not fully understood but may involve the local production of vasoactive mediators in the kidney. Studies have shown that myoglobin stimulates endothelin-1 (ET-1) production in glomerular mesangial cells. Circulating ET-1 is also increased in rats subjected to glycerol-induced rhabdomyolysis. However, the upstream mechanisms of ET-1 production and downstream effectors of ET-1 actions in rhabdomyolysis-induced AKI remain unclear. Vasoactive ET-1 is generated by ET converting enzyme 1 (ECE-1)-induced proteolytic processing of inactive big ET to biologically active peptides. The downstream ion channel effectors of ET-1-induced vasoregulation include the transient receptor potential cation channel, subfamily C member 3 (TRPC3). This study demonstrates that glycerol-induced rhabdomyolysis in Wistar rats promotes ECE-1-dependent ET-1 production, RVR increase, GFR decrease, and AKI. Rhabdomyolysis-induced increases in RVR and AKI in the rats were attenuated by post-injury pharmacological inhibition of ECE-1, ET receptors, and TRPC3 channels. CRISPR/Cas9-mediated knockout of TRPC3 channels attenuated ET-1-induced renal vascular reactivity and rhabdomyolysis-induced AKI. These findings suggest that ECE-1-driven ET-1 production and downstream activation of TRPC3-dependent renal vasoconstriction contribute to rhabdomyolysis-induced AKI. Hence, post-injury inhibition of ET-1-mediated renal vasoregulation may provide therapeutic targets for rhabdomyolysis-induced AKI.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 4","pages":"zqad022"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/06/c0/zqad022.PMC10278989.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10003895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Some Like It Hot: Dynamic Control of Cav2.2 Channels By Chili Peppers.","authors":"Paz Duran,&nbsp;Rajesh Khanna","doi":"10.1093/function/zqac066","DOIUrl":"https://doi.org/10.1093/function/zqac066","url":null,"abstract":"Spicy meals causes the production of happy endorphins together with the triggering of heat and pain, similar to a runner’s high. The active ingredient in hot chili peppers that causes their distinctive burning sensation is called capsaicin (8-methylN-vanillyl-6-nonenamide). This bioactive substance binds to the primary afferent neurons’ transient receptor potential vanilloid 1 (TRPV1) cation channels, which when activated, cause a sensation of heat. Capsaicin has been utilized as a tool to study the regulation of pain since TRPV1 channels have been reported to be crucial for heat nociception.1 Despite reports that capsaicin binding to TRPV1 channels causes pain, it has been demonstrated that prolonged exposures to capsaicin can desensitize dorsal root ganglion (DRG) neurons, thus reducing afferent drive and reducing synaptic transmission in the dorsal horn.2 Several studies have established that voltage-gated calcium channels (VGCCs) are key modulators of nociceptive and nociplastic pain.3 VGCCs are transmembrane proteins composed of a principal pore-forming α subunit that mediates Ca2+ entry into the cell in response to membrane potential changes. Based on their biophysical characteristics, VGCCs are classified into low voltage activated (LVA) and high voltage activated (HVA) families. HVA channels are typically expressed with auxiliary subunits β and α2δ that regulate the trafficking and function of these channels. The N-type calcium channel, also known as CaV2.2, is a member of the HVA family that is expressed at high levels in sensory neurons where they are key mediators of neurotransmitter release and the transmission of sensory information from the periphery to central sites.4 Given that CaV2.2 channels are the main presynaptic VGCCs and have a critical role in regulating nociceptive transmission, it is reasonable to predict a regulation mediated by capsaicin and TRPV1. However, little is known about the underlying mechanisms of the functional interaction between these channels and their presynaptic function. This gap in knowledge was explored in a very ingenious way by Krishma Ramgoolam and Annette Dolphin in a new study reported in this issue of FUNCTION.5The authors build on their long-standing expertise of N-type calcium channels (CaV2.2) to investigate their functional presynaptic expression and explore their interaction with TRPV1 channels in primary nociceptors. Here, the Dolphin group used their previously described CaV2.2 HA knock-in mouse line, which expresses CaV2.2 with a hemagglutinin (HA) exofacial epitope tag to easily localize endogenous CaV2.2 channels.5 Using co-cultures of DRG neurons isolated from CaV2.2 HA knock-in mice with spinal cord neurons from wild-type (WT) mice and approaches, including immunofluorescence staining and calcium imaging, this study investigated the neuronal maturation, synapse formation, distribution, and presynaptic function of the tagged Ntype calcium channels. First, CaV2.2 localization during n","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac066"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10740530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-and Postfusion Tuning of Regulated Exocytosis by Cell Metabolites.","authors":"Robert Zorec,&nbsp;Alexei Verkhratsky","doi":"10.1093/function/zqac062","DOIUrl":"https://doi.org/10.1093/function/zqac062","url":null,"abstract":"1Laboratory of Cell Engineering, Celica Biomedical, 1000 Ljubljana, Slovenia, 2Laboratory of Neuroendocrinology – Molecular Cell Physiology, Institute of Pathophysiology, University of Ljubljana, Medical Faculty, 1000 Ljubljana, Slovenia, 3Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK and 4Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain ∗Address correspondence to R.Z. (e-mail: robert.zorec@mf.uni.lj.si)","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac062"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b8/d5/zqac062.PMC9789503.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10680268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium Transients at ER Subdomains Initiate Autophagosome Formation: A Single Spark Can Start a Prairie Fire.","authors":"Shuang Peng","doi":"10.1093/function/zqad004","DOIUrl":"https://doi.org/10.1093/function/zqad004","url":null,"abstract":"Autophagy is an evolutionarily conserved and tightly regulated lysosome-mediated intracellular bulk degradation pathway by which intracellular macromolecules are sequestered in autophagosomes and delivered to lysosomes for degradation and recycling. Identification of autophagy-related (ATG) genes in yeast has promoted the understanding of the molecular mechanism of autophagosome formation. 1 The proteins encoded by these genes play a crucial role at different steps of autophagosome formation. For example, Atg17/Atg13/Atg1 complexes form condensates and localize on the vacuole membrane, thereby recruiting downstream autophagy proteins to promote the formation of the isolation membrane on the vacuole. 2 Autophagosome biogenesis involves nucleation, expansion, and closure of the isolation membrane. Calcium (Ca 2 + ) is well known as an essential second messenger in eukaryotic cells. 3 Ca 2 + levels are distinct in different sub-cellular compartments and are built up by Ca 2 + channels and pumps located in the plasma membrane and organelles. Due to the resulting highly localized gradients, cytoplasmic Ca 2 + signals display spatiotemporal heterogeneity in the form of sparks,","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 2","pages":"zqad004"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9363206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Capillary-Mitochondrial Oxygen Transport in Muscle: Paradigm Shifts.","authors":"David C Poole,&nbsp;Timothy I Musch","doi":"10.1093/function/zqad013","DOIUrl":"https://doi.org/10.1093/function/zqad013","url":null,"abstract":"<p><p>When exercising humans increase their oxygen uptake (V̇O₂) 20-fold above rest the numbers are staggering: Each minute the O₂ transport system - lungs, cardiovascular, active muscles - transports and utilizes 161 sextillion (10 ²¹) O₂ molecules. Leg extension exercise increases the quadriceps muscles' blood flow 100-times; transporting 17 sextillion O₂ molecules per kilogram per minute from microcirculation (capillaries) to mitochondria powering their cellular energetics. Within these muscles, the capillary network constitutes a prodigious blood-tissue interface essential to exchange O₂ and carbon dioxide requisite for muscle function. In disease, microcirculatory dysfunction underlies the pathophysiology of heart failure, diabetes, hypertension, pulmonary disease, sepsis, stroke and senile dementia. Effective therapeutic countermeasure design demands knowledge of microvascular/capillary function in health to recognize and combat pathological dysfunction. Dated concepts of skeletal muscle capillary (from the Latin <i>capillus</i> meaning 'hair') function prevail despite rigorous data-supported contemporary models; hindering progress in the field for future and current students, researchers and clinicians. Following closely the 100th anniversary of August Krogh's 1920 Nobel Prize for capillary function this Evidence Review presents an anatomical and physiological development of this dynamic field: Constructing a scientifically defensible platform for our current understanding of microcirculatory physiological function in supporting blood-mitochondrial O₂ transport. New developments include: 1. Putative roles of red blood cell aquaporin and rhesus channels in determining tissue O₂ diffusion. 2. Recent discoveries regarding intramyocyte O₂ transport. 3. Developing a comprehensive capillary functional model for muscle O₂ delivery-to-V̇O₂ matching. 4. Use of kinetics analysis to discriminate control mechanisms from collateral or pathological phenomena.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 3","pages":"zqad013"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9479237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Molecular Circadian Clock of Phox2b-expressing Cells Drives Daily Variation of the Hypoxic but Not Hypercapnic Ventilatory Response in Mice.","authors":"Aaron A Jones,&nbsp;Gabriella M Marino,&nbsp;Allison R Spears,&nbsp;Deanna M Arble","doi":"10.1093/function/zqad023","DOIUrl":"https://doi.org/10.1093/function/zqad023","url":null,"abstract":"<p><p>While the suprachiasmatic nucleus (SCN) controls 24-h rhythms in breathing, including minute ventilation (V_E), the mechanisms by which the SCN drives these daily changes are not well understood. Moreover, the extent to which the circadian clock regulates hypercapnic and hypoxic ventilatory chemoreflexes is unknown. We hypothesized that the SCN regulates daily breathing and chemoreflex rhythms by synchronizing the molecular circadian clock of cells. We used whole-body plethysmography to assess ventilatory function in transgenic BMAL1 knockout (KO) mice to determine the role of the molecular clock in regulating daily rhythms in ventilation and chemoreflex. Unlike their wild-type littermates, BMAL1 KO mice exhibited a blunted daily rhythm in V_E and failed to demonstrate daily variation in the hypoxic ventilatory response (HVR) or hypercapnic ventilatory response (HCVR). To determine if the observed phenotype was mediated by the molecular clock of key respiratory cells, we then assessed ventilatory rhythms in BMAL1^fl/fl; Phox2b^Cre/+ mice, which lack BMAL1 in all Phox2b-expressing chemoreceptor cells (hereafter called BKOP). BKOP mice lacked daily variation in HVR, similar to BMAL1 KO mice. However, unlike BMAL1 KO mice, BKOP mice exhibited circadian variations in V_E and HCVR comparable to controls. These data indicate that the SCN regulates daily rhythms in V_E, HVR, and HCVR, in part, through the synchronization of the molecular clock. Moreover, the molecular clock of Phox2b-expressing cells is specifically necessary for daily variation in the hypoxic chemoreflex. These findings suggest that disruption of circadian biology may undermine respiratory homeostasis, which, in turn, may have clinical implications for respiratory disease.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 4","pages":"zqad023"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d7/c6/zqad023.PMC10278984.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}