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Senior Investigator

Ling-Gang Wu, M.D., Ph.D.

Synaptic Transmission Section

Porter Neuroscience Research Center
Building 35 Room 2B-1012
35 Convent Drive MSC 3706
Bethesda MD 20892-3706
Office: (301) 451-3338
Lab: (301) 451-3338
Fax: (301) 480-1466

Dr. Wu received his M.D. in 1985 from Second Military Medical College, Shanghai, and his Ph.D. in neuroscience in 1994 from Baylor College of Medicine in Houston, where he worked with Peter Saggau studying how calcium channels control transmitter release. From 1994 to 1996, he was a postdoc in professor William Betz's lab at Univ. Colorado Medical School, where he studied how vesicle endocytosis is regulated. From 1996 to 1999, he was a postdoc in Bert Sakmann's lab at the Max Planck Institute in Heidelberg, Germany, where he studied release mechanisms and short-term synaptic plasticity. From 1999 to 2003 he was an assistant professor at Washington University in St. Louis. Dr. Wu joined NINDS as an investigator in 2003 and was promoted to senior investigator in 2007. His laboratory investigates the fundamental process of exocytosis and endocytosis, such as how the fusion pore opens, expands, constricts, or close, how membrane curvature is generated, how endocytosis is initiated and mediated, how synaptic transmission is controlled by different modes of exocytosis, endocytosis and by calcium channels at nerve terminals and neuroendocrine cells.

Exocytosis and endocytosis are two fundamental cellular processes in nearly all cells, including neurons. They underlie many important functions, such as intracellular trafficking, nutrient uptake, viral infection, hormone secretion, blood glucose regulation, and synaptic transmission that is essential for our brain functions. We aim at understanding vesicle exo- and endocytosis with respect to their dynamic structural changes, molecular mechanisms, and functions at the sub-vesicle resolution at millisecond time scale. We study the structural changes and molecular mechanisms that mediate fusion between two bilayer membranes, that open a fusion pore, that expand a fusion pore, that constrict a fusion or fission pore, that close a fusion or fission pore and that generate a membrane curvature. We study how these structural changes control release of vesicular contents and recycling of vesicles. We used a variety of advanced techniques, including confocal imaging, super-resolution STED imaging, super-resolution STORM imaging, molecular biological techniques, electron microscopy, and advanced electrophysiological techniques (e.g., whole-cell current and capacitance recordings, cell-attached single channel current and capacitance recordings). We used three preparations, the giant calyx of Held nerve terminal, the cultured hippocampal synapse and the neuroendocrine adrenal chromaffin cell.

The lab is constantly seeking highly talented and motivated postdoctoral candidates with experience in molecular biology (e.g., knockdown or knockout), cell biology (e.g., live-cell fluorescence imaging), electron microscopy, and/or electrophysiology. The lab is also seeking graduate students majored in Neurobiology, Cell Biology, Pharmacology, Genetics, and Biomedical Engineering, with an interest in exo- and endocytosis. Contact Dr. Wu for further information.

Figure 1. Real time observation of hemi-fusion and hemi-to-full fusion transition in live cells (Zhao et al, Nature 543, 548-552, 2016)

Figure 2. Real-time observation of rapid fusion pore opening and closure (Shin et al., Cell 173:934-945, 2018)

Staff Image
  • Giantivo Arpino, B.A.
    Graduate Student

  • Keith Chan, Ph.D.
    Postdoctoral Visiting Fellow

  • Yousseff Faragalla, B.S.

  • Claude Fu, Ph.D.
    Postdoctoral Visiting Fellow

  • Lihao Ge, Ph.D.
    Postdoctoral Fellow

  • Xiaoli Guo, Ph.D.
    Research Fellow

  • Chen Ji, Ph.D.
    Postdoctoral Visiting Fellow

  • Bo Shi, B.A.
    Graduate Student

  • Wonchul Shin, Ph.D.
    Research Scientist

  • Jaymie Turechek, B.S.
    Laboratory Technician

  • Lisi Wei, Ph.D.
    Postdoctoral Visiting Fellow

  • Xin-Sheng Wu, Ph.D.
    Research Scientist
    (301) 451-3345

  • 1) Shin W1, Ge L1, Arpino G1, Villarreal SA, Hamid E, Liu H, Zhao WD, Wen PJ, Chiang HC, Wu LG (2018)
  • Visualization of Membrane Pore in Live Cells Reveals a Dynamic-Pore Theory Governing Fusion and Endocytosis
  • Cell, 173, 934-945
  • 2) Wen PJ, Grenklo S, Arpino G, Tan X, Liao HS, Heureaux J, Peng SY, Chiang HC, Hamid E, Zhao WD, Shin W, Näreoja T, Evergren E, Jin Y, Karlsson R, Ebert SN, Jin A, Liu AP, Shupliakov O, Wu LG. (2016)
  • Actin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane
  • Nat Commun., 7, 12604
  • 3) Zhao WD, Hamid E, Shin W, Wen PJ, Krystofiak ES, Villarreal SA, Chiang HC, Kachar B, Wu LG. (2016)
  • Hemi-fused structure mediates and controls fusion and fission in live cells
  • Nature, 543, 548-552
  • 4) Xin-Sheng Wu, Sunghoon Lee, Jiansong Sheng, Zhen Zhang, Weidong Zhao, Dongsheng Wang, Yinghui Jin, Patrick Charnay, James M. Ervasti, and Ling-Gang Wu (2016)
  • Actin is crucial for all kinetically distinguishable forms of endocytosis at synapses
  • Neuron, 92, 1020-1035
  • 5) Wu LG,Hamid E,Shin W,Chiang HC (2014)
  • Exocytosis and endocytosis: modes, functions, and coupling mechanisms.
  • Annu. Rev. Physiol., 76, 301
  • 6) Chiang HC,Shin W,Zhao WD,Hamid E,Sheng J,Baydyuk M,Wen PJ,Jin A,Momboisse F,Wu LG (2014)
  • Post-fusion structural changes and their roles in exocytosis and endocytosis of dense-core vesicles.
  • Nat Commun, 5, 3356
  • 7) Sheng J, He L, Zheng H, Xue L, Luo F, Shin W, Sun T, Kuner T, Yue DT, Wu LG. (2012)
  • Calcium-channel number critically influences synaptic strength and plasticity at the active zone.
  • Nat Neurosci. , 15(7), 998-1006
  • 8) Wu XS, McNeil BD, Xu J, Fan J, Xue L, Melicoff E, Adachi R, Bai L, Wu LG (2009)
  • Ca(2+) and calmodulin initiate all forms of endocytosis during depolarization at a nerve terminal
  • Nat Neurosci., 12(8), 1003-10
  • 9) Paradiso K and Wu LG (2009)
  • Small voltage changes at nerve terminals travel up axons to affect action potential initiation
  • Nature Neuroscience, 12, 541 - 543
  • 10) He L, Xue L, Xu J, McNell B, Bai L, Melicoff E, Adachi R and Wu LG. (2009)
  • Compound vesicle fusion increases quantal size and potentiates synaptic transmission
  • Nature, 459, 93-98
  • 11) Xu J, McNeil B, Wu W, Nees D, Bai L, Wu LG. (2008)
  • GTP-independent rapid and slow endocytosis at a central synapse
  • Nat Neurosci., 11(1), 45-53
  • 12) He L, Wu XS, Mohan R, and Wu LG. (2006)
  • Two modes of fusion pore openings revealed by cell-attached recordings at a synapse
  • Nature, 444, 102-105
  • 13) Xu J and Wu LG (2005)
  • The decrease in the presynaptic calcium current is a major cause of short-term depression at a calyx-type synapse.
  • Neuron, 46, 633-645
  • 14) Sun JY, Wu XS, Wu LG (2002)
  • Single and multiple vesicle fusion induce different rates of endocytosis at a central synapse
  • Nature, 417, 555-559
  • 15) Sun JY Wu LG (2001)
  • Fast kinetics of exocytosis revealed by simultaneous measurements of presynaptic capacitance and postsynaptic currents at a central synapse.
  • Neuron , 30 , 171-82
  • 16) Wu LG Borst JG (1999)
  • The reduced release probability of releasable vesicles during recovery from short-term synaptic depression.
  • Neuron , 23 , 821-832
  • 17) Kay AR Alfonso A Alford S Cline HT Holgado AM Sakmann B Snitsarev VA Stricker TP Takahashi M Wu LG (1999)
  • Imaging synaptic activity in intact brain and slices with FM1-43 in C. elegans, lamprey, and rat.
  • Neuron , 24 , 809-17
  • 18) Wu LG, Betz WJ (1996)
  • Nerve activity but not intracellular calcium determines the time course of endocytosis at the frog neuromuscular junction
  • Neuron , 17, 769-779
  • 19) Wu LG, Saggau P (1994)
  • Adenosine inhibits evoked synaptic transmission primarily by reducing presynaptic calcium influx in area CA1 of hippocampus
  • Neuron , 12, 1139‑1148
  • 20) Wu XS, Elias S, Liu H, Heureaux J, Wen PJ, Liu AP, Kozlov MM, Wu LG (2017)
  • Membrane Tension Inhibits Rapid and Slow Endocytosis in Secretory Cells
  • Biophys J, 113, 2406-2414
  • 21) Villarreal S, Lee SH, Wu LG (2017)
  • Measuring Synaptic Vesicle Endocytosis in Cultured Hippocampal Neurons
  • J Vis Exp, 127
  • 22) Xu J,Wu XS,Sheng J,Zhang Z,Yue HY,Sun L,Sgobio C,Lin X,Peng S,Jin Y,Gan L,Cai H,Wu LG (2016)
  • α-Synuclein Mutation Inhibits Endocytosis at Mammalian Central Nerve Terminals.
  • J. Neurosci., 36, 4408
  • 23) Baydyuk M,Xu J,Wu LG (2016)
  • The calyx of Held in the auditory system: Structure, function, and development.
  • Hear Res., 338, 22
  • 24) Peng S,Xu J,Pelkey KA,Chandra G,Zhang Z,Bagh MB,Yuan X,Wu LG,McBain CJ,Mukherjee AB (2016)
  • Suppression of agrin-22 production and synaptic dysfunction in Cln1 (-/-) mice.
  • Ann Clin Transl Neurol, 2, 1085
  • 25) Wu XS,Zhang Z,Zhao WD,Wang D,Luo F,Wu LG (2015)
  • Calcineurin is universally involved in vesicle endocytosis at neuronal and nonneuronal secretory cells.
  • Cell Rep, 7, 982
  • 26) Sun CK,Zhou D,Zhang Z,He L,Zhang F,Wang X,Yuan J,Chen Q,Wu LG,Yang Q (2015)
  • Senescence impairs direct conversion of human somatic cells to neurons.
  • Nat Commun, 5, 4112
  • 27) Savoia CP,Liu QH,Zheng YM,Yadav V,Zhang Z,Wu LG,Wang YX (2015)
  • Calcineurin upregulates local Ca(2+) signaling through ryanodine receptor-1 in airway smooth muscle cells.
  • Am. J. Physiol. Lung Cell Mol. Physiol., 307, L781
  • 28) Zhou D,Zhang Z,He LM,Du J,Zhang F,Sun CK,Zhou Y,Wang XW,Lin G,Song KM,Wu LG,Yang Q (2015)
  • Conversion of fibroblasts to neural cells by p53 depletion.
  • Cell Rep, 9, 2034
  • 29) Baydyuk M,Wu XS,He L,Wu LG (2015)
  • Brain-derived neurotrophic factor inhibits calcium channel activation, exocytosis, and endocytosis at a central nerve terminal.
  • J. Neurosci., 35, 4676
  • 30) Park S,Ahuja M,Kim MS,Brailoiu GC,Jha A,Zeng M,Baydyuk M,Wu LG,Wassif CA,Porter FD,Zerfas PM,Eckhaus MA,Brailoiu E,Shin DM,Muallem S (2015)
  • Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV.
  • EMBO Rep., 17, 266
  • 31) Cai Z,Jitkaew S,Zhao J,Chiang HC,Choksi S,Liu J,Ward Y,Wu LG,Liu ZG (2014)
  • Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis.
  • Nat. Cell Biol., 16, 55
  • 32) Xiong W,Chen SR,He L,Cheng K,Zhao YL,Chen H,Li DP,Homanics GE,Peever J,Rice KC,Wu LG,Pan HL,Zhang L (2014)
  • Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease.
  • Nat. Neurosci., 17, 232
  • 33) Wu XS,Wu LG (2014)
  • The yin and yang of calcium effects on synaptic vesicle endocytosis.
  • J. Neurosci., 34, 2652
  • 34) Xue L,Zhang Z,McNeil BD,Luo F,Wu XS,Sheng J,Shin W,Wu LG (2013)
  • Voltage-dependent calcium channels at the plasma membrane, but not vesicular channels, couple exocytosis to endocytosis.
  • Cell Rep, 1, 632
  • 35) Xu J,Luo F,Zhang Z,Xue L,Wu XS,Chiang HC,Shin W,Wu LG (2013)
  • SNARE proteins synaptobrevin, SNAP-25, and syntaxin are involved in rapid and slow endocytosis at synapses.
  • Cell Rep, 3, 1414
  • 36) Xue L,Sheng J,Wu XS,Wu W,Luo F,Shin W,Chiang HC,Wu LG (2013)
  • Most vesicles in a central nerve terminal participate in recycling.
  • J. Neurosci., 33, 8820
  • 37) Zhang Z,Wang D,Sun T,Xu J,Chiang HC,Shin W,Wu LG (2013)
  • The SNARE proteins SNAP25 and synaptobrevin are involved in endocytosis at hippocampal synapses.
  • J. Neurosci., 33, 9169
  • 38) Lin X,Parisiadou L,Sgobio C,Liu G,Yu J,Sun L,Shim H,Gu XL,Luo J,Long CX,Ding J,Mateo Y,Sullivan PH,Wu LG,Goldstein DS,Lovinger D,Cai H (2012)
  • Conditional expression of Parkinson's disease-related mutant α-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1.
  • J. Neurosci., 32, 9284
  • 39) Xue L, Zhang Z, McNell B, Luo FJ, Wu XS, Sheng J, Shin W, Wu LG (2012)
  • Voltage-Dependent Calcium Channels at the Plasma Membrane, but Not Vesicular Channels, Couple Exocytosis to Endocytosis
  • Cell reports, 1(6), 632¨C638
  • 40) Xue L, McNeil BD, Wu XS, Luo F, He L, Wu LG. (2012)
  • A membrane pool retrieved via endocytosis overshoot at nerve terminals: a study of its retrieval mechanism and role.
  • J Neurosci., 32(10), 3398-404
  • 41) Xue L, Wu LG. (2010)
  • Post-tetanic potentiation is caused by two signalling mechanisms affecting quantal size and quantal content.
  • Journal of Physiology, 588(Pt 24):, 4987-94.
  • 42) Yim YI, Sun T, Wu LG, Raimondi A, De Camilli P, Eisenberg E, Greene LE. (2010)
  • Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice.
  • Proc Natl Acad Sci., 107(9):, 4412-7.
  • 43) Sun T, Wu XS, Xu J, McNeil BD, Pang ZP, Yang W, Bai L, Qadri S, Molkentin JD, Yue DT, Wu LG. (2010)
  • The role of calcium/calmodulin-activated calcineurin in rapid and slow endocytosis at central synapses.
  • Journal of Neuroscience., 30(35):, 11838-47
  • 44) Wu XS, Wu LG. (2009)
  • Rapid endocytosis does not recycle vesicles within the readily releasable pool.
  • J Neurosci. , 29(35), 11038-42
  • 45) McNeil BD, Wu LG (2009)
  • Location Matters: Synaptotagmin Helps Place Vesicles Near Calcium Channels
  • Neuron, 63(4), 419-421
  • 46) Wu XS, Xue L, Mohan R, Paradiso K, Gillis KD, Wu LG. (2007)
  • The origin of quantal size variation: vesicular glutamate concentration plays a significant role.
  • J Neurosci., 27(11), 3046-56
  • 47) He L, Wu LG. (2007)
  • The debate on the kiss-and-run fusion at synapses.
  • Trends in Neuroscience, 30(9), 447-55
  • 48) Wu W, Wu LG. (2007)
  • Rapid bulk endocytosis and its kinetics of fission pore closure at a central synapse.
  • Proc Natl Acad Sci U S A., 104(24), 10234-9
  • 49) Xu J, He L, Wu LG. (2007)
  • Role of Ca(2+) channels in short-term synaptic plasticity.
  • Curr Opin Neurobiol. , 17(3), 352-9
  • 50) Wu LG, Ryan TA, Lagnado L. (2007)
  • Modes of vesicle retrieval at ribbon synapses, calyx-type synapses, and small central synapses
  • J Neurosci. , 27(44), 11793-802
  • 51) Purow BW, Haque RM, Noel MW, Qin S, Burdick MJ, Jeongwu L, Dragan M, Tilak S, Pastorino S, Mikolaenko I, Eberhart CG, Fine HA (2005)
  • Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation
  • Cancer Research
  • 52) Wu W, Xu J, Wu XS, Wu LG. (2005)
  • acceleration of endocytosis at a ceActivity-dependent ntral synapse.
  • J Neurosci. , 25, 11676-11683
  • 53) Sun JY, Wu XS, Wu W, Jin SX, Dondzillo A, Wu LG (2004)
  • Capacitance measurements at the calyx of Held in the medial nucleus of the trapezoid body
  • J Neurosci Meth , 134, 121-131
  • 54) Wu LJ, Leenders AG, Cooperman S, Meyron-Holtz E, Smith S, Land W, Tsai RY, Berger UV, Sheng ZH, Rouault TA (2004)
  • Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier
  • Brain Res. , 1001, 108-17
  • 55) Steinbach JH, Wu LG (2004)
  • Synaptic transmission at the neuromuscular junction. in Anesthetic Pharmacology: Physiologic Principles and Clinical Practice
  • Evers AS and Maze M. Harcourt Health Sciences, 157-172
  • 56) Wu LG (2004)
  • Kinetic regulation of vesicle endocytosis at synapses
  • Trends Neurosci, 27, 548-554
  • 57) Wu XS, Evers AS, Crowder M, Wu LG (2004)
  • Isoflurane inhibits transmitter release and the presynaptic action potential
  • Anesthesiology, 100, 663-700
  • 58) Wu X, Wu LG (2001)
  • Activation of protein kinase C enhances the release probability of the release machinery downstream of the binding between Ca2+ and its sensor
  • J Neurosci, 21, 7928-7936
  • 59) Wu LG, Betz WJ (1999)
  • Spatial variability in release at the frog neuromuscular junction measured with FM1-43
  • Can J Physiol Pharmacol , 77, 672-678
  • 60) Wu LG, Westenbroek RE, Borst JGG, Catterall WA, Sakmann B (1999)
  • Calcium channel types with distinct presynaptic localization couple differentially to transmitter release in single calyx-type synapses
  • J Neurosci , 19, 726-736
  • 61) Wu LG, Betz WJ (1998)
  • Kinetics of synaptic depression and vesicle recycling after tetanic stimulation of frog motor nerve terminals
  • Biophys J, 74, 3003-3009
  • 62) Wu LG, Borst JGG, Sakmann B (1998)
  • R-type Ca2+ currents evoke transmitter release in a rat central synapse
  • Proc Natl Acad Sci USA , 95, 4720-4725
  • 63) Wu LG, Saggau P (1997)
  • Presynaptic inhibition of elicited neurotransmitter release.
  • Trends Neurosci , 20, 204-212
  • 64) Sinha SR, Wu LG, Saggau P (1997)
  • Presynaptic calcium dynamics and transmitter release evoked by single action potentials at mammalian central synapses
  • Biophys J , 72, 637-651
  • 65) Wu LG, Saggau P (1995)
  • GABAB receptor-mediated presynaptic inhibition in guinea pig hippocampus is caused by reduction of presynaptic Ca2+ influx
  • J Physiol (Lond), 485, 649-657
  • 66) Betz WJ, Wu LG (1995)
  • Kinetics of synaptic vesicle recycling
  • Curr Biol , 5, 1098-1101
  • 67) Wu LG, Saggau P (1995)
  • Block of multiple presynaptic calcium channel types by w‑conotoxin ‑MVIIC at hippocampal CA3 to CA1 synapses
  • J Neurophysiol , 73, 1965-1972
  • 68) Wu LG, Saggau P (1994)
  • Pharmacological identification of two types of presynaptic voltage‑ dependent calcium channels at CA3 to CA1 synapses of the hippocampus
  • J Neurosci , 14, 5613‑5622
  • 69) Wu LG, Saggau P (1994)
  • Presynaptic calcium is increased during normal synaptic transmission and paired‑pulse facilitation, but not in long‑term potentiation in area CA1 of hippocampus
  • J Neurosci , 14, 645-654
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