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Evolutionary trajectory of TRPM2 channel activation by adenosine diphosphate ribose and calcium

Science Bulletin 2024年第18期69卷 2892-2905页

作者： Cheng Ma Yanping Luo Congyi Zhang Cheng Cheng Ning Hua Xiaocao Liu Jianan Wu Luying Qin Peilin Yu Jianhong Luo Fan Yang Lin-Hua Jiang Guojie Zhang Wei Yang Department of biophysics and Department of Neurosurgery The Fourth Affiliated HospitalZhejiang University School of MedicineHangzhou 310058China Protein Facility Core FacilitiesZhejiang University School of MedicineZhejiang UniversityHangzhou 310058China Department of Toxicology and Department of Medical Oncology of The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310058China Department of Neurobiology Affiliated Mental Health CenterCollege of Brain Science and Brain MedicineZhejiang University School of MedicineHangzhou 310058China Department of biophysics and Kidney Disease Center of The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310058China Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province and Department of Physiology and PathophysiologyXinxiang Medical UniversityXinxiang 453004China Henan Collaborative Innovation Center of Prevention and Treatment of Mental Disorder The Second Affiliated Hospital of Xinxiang Medical UniversityXinxiang 453004China Evolutionary&Organismal Biology Research Center School of MedicineZhejiang UniversityHangzhou 310058China GuiZhou University Medical College Guiyang 550025China

Ion channel activation upon ligand gating triggers a myriad of biological events and,therefore,evolution of ligand gating mechanism is of fundamental ***2,a typical ancient ion channel,is activated by adenosine diphosphate ribose(ADPR)and calcium and its activation has evolved from a simple mode in invertebrates to a more complex one in vertebrates,but the evolutionary process is still *** evolutionary analysis of TRPM2s from more than 280 different animal species has revealed that,the C-terminal NUDT9-H domain has evolved from an enzyme to a ligand binding site for activation,while the N-terminal MHR domain maintains a conserved ligand binding *** gating pattern has also evolved,from one Ca^(2+)-binding site as in sea anemones to three sites as in ***,we identified a new group represented by olTRPM2,which has a novel gating mode and fills the missing link of the channel gating *** conclude that the TRPM2 ligand binding or activation mode evolved through at least three identifiable stages in the past billion years from simple to complicated and *** findings benefit the evolutionary investigations of other channels and proteins.

关键词： TRPM2 channel Activation mode molecular evolution

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E224G Regulation of the PIP2-Induced Gating Kinetics of Kir2.1 Channels

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Chinese Physics Letters 2017年第1期34卷 86-89页

作者：任树喜李军委张素花 D.E.Logothetis 安海龙展永 Key Laboratory of molecular biophysics of Hebei Province Institute of BiophysicsSchool of SciencesHebei University of TechnologyTianjin 300401 Department of physiology and biophysics School of MedicineVirginia Commonwealth UniversityVirginiaUSA

As a member of the inwardly rectifying channel (Kir) family, Kir2.1 allows to influx the cell more easily than to efflux, a biophysical phenomenon named inward rectification. The function of Kir2.1 is to set the resting membrane potential and modulate membrane excitability. It has been reported that residue E224 plays a key role in regulating inward rectification. The mutant Kir2.1 (E224G) displays weaker inward rectification than the WT channel. Gating of Kir2.1 depends on the membrane lipid, PIP2, such that the channel gates are closed in the absence of PIP2. Here we perform electrophysiological and computational approaches, and demonstrate that E224 also plays an important role in the PIP2-dependent activation of Kir2.1 in addition to its influence on inward rectification. The E224G mutant takes 4.5 times longer to be activated by PIP2. To probe the mechanism by which E224G slows the channel opening kinetics, we perform targeted molecular dynamics simulations and find that the mutant weakens the interactions between CD-loop and C-linker (H221-R189) and the adjacent G-loops (R312-E303) which are thought to stabilize the open state of the channel in our previous work. These data provide new insights into the regulation of Kir2.1 channel activity and suggest that a common mechanism may be involved in the distinct biophysical processes, such as inward rectification and PIP2-induced gating.

关键词： WT PIP E224G Regulation of the PIP2-Induced Gating Kinetics of Kir2.1 Channels

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Genome and clonal hematopoiesis stability contrasts with immune,cfDNA,mitochondrial,and telomere length changes during short duration spaceflight

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Precision Clinical medicine 2024年第1期7卷 1-13页

作者： J.Sebastian Garcia-Medina Karolina Sienkiewicz S.Anand Narayanan Eliah G.Overbey Kirill Grigorev Krista A.Ryon Marissa Burke Jacqueline Proszynski Braden Tierney Caleb M.Schmidt Nuria Mencia-Trinchant Remi Klotz Veronica Ortiz Jonathan Foox Christopher Chin Deena Najjar Irina Matei Irenaeus Chan Carlos Cruchaga Ashley Kleinman JangKeun Kim Alexander Lucaci Conor Loy Omary Mzava Iwijn De Vlaminck Anvita Singaraju Lynn E.Taylor Julian C.Schmidt Michael A.Schmidt Kelly Blease Juan Moreno Andrew Boddicker Junhua Zhao Bryan Lajoie Andrew Altomare Semyon Kruglyak Shawn Levy Min Yu Duane C.Hassane Susan M.Bailey Kelly Bolton Jaime Mateus Christopher E.Mason Department of physiology and biophysics Weill Cornell MedicineCornell UniversityNew YorkNY 10021USA The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine Weill Cornell MedicineNew YorkNY 10021USA Department of Immunology Weill Cornell MedicineCornell UniversityNew YorkNY 10021USA Department of Stem Cell Biology and Regenerative medicine Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Space Exploration Technologies Corporation HawthomeCA 90250USA Sovaris Aerospace BoulderCO 80302USA Advanced Pattern Analysis&Human Performance Group BoulderCO 80302USA Children's Cancer and Blood Foundation Laboratories Departments of Pediatrics and Cell and Developmental BiologyDrukier Institute for Children's HealthMeyer Cancer CenterWeill Cornell MedicineNew YorkNY 10021USA Meyer Cancer Center Weill Cornell MedicineNew YorkNY 10065USA Department of Nutrition and Integrative physiology Florida State UniversityTallahasseeFL 32306USA Department of Systems Engineering Colorado State UniversityFort CollinsCO 80523USA Element Biosciences San DiegoCA 10055USA Department of Environmental and Radiological Health Sciences Colorado State UniversityFort CollinsCO 80523USA Cell and molecular Biology Program Colorado State UniversityFort CollinsCO 80523USA BioAstra Inc New YorkNYUSA Washington University St Louis Oncology Division St.LouisMO 63100USA Meinig School of Biomedical Engineering Cornell UniversityIthacaNY 14853USA The Feil Family Brain and Mind Research Institute Weill Cornell MedicineNY 10021USA WorldQuant Initiative for Quantitative Prediction Weill Cornell MedicineNew YorkNY 10021USA

Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic *** advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation *** To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA *** length was measured by quantitative PCR,while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations.A robust bioinformatic pipeline was used for data analysis,including variant calling to assess mutational *** Telomere elongation occurred during spaceflight and shortened after return to ***-free DNA analysis revealed increased immune cell signatures *** significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was *** long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months *** Our findings provide valuable insights into the physiological consequences of short-duration spaceflight,with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to *** sequencing data will serve as a reference point for studying the early development of CHIP in astronauts,an understudied phenomenon as previous studies have focused on career *** study will serve as a reference point for future commercial and non-commercial spaceflight,low Earth orbit(LEO)missions,and deep-space exploration.

关键词： genomes clonal hematopoiesis stability immune mitochondria ribosomes spaceflight

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Defects in the Ryanodine Receptor Channel Associated with Cardiac Arrhythmias

Defects in the Ryanodine Receptor Channel Associated with Ca...

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中国药理学会药学监护专业委员会第一届第三次学术大会

作者： Xander H.T.Wehrens dept.of molecular physiology and biophysics and medicine Baylor College of MedicineHoustonTX

Cardiac arrhythmia is an important cause of death in patients with heart failure (HF)and inherited arrhythmia syndromes,such as catecholaminergic polymorphic ventricular tachycardia(CPVT).Recent studies indicate that ...

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Fatty acid oxidation and autophagy promote endoxifen resistance and counter the effect of AKT inhibition in ER-positive breast cancer cells

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Journal of molecular Cell Biology 2021年第6期13卷 433-444页

作者： Lei Duan Sarah Calhoun Daeun Shim Ricardo E.Perez Lothar A.Blatter Carl G.Maki Department of Cell and molecular medicine Rush University Medical CenterChicagoIL 60612USA Department of molecular biophysics and physiology Rush University Medical CenterChicagoIL 60612USA

Tamoxifen(TAM)is the first-line endocrine therapy for estrogen receptor-positive(ER+)breast cancer(BC).However,acquired resistance occurs in∼50%***,although the PI3K/AKT/mTOR pathway is a viable target for treatment of endocrine therapy-refractory patients,complex signaling feedback loops exist,which can counter the effectiveness of inhibitors of this ***,we analyzed signaling pathways and metabolism in ER+MCF7 BC cell line and their TAM-resistant derivatives that are co-resistant to endoxifen using immunoblotting,quantitative polymerase chain reaction,and the Agilent Seahorse XF *** found that activation of AKT and the energy-sensing kinase AMPK was increased in TAM and endoxifen-resistant ***,ERRα/PGC-1βand their target genes MCAD and CPT-1 were increased and regulated by AMPK,which coincided with increased fatty acid oxidation(FAO)and autophagy in TAM-resistant *** of AKT feedback-activates AMPK and ERRα/PGC-1β-MCAD/CPT-1 with a consequent increase in FAO and autophagy that counters the therapeutic effect of endoxifen and AKT ***,our results indicate increased activation of AKT and AMPK with metabolic reprogramming and increased autophagy in TAM-resistant *** inhibition of AKT and FAO/autophagy is necessary to fully sensitize resistant cells to endoxifen.

关键词： endoxifen fatty acid oxidation autophagy AMPK AKT

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Ryanodine receptors as pharmacological targets for heart disease

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Acta Pharmacologica Sinica 2007年第7期28卷 937-944页

作者： Marco SANTONASTAS Xander H T WEHRENS Departments of molecular physiology and biophysics Departments of molecular physiology and biophysics and Medieine(Cardiology) Baylor College of MedicineHoustonTexas 77030USA

Calcium release from intracellular stores plays an important role in the regulationof muscle contraction and electrical signals that determine the heart *** receptor （RyR） is the major calcium (Ca2+) release channel required forexcitation-contraction coupling in the *** studies have demonstratedthat RyR are macromolecular complexes comprising of 4 pore-forming channelsubunits,each of which is associated with regulatory *** andexperimental studies over the past 5 years have provided compelling evidencethat intracellular Ca2+release channels play a pivotal role in the development ofcardiac arrhythmias and heart *** in the channel regulation andsubunit composition are believed to cause diastolic calcium leakage from thesarcoplasmic reticulum,which could trigger arrhythmias and weaken ***,cardiac RyR have emerged as potential therapeutic tar-gets for the treatment of heart ***,there is a strong desire toidentify and/or develop novel pharmacological agents that may target these Ca2+signaling *** agents known to modulate RyR in the heart,and their potential application towards the treatment of heart disease are dis-cussed in this review.

关键词： arrhythmias calcium release channel heart failure pharmacology ryanodine receptor

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In vivo generation and regeneration ofβcells in zebrafish

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Cell Regeneration 2020年第1期9卷 92-101页

作者： Bingyuan Yang Brittney A.Covington Wenbiao Chen Department of molecular physiology&biophysics Vanderbilt University School of Medicine2215 Garland AvenueNashvilleTN 37232USA

The pathological feature of diabetes,hyperglycemia,is a result of an inadequate number and/or function of insulin producingβ*** functionalβcells is a strategy to cure the ***β-cell regeneration occurs in animal models under certain conditions,humanβcells are refractory to proliferation.A better understanding of both the positive and the negative regulatory mechanisms ofβ-cell regeneration in animal models is essential to develop novel strategies capable of inducing functionalβcells in *** are an attractive model system for studyingβ-cell regeneration due to the ease to which genetic and chemical-genetic approaches can be used as well as their high regenerative ***,we highlight the current state ofβ-cell regeneration studies in zebrafish with an emphasis on cell signaling mechanisms.

关键词： βcell attractive fish

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Reevaluation of the safety of induced pluripotent stem cells: a call from somatic mosaicism

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Protein & Cell 2013年第2期4卷 83-85页

作者： Wensu Liu Ming Li Jing Qu Fei Yi Guang-Hui Liu National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Department of molecular and Cellular physiology Stanford University School of MedicineStanfordCA 94305USA

Recent studies have been raising doubts on the safety of induced pluripotent stem cells(iPSCs)and proposing that the process of reprogramming brought about copy number variations(CNVs)in ***,a recent paper published in Nature provided evidence showing that most CNVs were pre-existed as somatic mosaicism but not resulted from the *** new finding would profoundly reshape some previous thoughts and endorse the confidence of iPSCs in both research and therapy.

关键词： doubt programming safety

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LIVE IMAGING OF EARLY DEVELOPMENTAL PROCESSES IN MAMMALIAN EMBRYOS WITH OPTICAL COHERENCE TOMOGRAPHY

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Journal of Innovative Optical Health Sciences 2009年第3期2卷 253-259页

作者： KIRILL V.LARIN IRINA V.LARINA MICHAEL LIEBLING MARY E.DICKINSON Department of Biomedical Engineering University of Houston HoustonTXUSA Department of molecular physiology and biophysics Baylor College of medicine HoustonTXUSA Department of Electrical and Computer Engineering University of California Santa BarbaraCAUSA

Early embryonic imaging of cardiovascular development in mammalian models requires a methodthat can penetrate through and distinguish the many tissue layers with high spatial and temporalresolution. In this paper we evaluate the capability of Optical Coherence Tomography (OCT)technique for structural 3D embryonic imaging in mouse embryos at different stages of thedevelopmental process ranging from 7.5 dpc up to 10.5 dpc. Obtained results suggest that thecollected data is suitable for quantitative and qualitative measurements to assess cardiovascularfunction in mouse models, which is likely to expand our knowledge of the complexity of theembryonic heart, and its development into an adult heart.

关键词： Optical Coherence Tomography non-invasive mouse embryos cardiovascular function.

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Lipolysis supports bone formation by providing osteoblasts with endogenous fatty acid substrates to maintain bioenergetic status

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Bone Research 2023年第4期11卷 876-894页

作者： Ananya Nandy Ron C.M.Helderman Santosh Thapa Shobana Jayapalan Alison Richards Nikita Narayani Michael P.Czech Clifford J.Rosen Elizabeth Rendina-Ruedy Department of medicine Division of Clinical PharmacologyVanderbilt University Medical CenterNashvilleTN 37232USA Program in molecular medicine University of Massachusetts Chan Medical SchoolWorcesterMA 01605USA Maine Medical Center Research Institute ScarboroughMEUSA molecular physiology and biophysics Vanderbilt UniversityNashvilleTN 37232USA

Bone formation is a highly energy-demanding process that can be impacted by metabolic *** has been considered the principal substrate for osteoblasts,although fatty acids are also important for osteoblast ***,we report that osteoblasts can derive energy from endogenous fatty acids stored in lipid droplets via lipolysis and that this process is critical for bone *** such,we demonstrate that osteoblasts accumulate lipid droplets that are highly dynamic and provide the molecular mechanism by which they serve as a fuel source for energy generation during osteoblast *** cytoplasmic lipolysis leads to both an increase in lipid droplet size in osteoblasts and an impairment in osteoblast *** fatty acids released by lipolysis from these lipid droplets become critical for cellular energy production as cellular energetics shifts towards oxidative phosphorylation during nutrient-depleted *** vivo,conditional deletion of the ATGL-encoding gene Pnpla2 in osteoblast progenitor cells reduces cortical and trabecular bone parameters and alters skeletal lipid ***,our data demonstrate that osteoblasts store fatty acids in the form of lipid droplets,which are released via lipolysis to support cellular bioenergetic status when nutrients are *** in this process result in impairment of bone formation,specifically reducing ATP production and overall osteoblast function.

关键词： endogenous maintain osteoblast

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