Publications by authors named "Boxing Li"

21 Publications

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Intracellular recording of cardiomyocyte action potentials by nanobranched microelectrode array.

Biosens Bioelectron 2020 Dec 12;169:112588. Epub 2020 Sep 12.

State Key Laboratory of Optoelectronic Materials and Technologies, Guangdong Province Key Laboratory of Display Material and Technology, School of Electronics and Information Technology, Sun Yat-sen University, Guangzhou 510006, China; The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China. Electronic address:

Electrophysiological study that records the action potential of cardiomyocyte served as excellent tool to explore cardiology and neuroscience, disease investigation and pharmacological screening. Advances of micro/nanotechnologies promote the development of three-dimensional (3D) nanodevices to record high-quality intracellular recordings by various perforation approaches of cells, however, the complicated fabrication processes limited their large-scale manufacture. In this work, a unique nanobranched microelectrode array (NBMEA) platform is developed to achieve high-quality intracellular recording of cultured cardiomyocytes in a minimally invasive manner. The NBMEA is consisting of high aspect ratio conductive nanobranches fabricated on patterned microelectrodes combining hydrothermal growth and standard microfabrication. The 3D structure of nanobranches enables the electrode to form tight coupling with cardiomyocytes to achieve the low voltage cell electroporation and high-quality intracellular recording. The recorded intracellular action potentials of cardiomyocytes by NBMEA exhibited significant enhancement on amplitude (~5 mV), signal-to-noise ratio (SNR) (~67.47 dB), recording duration (up to 105 min), and recording yield (69.5 ± 17.8%). This NBMEA platform is a promising and powerful tool for electrophysiology that opens up new opportunities for high-quality and stable intracellular recording of cardiomyocytes.
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http://dx.doi.org/10.1016/j.bios.2020.112588DOI Listing
December 2020

Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.

Cell 2020 06 2;181(7):1547-1565.e15. Epub 2020 Jun 2.

Department of Neuroscience and Physiology, Neuroscience Institute, NYU Grossman Medical Center, New York, NY 10016, USA; Center for Neural Science, New York University, New York, NY 10003, USA. Electronic address:

Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca-permeable AMPA receptor upregulation, L-type Ca channel activation, enhanced spine Ca transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed ∼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.
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http://dx.doi.org/10.1016/j.cell.2020.05.013DOI Listing
June 2020

Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella pneumoniae.

Cell Metab 2019 10 19;30(4):675-688.e7. Epub 2019 Sep 19.

Computational Virology Group, Center for Bacteria and Virus Resources and Application, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 101408, China. Electronic address:

The underlying etiology of nonalcoholic fatty liver disease (NAFLD) is believed to be quite varied. Changes in the gut microbiota have been investigated and are believed to contribute to at least some cases of the disease, though a causal relationship remains unclear. Here, we show that high-alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) is associated with up to 60% of individuals with NAFLD in a Chinese cohort. Transfer of clinical isolates of HiAlc Kpn by oral gavage into mice induced NAFLD. Likewise, fecal microbiota transplant (FMT) into mice using a HiAlc-Kpn-strain-containing microbiota isolated from an individual with NASH induced NAFLD. However, selective elimination of the HiAlc Kpn strain before FMT prevented NAFLD in the recipient mice. These results suggest that at least in some cases of NAFLD an alteration in the gut microbiome drives the condition due to excess endogenous alcohol production.
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http://dx.doi.org/10.1016/j.cmet.2019.08.018DOI Listing
October 2019

Inulin Can Alleviate Metabolism Disorders in ob/ob Mice by Partially Restoring Leptin-related Pathways Mediated by Gut Microbiota.

Genomics Proteomics Bioinformatics 2019 02 23;17(1):64-75. Epub 2019 Apr 23.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Key Laboratory of Microbial Drug Resistance and Resistome, Beijing 100101, China; Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China. Electronic address:

Inulin has been used as a prebiotic to alleviate glucose and lipid metabolism disorders in mice and humans by modulating the gut microbiota. However, the mechanism underlying the alleviation of metabolic disorders by inulin through interactions between the gut microbiota and host cells is unclear. We use ob/ob mice as a model to study the effect of inulin on the cecal microbiota by 16S rRNA gene amplicon sequencing and its interaction with host cells by transcriptomics. The inulin-supplemented diet improved glucose and lipid metabolism disorder parameters in ob/ob mice, alleviating fat accumulation and glucose intolerance. The α diversity of gut microbial community of ob/ob mice was reduced after inulin treatment, while the β diversity tended to return to the level of wild type mice. Interestingly, Prevotellaceae UCG 001 (family Prevotellaceae) was obviously enriched after inulin treatment. A comparative analysis of the gene expression profile showed that the cecal transcriptome was changed in leptin gene deficiency mice, whereas the inulin-supplemented diet partially reversed the changes in leptin gene-related signaling pathways, especially AMPK signaling pathway, where the levels of gene expression became comparable to those in wild type mice. Further analysis indicated that Prevotellaceae UCG 001 was positively correlated with the AMPK signaling pathway, which was negatively correlated with markers of glycolipid metabolism disorders. Our results suggest that the inulin-supplemented diet alleviates glucose and lipid metabolism disorders by partially restoring leptin related pathways mediated by gut microbiota.
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http://dx.doi.org/10.1016/j.gpb.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520907PMC
February 2019

The Gut Microbiome Signatures Discriminate Healthy From Pulmonary Tuberculosis Patients.

Front Cell Infect Microbiol 2019 3;9:90. Epub 2019 Apr 3.

Translational Medicine Research Center, Beijing Chest Hospital, Capital Medical University, Beijing, China.

Cross talk occurs between the human gut and the lung through a gut-lung axis involving the gut microbiota. However, the signatures of the human gut microbiota after active infection have not been fully understood. Here, we investigated changes in the gut microbiota in tuberculosis (TB) patients by shotgun sequencing the gut microbiomes of 31 healthy controls and 46 patients. We observed a dramatic changes in gut microbiota in tuberculosis patients as reflected by significant decreases in species number and microbial diversity. The gut microbiota of TB patients were mostly featured by the striking decrease of short-chain fatty acids (SCFAs)-producingbacteria as well as associated metabolic pathways. A classification model based on the abundance of three species, , and , performed well for discriminating between healthy and diseased patients. Additionally, the healthy and diseased states can be distinguished by SNPs in the species of . We present a comprehensive profile of changes in the microbiota in clinical TB patients. Our findings will shed light on the design of future diagnoses and treatments for infections.
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http://dx.doi.org/10.3389/fcimb.2019.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456665PMC
December 2019

Effect of Functional Oligosaccharides and Ordinary Dietary Fiber on Intestinal Microbiota Diversity.

Front Microbiol 2017 20;8:1750. Epub 2017 Sep 20.

Institute of Disease Control and Prevention, Academy of Military Medical SciencesBeijing, China.

Functional oligosaccharides, known as prebiotics, and ordinary dietary fiber have important roles in modulating the structure of intestinal microbiota. To investigate their effects on the intestinal microecosystem, three kinds of diets containing different prebiotics were used to feed mice for 3 weeks, as follows: GI (galacto-oligosaccharides and inulin), PF (polydextrose and insoluble dietary fiber from bran), and a GI/PF mixture (GI and PF, 1:1), 16S rRNA gene sequencing and metabolic analysis of mice feces were then conducted. Compared to the control group, the different prebiotics diets had varying effects on the structure and diversity of intestinal microbiota. GI and PF supplementation led to significant changes in intestinal microbiota, including an increase of and a decrease of in the GI-fed, but those changes were opposite in PF fed group. Intriguing, in the GI/PF mixture-fed group, intestinal microbiota had the similar structure as the control groups, and flora diversity was upregulated. Fecal metabolic profiling showed that the diversity of intestinal microbiota was helpful in maintaining the stability of fecal metabolites. Our results showed that a single type of oligosaccharides or dietary fiber caused the reduction of bacteria species, and selectively promoted the growth of or bacteria, resulting in an increase in diamine oxidase (DAO) and/or trimethylamine N-oxide (TMAO) values which was detrimental to health. However, the flora diversity was improved and the DAO values was significantly decreased when the addition of nutritionally balanced GI/PF mixture. Thus, we suggested that maintaining microbiota diversity and the abundance of dominant bacteria in the intestine is extremely important for the health, and that the addition of a combination of oligosaccharides and dietary fiber helps maintain the health of the intestinal microecosystem.
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http://dx.doi.org/10.3389/fmicb.2017.01750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611707PMC
September 2017

Community-Metabolome Correlations of Gut Microbiota from Child-Turcotte-Pugh of A and B Patients.

Front Microbiol 2016 16;7:1856. Epub 2016 Nov 16.

Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Fengtai District Beijing, China.

The gut flora are widely involved in the cometabolism with the host and have evident effects on the metabolic phenotype of host. This study performed a metabolome analysis of the intestinal microbiota specific for liver cirrhosis. The study population included patients with Child-Turcotte-Pugh score of A (AP, = 5) and B (BP, = 5), and control subjects (NM, = 3). Metagenomic DNA from fecal microbiota was extracted followed by metagenomic sequencing through Illumina MiSeq high throughput sequencing of 16S rRNA regions. The detection of metabolites from fecal samples was performed using high-performance liquid phase chromatography and gas chromatography coupled with tandem mass spectrometry. Intestinal microbiota community and metabolite analysis both showed separation of cirrhotic patients from control participants, moreover, the microbiota-metabolite correlations changed in cirrhotic patients. Fecal microbiota from cirrhotic patients, with the reduced diversity, contained a decreased abundance of Bacteroidetes and an increased abundance of Firmicutes and Proteobacteria compared with the normal samples. Analysis of metabolome revealed a remarkable change in the metabolic potential of the microbiota in cirrhotic patients, with specific higher concentrations of amine, unsaturated fatty acid, and short-chain fatty acids, and lower concentrations of sugar alcohol and amino acid, suggesting the initial equilibrium of gut microbiota community and co-metabolism with the host were perturbed by cirrhosis. Our study illustrated the relationship between fecal microbiota composition and metabolome in cirrhotic patients, which may improve the clinical prognosis of cirrhosis.
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http://dx.doi.org/10.3389/fmicb.2016.01856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110571PMC
November 2016

Cirrhosis related functionality characteristic of the fecal microbiota as revealed by a metaproteomic approach.

BMC Gastroenterol 2016 Oct 4;16(1):121. Epub 2016 Oct 4.

Institute of Disease Control and Prevention, Academy of Military Medical Sciences, No. 20 Dongda Street, Fengtai District, 100071, Beijing, China.

Background: Intestinal microbiota operated as a whole and was closely related with human health. Previous studies had suggested close relationship between liver cirrhosis (LC) and gut microbiota.

Methods: To determine the functional characteristic of the intestinal microbiota specific for liver cirrhosis, the fecal metaproteome of three LC patients with Child-Turcotte-Pugh (CTP) score of A, B, and C, and their spouse were first compared using high-throughput approach based on denaturing polyacrylamide gel electrophoresis and liquid chromatography-tandem mass spectrometry in our study.

Results: A total of 5,020 proteins (88 % from bacteria, 12 % form human) were identified and annotated based on the GO and KEGG classification. Our results indicated that the LC patients possessed a core metaproteome including 119 proteins, among which 14 proteins were enhanced expressed and 7 proteins were unique for LC patients compared with the normal, which were dominant at the function of carbohydrate metabolism. In addition, LC patients have unique biosynthesis of branched chain amino acid (BCAA), pantothenate, and CoA, enhanced as CTP scores increased. Those three substances were all important in a wide array of key and essential biological roles of life.

Conclusions: We observed a highly comparable cirrhosis-specific metaproteome clustering of fecal microbiota and provided the first supportive evidence for the presence of a LC-related substantial functional core mainly involved in carbohydrate, BCAA, pantothenate, and CoA metabolism, suggesting the compensation of intestinal microbiota for the fragile and innutritious body of cirrhotic patients.
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http://dx.doi.org/10.1186/s12876-016-0534-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5051048PMC
October 2016

Corrigendum: Survey and Visual Detection of Zaire Ebolavirus in Clinical Samples Targeting the Nucleoprotein Gene in Sierra Leone.

Front Microbiol 2016 15;7:948. Epub 2016 Jun 15.

Institute of Disease Control and Prevention, Academy of Military Medical Sciences Beijing, China.

[This corrects the article on p. 1332 in vol. 6, PMID: 26648918.].
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http://dx.doi.org/10.3389/fmicb.2016.00948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908859PMC
July 2016

Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression.

Science 2016 Feb;351(6275):863-7

Department of Neuroscience and Physiology and New York University Neuroscience Institute, New York, NY 10016, USA. Department of Molecular and Cellular Physiology, Beckman Center, School of Medicine, Stanford University, Stanford, CA 94305, USA.

Voltage-gated CaV1.2 channels (L-type calcium channel α1C subunits) are critical mediators of transcription-dependent neural plasticity. Whether these channels signal via the influx of calcium ion (Ca(2+)), voltage-dependent conformational change (VΔC), or a combination of the two has thus far been equivocal. We fused CaV1.2 to a ligand-gated Ca(2+)-permeable channel, enabling independent control of localized Ca(2+) and VΔC signals. This revealed an unexpected dual requirement: Ca(2+) must first mobilize actin-bound Ca(2+)/calmodulin-dependent protein kinase II, freeing it for subsequent VΔC-mediated accumulation. Neither signal alone sufficed to activate transcription. Signal order was crucial: Efficiency peaked when Ca(2+) preceded VΔC by 10 to 20 seconds. CaV1.2 VΔC synergistically augmented signaling by N-methyl-d-aspartate receptors. Furthermore, VΔC mistuning correlated with autistic symptoms in Timothy syndrome. Thus, nonionic VΔC signaling is vital to the function of CaV1.2 in synaptic and neuropsychiatric processes.
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http://dx.doi.org/10.1126/science.aad3647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467645PMC
February 2016

Proteomic Profiling of Bifidobacterium bifidum S17 Cultivated Under In Vitro Conditions.

Front Microbiol 2016 12;7:97. Epub 2016 Feb 12.

Institute of Disease Control and Prevention, Academy of Military Medical Sciences Beijing, China.

Bifidobacteria are frequently used in probiotic food and dairy products. Bifidobacterium bifidum S17 is a promising probiotic candidate strain that displays strong adhesion to intestinal epithelial cells and elicits potent anti-inflammatory capacity both in vitro and in murine models of colitis. The recently sequenced genome of B. bifidum S17 has a size of about 2.2 Mb and encodes 1,782 predicted protein-coding genes. In the present study, a comprehensive proteomic profiling was carried out to identify and characterize proteins expressed by B. bifidum S17. A total of 1148 proteins entries were identified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), representing 64.4% of the predicted proteome. 719 proteins could be assigned to functional categories according to cluster of orthologous groups of proteins (COGs). The COG distribution of the detected proteins highly correlates with that of the complete predicted proteome suggesting a good coverage and representation of the genomic content of B. bifidum S17 by the proteome. COGs that were highly present in the proteome of B. bifidum S17 were Translation, Amino Acid Transport and Metabolism, and Carbohydrate Transport and Metabolism. Complete sets of enzymes for both the bifidus shunt and the Embden-Meyerh of pathway were identified. Further bioinformatic analysis yielded 28 proteins with a predicted extracellular localization including 14 proteins with an LPxTG-motif for cell wall anchoring and two proteins (elongation factor Tu and enolase) with a potential moonlighting function in adhesion. Amongst the predicted extracellular proteins were five of six pilin proteins encoded in the B. bifidum S17 genome as well as several other proteins with a potential role in interaction with host structures. The presented results are the first compilation of a proteomic reference profile for a B. bifidum strain and will facilitate analysis of the molecular mechanisms of physiology, host-interactions and beneficial effects of a potential probiotic strain.
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http://dx.doi.org/10.3389/fmicb.2016.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751264PMC
February 2016

Survey and Visual Detection of Zaire ebolavirus in Clinical Samples Targeting the Nucleoprotein Gene in Sierra Leone.

Front Microbiol 2015 1;6:1332. Epub 2015 Dec 1.

Institute of Disease Control and Prevention, Academy of Military Medical Sciences Beijing, China.

Ebola virus (EBOV) can lead to severe hemorrhagic fever with a high risk of death in humans and other primates. To guide treatment and prevent spread of the viral infection, a rapid and sensitive detection method is required for clinical samples. Here, we described and evaluated a reverse transcription loop-mediated isothermal amplification (RT-LAMP) method to detect Zaire ebolavirus using the nucleoprotein gene (NP) as a target sequence. Two different techniques were used, a calcein/Mn(2+) complex chromogenic method and real-time turbidity monitoring. The RT-LAMP assay detected the NP target sequence with a limit of 4.56 copies/μL within 45 min under 61°C, a similar even or increase in sensitivity than that of real-time reverse transcription-polymerase chain reaction (RT-PCR). Additionally, all pseudoviral particles or non- Zaire EBOV genomes were negative for LAMP detection, indicating that the assay was highly specific for EBOV. To appraise the availability of the RT-LAMP method for use in clinical diagnosis of EBOV, of 417 blood or swab samples collected from patients with clinically suspected infections in Sierra Leone, 307 were identified for RT-LAMP-based surveillance of EBOV. Therefore, the highly specific and sensitive RT-LAMP method allows the rapid detection of EBOV, and is a suitable tool for clinical screening, diagnosis, and primary quarantine purposes.
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http://dx.doi.org/10.3389/fmicb.2015.01332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664619PMC
December 2015

Evolutionary and functional perspectives on signaling from neuronal surface to nucleus.

Biochem Biophys Res Commun 2015 Apr;460(1):88-99

NYU Neuroscience Institute and Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address:

Reliance on Ca(2+) signaling has been well-preserved through the course of evolution. While the complexity of Ca(2+) signaling pathways has increased, activation of transcription factors including CREB by Ca(2+)/CaM-dependent kinases (CaMKs) has remained critical for long-term plasticity. In C. elegans, the CaMK family is made up of only three members, and CREB phosphorylation is mediated by CMK-1, the homologue of CaMKI. CMK-1 nuclear translocation directly regulates adaptation of thermotaxis behavior in response to changes in the environment. In mammals, the CaMK family has been expanded from three to ten members, enabling specialization of individual elements of a signal transduction pathway and increased reliance on the CaMKII subfamily. This increased complexity enables private line communication between Ca(2+) sources at the cell surface and specific cellular targets. Using both new and previously published data, we review the mechanism of a γCaMKII-CaM nuclear translocation. This intricate pathway depends on a specific role for multiple Ca(2+)/CaM-dependent kinases and phosphatases: α/βCaMKII phosphorylates γCaMKII to trap CaM; CaN dephosphorylates γCaMKII to dispatch it to the nucleus; and PP2A induces CaM release from γCaMKII so that CaMKK and CaMKIV can trigger CREB phosphorylation. Thus, while certain basic elements have been conserved from C. elegans, evolutionary modifications offer opportunities for targeted communication, regulation of key nodes and checkpoints, and greater specificity and flexibility in signaling.
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http://dx.doi.org/10.1016/j.bbrc.2015.02.146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701207PMC
April 2015

Distinct roles of multiple isoforms of CaMKII in signaling to the nucleus.

Biochim Biophys Acta 2015 Sep 17;1853(9):1953-7. Epub 2015 Feb 17.

NYU Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address:

Long-lasting synaptic changes following information acquisition are critical steps for memory. In this process, long-term potentiation (LTP) is widely considered as one of the major cellular mechanisms modifying synaptic strength. It can be classified into early phase LTP (E-LTP) and late phase LTP (L-LTP) based on its duration. Using genetically modified mice, investigators have recognized the critical role of CaMKII in E-LTP and memory. However, its function in L-LTP, which is strongly dependent on gene transcription and protein synthesis, is still unclear. In this review, we discuss how different isoforms of CaMKII are coordinated to regulate gene expression in an activity-dependent manner, and thus contribute to L-LTP and memory. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.
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http://dx.doi.org/10.1016/j.bbamcr.2015.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522395PMC
September 2015

γCaMKII shuttles Ca²⁺/CaM to the nucleus to trigger CREB phosphorylation and gene expression.

Cell 2014 Oct;159(2):281-94

Department of Neuroscience and Physiology, Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address:

Activity-dependent CREB phosphorylation and gene expression are critical for long-term neuronal plasticity. Local signaling at CaV1 channels triggers these events, but how information is relayed onward to the nucleus remains unclear. Here, we report a mechanism that mediates long-distance communication within cells: a shuttle that transports Ca(2+)/calmodulin from the surface membrane to the nucleus. We show that the shuttle protein is γCaMKII, its phosphorylation at Thr287 by βCaMKII protects the Ca(2+)/CaM signal, and CaN triggers its nuclear translocation. Both βCaMKII and CaN act in close proximity to CaV1 channels, supporting their dominance, whereas γCaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca(2+)/CaM activates CaMKK and its substrate CaMKIV, the CREB kinase. This mechanism resolves long-standing puzzles about CaM/CaMK-dependent signaling to the nucleus. The significance of the mechanism is emphasized by dysregulation of CaV1, γCaMKII, βCaMKII, and CaN in multiple neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.cell.2014.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201038PMC
October 2014

Mitochondrial KATP Channels Control Glioma Radioresistance by Regulating ROS-Induced ERK Activation.

Mol Neurobiol 2015 Aug 24;52(1):626-37. Epub 2014 Sep 24.

Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, China.

Malignant glioma is the most prevalent form of malignant brain tumor. Although radiotherapy is widely used in glioma treatment, the radioresistance of glioma cells limits the success of the glioma treatment. The lack of effective targets and signaling pathways to reverse glioma radioresistance is the critical obstacle in successful treatment. In this study, we demonstrate that mitochondrial ATP-sensitive potassium channels (mtK(ATP) channels) are overexpressed in glioma cells and are closely related to the malignancy grade and the overall survival of the patients. Importantly, we showed that mtK(ATP) channels could control glioma radioresistance by regulating reactive oxygen species (ROS)-induced ERK activation. The inhibition of mtK(ATP) channels suppresses glioma radioresistance by inhibiting ERK activation both in vitro and in vivo. These findings reveal the important roles of the mitochondria and mtK(ATP) channels as key regulators in the radioresistance of glioma cells, and suggest that mtK(ATP) channel blockers and MAPK/ERK kinase (MEK) inhibitors are potential targets for drug development of glioma treatments.
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http://dx.doi.org/10.1007/s12035-014-8888-1DOI Listing
August 2015

Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling.

Nat Neurosci 2014 Aug 22;17(8):1055-63. Epub 2014 Jun 22.

1] State Key Laboratory of Organ Failure Research, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. [2] Key Laboratory of Neuroplasticity of Guangdong Higher Education Institutes, Southern Medical University, Guangzhou, China.

Ion channels are essential for the regulation of neuronal functions. The significance of plasma membrane, mitochondrial, endoplasmic reticulum and lysosomal ion channels in the regulation of Ca(2+) is well established. In contrast, surprisingly little is known about the function of ion channels on the nuclear envelope (NE). Here we demonstrate the presence of functional large-conductance, calcium-activated potassium channels (BK channels) on the NE of rodent hippocampal neurons. Functionally, blockade of nuclear BK channels (nBK channels) induces NE-derived Ca(2+) release, nucleoplasmic Ca(2+) elevation and cyclic AMP response element binding protein (CREB)-dependent transcription. More importantly, blockade of nBK channels regulates nuclear Ca(2+)-sensitive gene expression and promotes dendritic arborization in a nuclear Ca(2+)-dependent manner. These results suggest that the nBK channel functions as a molecular link between neuronal activity and nuclear Ca(2+) to convey signals from synapse to nucleus and is a new modulator, operating at the NE, of synaptic activity-dependent neuronal functions.
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http://dx.doi.org/10.1038/nn.3744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115017PMC
August 2014

Exploring the dominant role of Cav1 channels in signalling to the nucleus.

Biosci Rep 2012 Dec 20;33(1):97-101. Epub 2012 Dec 20.

NYU Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA.

Calcium is important in controlling nuclear gene expression through the activation of multiple signal-transduction pathways in neurons. Compared with other voltage-gated calcium channels, Ca(V)1 channels demonstrate a considerable advantage in signalling to the nucleus. In this review, we summarize the recent progress in elucidating the mechanisms involved. Ca(V)1 channels, already advantaged in their responsiveness to depolarization, trigger communication with the nucleus by attracting colocalized clusters of activated CaMKII (Ca(2+)/calmodulin-dependent protein kinase II). Ca(V)2 channels lack this ability, but must work at a distance of >1 μm from the Ca(V)1-CaMKII co-clusters, which hampers their relative efficiency for a given rise in bulk [Ca(2+)](i) (intracellular [Ca(2+)]). Moreover, Ca(2+) influx from Ca(V)2 channels is preferentially buffered by the ER (endoplasmic reticulum) and mitochondria, further attenuating their effectiveness in signalling to the nucleus.
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http://dx.doi.org/10.1042/BSR20120099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546354PMC
December 2012

ATP-sensitive potassium channels control glioma cells proliferation by regulating ERK activity.

Carcinogenesis 2009 May 28;30(5):737-44. Epub 2009 Jan 28.

Department of Occupational Health and Occupational medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.

Ion channels are found in a variety of cancer cells and necessary for cell cycle and cell proliferation. The roles of K(+) channels in the process are, however, poorly understood. In the present study, we report that adenosine triphosphate (ATP)-sensitive potassium channel activity plays a critical role in the proliferation of glioma cells. The expression of K(ATP) channels in glioma tissues was greatly increased than that in normal tissues. Treatment of glioma cells with tolbutamide, K(ATP) channels inhibitor, suppressed the proliferation of glioma cells and blocked glioma cell cycle in G(0)/G(1) phase. Similarly, downregulation of K(ATP) channels by small interfering RNA (siRNA) inhibited glioma cell proliferation. On the other hand, K(ATP) channels agonist diazoxide and overexpression of K(ATP) channels promoted the proliferation of glioma cells. Moreover, inhibiting K(ATP) channels slowed the formation of tumor in nude mice generated by injection of glioma cells. Whereas activating K(ATP) channels promoted development of tumor in vivo. The effect of K(ATP) channels activity on glioma cells proliferation is mediated by extracellular signal-regulated kinase (ERK) activation. We found that activating K(ATP) channel triggered ERK activation and inhibiting K(ATP) channel depressed ERK activation. U-0126, the mitogen-activated protein kinase kinase (MAPK kinase) inhibitors blocked ERK activation and cell proliferation induced by diazoxide. Furthermore, constitutively activated MEK plasmids transfection reversed the inhibitory effects of tolbutamide on glioma proliferation, lending further support for a role of ERK in mediating this process. Our results suggest that K(ATP) channels control glioma cell proliferation via regulating ERK pathway. We concluded that K(ATP) channels are important in pathological cell proliferation and open a promising pathway for novel targeted therapies.
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http://dx.doi.org/10.1093/carcin/bgp034DOI Listing
May 2009

Activation of ATP-sensitive K channels protects hippocampal CA1 neurons from hypoxia by suppressing p53 expression.

Neurosci Lett 2006 May 19;398(1-2):34-8. Epub 2006 Jan 19.

School of Public Health and Tropical Medicine, Guangzhou, Guangdong 510515, China.

Oxygen-sensing and responses to changes in oxygen concentration is a fundamental property of cellular physiology. In the central nervous system (CNS), hippocampal CA1 neurons are known to be extremely vulnerable to low oxygen concentrations or anoxia. Understanding the mechanisms governing tolerance to oxygen depletion is vital for developing strategies to protect the brain from hypoxic-ischemic insult. Our current study demonstrates the protective mechanism of KATP channels on hippocampal CA1 neurons subjected to hypoxic or anoxic conditions. Specifically, we show that CA1 neurons undergo apoptosis when depleted of oxygen for 12 or 24 h. A KATP channels agonist diazoxide inhibits the observed apoptosis. The inhibition of apoptosis is mediated through diazoxide's ability to reduce p53 expression. On the other hand, tolbutamide, a KATP channels antagonist which blocks the cellular sulphonylureas receptor, significantly increases p53 expression and apoptosis under hypoxic/anoxic conditions. Trichostatin (TSA), a p53 inhibitor, can block the effects of tolbutamide, lending further support for a role of p53 in mediating this process. These studies demonstrate that KATP channels act as an upstream antagonist of p53 in hippocampal CA1 neurons, and suggests their protective role in cerebral hypoxia.
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http://dx.doi.org/10.1016/j.neulet.2005.12.075DOI Listing
May 2006