Function (Oxford, England)最新文献

{"title":"BMAL1 in the Adrenal Gland: It's About Time-A Perspective on \"Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior\".","authors":"Brittni N Moore, Jennifer L Pluznick","doi":"10.1093/function/zqad008","DOIUrl":"10.1093/function/zqad008","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9972345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9115352","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":"Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior.","authors":"Hannah M Costello, G Ryan Crislip, Kit-Yan Cheng, I Jeanette Lynch, Alexandria Juffre, Phillip Bratanatawira, Annalisse Mckee, Ryanne S Thelwell, Victor M Mendez, Charles S Wingo, Lauren G Douma, Michelle L Gumz","doi":"10.1093/function/zqad001","DOIUrl":"10.1093/function/zqad001","url":null,"abstract":"<p><p>Brain and muscle ARNT-like 1 (BMAL1) is a core circadian clock protein and transcription factor that regulates many physiological functions, including blood pressure (BP). Male global <i>Bmal1</i> knockout (KO) mice exhibit ∼10 mmHg reduction in BP, as well as a blunting of BP rhythm. The mechanisms of how BMAL1 regulates BP remains unclear. The adrenal gland synthesizes hormones, including glucocorticoids and mineralocorticoids, that influence BP rhythm. To determine the role of adrenal BMAL1 on BP regulation, adrenal-specific <i>Bmal1</i> (<i>AS^Cre/+</i> ::<i>Bmal1</i>) KO mice were generated using aldosterone synthase Cre recombinase to KO <i>Bmal1</i> in the adrenal gland zona glomerulosa. We confirmed the localization and efficacy of the KO of BMAL1 to the zona glomerulosa. Male <i>AS^Cre/+</i> ::<i>Bmal1</i> KO mice displayed a shortened BP and activity period/circadian cycle (typically 24 h) by ∼1 h and delayed peak of BP and activity by ∼2 and 3 h, respectively, compared with littermate Cre- control mice. This difference was only evident when KO mice were in metabolic cages, which acted as a stressor, as serum corticosterone was increased in metabolic cages compared with home cages. <i>A</i>S <i>^Cre/+</i> ::<i>Bmal1</i> KO mice also displayed altered diurnal variation in serum corticosterone. Furthermore, these mice have altered eating behaviors where they have a blunted night/day ratio of food intake, but no change in overall food consumed compared with controls. Overall, these data suggest that adrenal BMAL1 has a role in the regulation of BP rhythm and eating behaviors.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/20/c0/zqad001.PMC9909366.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10822439","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":"Differential Control of Small-conductance Calcium-activated Potassium Channel Diffusion by Actin in Different Neuronal Subcompartments.","authors":"Shiju Gu,&nbsp;Anastasios V Tzingounis,&nbsp;George Lykotrafitis","doi":"10.1093/function/zqad018","DOIUrl":"https://doi.org/10.1093/function/zqad018","url":null,"abstract":"<p><p>Small-conductance calcium-activated potassium (SK) channels show a ubiquitous distribution on neurons, in both somatodendritic and axonal regions. SK channels are associated with neuronal activity regulating action potential frequency, dendritic excitability, and synaptic plasticity. Although the physiology of SK channels and the mechanisms that control their surface expression levels have been investigated extensively, little is known about what controls SK channel diffusion in the neuronal plasma membrane. This aspect is important, as the diffusion of SK channels at the surface may control their localization and proximity to calcium channels, hence increasing the likelihood of SK channel activation by calcium. In this study, we successfully investigated the diffusion of SK channels labeled with quantum dots on human embryonic kidney cells and dissociated hippocampal neurons by combining a single-particle tracking method with total internal reflection fluorescence microscopy. We observed that actin filaments interfere with SK mobility, decreasing their diffusion coefficient. We also found that during neuronal maturation, SK channel diffusion was gradually inhibited in somatodendritic compartments. Importantly, we observed that axon barriers formed at approximately days <i>in vitro</i> 6 and restricted the diffusion of SK channels on the axon initial segment (AIS). However, after neuron maturation, SK channels on the AIS were strongly immobilized, even after disruption of the actin network, suggesting that crowding may cause this effect. Altogether, our work provides insight into how SK channels diffuse on the neuronal plasma membrane and how actin and membrane crowding impacts SK channel diffusion.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"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/70/69/zqad018.PMC10165553.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9691399","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":"What Does Physiological Mean?","authors":"Ole H Petersen","doi":"10.1093/function/zqad042","DOIUrl":"https://doi.org/10.1093/function/zqad042","url":null,"abstract":"S © t a r ecentl y r e vie wed an original paper with a title including he words “physiological stimulation.” In this particular case, t turned out that the stim ulation w as far fr om physiological. he concentration of the hormone used for acti v ation w as w ay bov e the maximal level ever observed in vivo, and this made e think about the use, and misuse, of the word “physiologial.” It is a word that we (physiologists) employ fr equentl y and erhaps too fr equentl y. Papers in physiological, and other, jourals often refer to “physiological conditions,” which sometimes s taken to indicate experiments in vi v o, but also fr equentl y ust means that experiments on single cells or tissue fragents were carried out with stimulation protocols and under ircumstances that are not unlike those that could happen n vi v o. We hav e li v ed thr ough a long and pr oducti v e period of singleell biology. Very important discoveries of real significance have een made, but it is now becoming incr easingl y clear that ther e r e many criticall y important inter actions betw een different djacent cell types in most tissues. To c har acterize these proesses, it is necessary to observe simultaneously more than one ell type in individual organs or tissues. Furthermore, the behavor of a particular cell type in isolation may not be the same as hen it is embedded in its normal environment. Of particular oncern is the tacit assumption in many studies that processes n cell lines reflect those in normal cells in situ. It may therefore e useful to reflect on the usefulness of working under real physological conditions, notwithstanding the obvious difficulties of oing so. In what follows, I’ll try to illuminate these issues by xamples from immunology, epithelial physiology, and neurocience. Ca 2 + signaling studies in imm une cells hav e been immensel y uccessful in unravelling key Ca 2 + transport events and, in articular, the properties of the Ca 2 + r elease acti v ated Ca 2 + CRAC) channel of the Orai type and its molecular control echanism. 1 Unlike the situation in epithelial cells, where Ca 2 +","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10433090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10424847","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":"Watching Ion Channels on the Move.","authors":"Luis A Pardo","doi":"10.1093/function/zqac072","DOIUrl":"https://doi.org/10.1093/function/zqac072","url":null,"abstract":"Ion channels remain fascinating molecular machines implicated in virtually every cellular function. Their activity can be studied in deep detail using biophysical techniques down to the single-molecule level. However, as large hydrophobic proteins embedded in a lipidic environment, their structure has traditionally been very difficult to study. Cryo-EM approaches have boosted our knowledge in the last few years, expanding the collection of resolved structures almost on a weekly basis. Yet, there are still open questions regarding the structure-function of the channels that are now starting to find answers. Ion channels react rapidly to a wide range of stimuli, opening a pathway for the flow of ions across the membrane. The coupling of the stimulus to the opening of the gate can be studied in ligand-gated channels by comparing the structures of the ligand-bound and unbound channels. Still, such a comparison is more difficult to achieve when the channel responds to physical rather than chemical stimuli, as is the case of voltage-gated channels. The molecular principles of voltage-dependent gating of ion channels have been known for four decades. The mechanism consists, in essence, of the movement of some parts of the protein (the voltage-sensing domains) relative to others. The displacement results in a conformational change that produces the opening of the gate, but the intimate molecular mechanisms linking both events remain only partly known in many cases. Although the problem might appear like an academic discussion for experts at first glance, it has many practical implications. On the one hand—mainly","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10740532","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":"A Perspective on \"Hypoxia Resistance is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle\".","authors":"Camila Padilha,&nbsp;Ashleigh M Philp","doi":"10.1093/function/zqad024","DOIUrl":"https://doi.org/10.1093/function/zqad024","url":null,"abstract":"; Hypoxias; r esistance; inher ent; phenotype; mouse Skeletal muscle is reliant on a constant oxygen supply for mov ement, cellular r espiration, and thermogenesis. Heter oge-neous fibre types exist in skeletal muscle as a continuum from slow- to fast-twitch to facilitate specialized function. Type I (oxidati v e fibr es) pr esent a slow-twitc h phenotype , c har acterized by high oxygen capacity and increased fatigue resistance. In contrast, type IIa (fast oxidati v e gl ycol ytic phenotype) and type IIx (fast gl ycol ytic) pr esent faster twitc h speeds and contr","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713055","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":"Redox Bridling of GIRK Channel Activity.","authors":"Anna Boccaccio,&nbsp;Rocio K Finol-Urdaneta","doi":"10.1093/function/zqad027","DOIUrl":"https://doi.org/10.1093/function/zqad027","url":null,"abstract":"pr otein-gated inw ardl y r ectifying potassium (GIRK, Kir3.x) hannels belong to the large family of inw ardl y r ectifying potasium (Kir) channels expressed throughout the body. Activation nd consequent opening of GIRK channels allow inward flow of otassium (K + ) ions into the cell resulting in membrane potenial hyperpolarization and decr eased excita bility. Thus, GIRK hannels play a key role in regulating the activity of neurons and ontrolling important physiological processes including neuonal excita bility, heart r ate , and pain per ception. 1 GIRK channels are integral membrane proteins, existing s homoor heterotetr amers. Eac h monomer features two embrane-spanning helices (M1 and M2), a re-entrant P-loop or controlling ion permeation and selectivity, and extensive ntracellular aminoand carboxy-termini crucial for channel ating. Permeation is regulated by an inner helix gate formed y the M2 segments and a cytoplasmic G-loop gate. 1 Acti v ation of GIRK channels is mediated by the direct interction of G βγ subunits, released from various G protein-coupled ece ptors (GPCRs) upon the acti v ation of inhibitory neuroransmitter r ece ptors. Howev er, the acti vity of GIRK channels epends on the presence of the membrane anionic phospholipid hosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 or PIP 2 ) while it s also modulated by ubiquitously present sodium (Na + ) ions. urthermore , GIRK c hannels ar e too r e gulated by c holesterol, hosphorylation, ethanol, etcetera. 1 The crystal structures of ecombinant GIRK channels have offered valuable insights into ow they are functionally regulated by various ligands. Thus, hannel opening is facilitated by PIP 2 at the plasma membrane, hereas G βγ and Na + modulate the c hannel’s inter action with IP 2 through conformational changes that govern the gating proess. 2 The intracellular milieu is a reducing environment charcterized by a balanced redox state. This state is crucial to upport cellular processes while serving as a pr otecti v e shield","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713057","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":"Urine-based Detection of Congenital Portosystemic Shunt in C57BL/6 Mice.","authors":"Beng San Yeoh,&nbsp;Rachel M Golonka,&nbsp;Piu Saha,&nbsp;Mrunmayee R Kandalgaonkar,&nbsp;Yuan Tian,&nbsp;Islam Osman,&nbsp;Andrew D Patterson,&nbsp;Andrew T Gewirtz,&nbsp;Bina Joe,&nbsp;Matam Vijay-Kumar","doi":"10.1093/function/zqad040","DOIUrl":"https://doi.org/10.1093/function/zqad040","url":null,"abstract":"<p><p>Sporadic occurrence of congenital portosystemic shunt (PSS) at a rate of ∼1 out of 10 among C57BL/6 J mice, which are widely used in biomedical research, results in aberrancies in serologic, metabolic, and physiologic parameters. Therefore, mice with PSS should be identified as outliers in research. Accordingly, we sought methods to, reliably and efficiently, identify PSS mice. Serum total bile acids ≥ 40 µm is a <i>bona fide</i> biomarker of PSS in mice but utility of this biomarker is limited by its cost and invasiveness, particularly if large numbers of mice are to be screened. This led us to investigate if assay of urine might serve as a simple, inexpensive, noninvasive means of PSS diagnosis. Metabolome profiling uncovered that Krebs cycle intermediates, that is, citrate, α-ketoglutarate, and fumarate, were strikingly and distinctly elevated in the urine of PSS mice. We leveraged the iron-chelating and pH-lowering properties of such metabolites as the basis for 3 urine-based PSS screening tests: urinary iron-chelation assay, pH strip test, and phenol red assay. Our findings demonstrate the feasibility of using these colorimetric assays, whereby their readout can be assessed by direct observation, to diagnose PSS in an inexpensive, rapid, and noninvasive manner. Application of our urinary PSS screening protocols can aid biomedical research by enabling stratification of PSS mice, which, at present, likely confound numerous ongoing studies.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"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/d4/cc/zqad040.PMC10413929.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10062481","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 Gut Microbiome-Endocannabinoidome Axis: A New Way of Controlling Metabolism, Inflammation, and Behavior.","authors":"Cristoforo Silvestri,&nbsp;Vincenzo Di Marzo","doi":"10.1093/function/zqad003","DOIUrl":"https://doi.org/10.1093/function/zqad003","url":null,"abstract":"1Centre de Recherche de l’Institut de Pneumologie et Cardiologie de l’Université Laval, Département de médecine, Faculté de Médecine, Université Laval, Québec G1V 4G5, Canada, 2Institut sur la Nutrition et les Aliments Fonctionnels, Centre NUTRISS, Québec G1V 0A6, Canada, 3Canada Research Excellence Chair on the Microbiome–Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec G1V 0A6, Canada and 4École de nutrition, Faculté des sciences de l’agriculture et de l’alimentation (FSAA), Université Laval, Québec G1V 0A6, Canada ∗Address correspondence to V.D. (e-mail: vincenzo.dimarzo@criucpq.ulaval.ca)","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10799506","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":"Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with K_ATP channel gain-of-function.","authors":"Michael J Davis,&nbsp;Jorge A Castorena-Gonzalez,&nbsp;Hae Jin Kim,&nbsp;Min Li,&nbsp;Maria Remedi,&nbsp;Colin G Nichols","doi":"10.1093/function/zqad017","DOIUrl":"https://doi.org/10.1093/function/zqad017","url":null,"abstract":"<p><p>Cantú Syndrome (CS) is an autosomal dominant disorder caused by gain-of-function (GoF) mutations in the Kir6.1 and SUR2 subunits of K_ATP channels. K_ATP overactivity results in a chronic reduction in arterial tone and hypotension, leading to other systemic cardiovascular complications. However, the underlying mechanism of lymphedema, developed by >50% of CS patients, is unknown. We investigated whether lymphatic contractile dysfunction occurs in mice expressing CS mutations in Kir6.1 (Kir6.1[V65M]) or SUR2 (SUR2[A478V], SUR2[R1154Q]). Pressure myograph tests of contractile function of popliteal lymphatic vessels over the physiological pressure range revealed significantly impaired contractile strength and reduced frequency of spontaneous contractions at all pressures in heterozygous Kir6.1[V65M] vessels, compared to control littermates. Contractile dysfunction of intact popliteal lymphatics in vivo was confirmed using near-infrared fluorescence microscopy. Homozygous SUR2[A478V] vessels exhibited profound contractile dysfunction ex vivo, but heterozygous SUR2[A478V] vessels showed essentially normal contractile function. However, further investigation of vessels from all three GoF mouse strains revealed significant disruption in contraction wave entrainment, decreased conduction speed and distance, multiple pacemaker sites, and reversing wave direction. Tests of 2-valve lymphatic vessels forced to pump against an adverse pressure gradient revealed that all CS-associated genotypes were essentially incapable of pumping under an imposed outflow load. Our results show that varying degrees of lymphatic contractile dysfunction occur in proportion to the degree of molecular GoF in Kir6.1 or SUR2. This is the first example of lymphatic contractile dysfunction caused by a smooth muscle ion channel mutation and potentially explains the susceptibility of CS patients to lymphedema.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10194823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10057746","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}