About

Ed Chapman is a Professor and Investigator at the Howard Hughes Medical Institute within the Department of Neuroscience at UW–Madison. He holds a Ph.D. from the University of Washington. His laboratory studies membrane trafficking and fusion in neurons, with the overarching goal of understanding presynaptic aspects of synaptic transmission and plasticity. His research is divided into three related subgroups: nanomechanics of membrane fusion, neuronal cell biology, and synaptic transmission and plasticity. In the nanomechanics of membrane fusion subgroup, Chapman uses various technologies, including a nanodisc-black lipid membrane electrophysiology system, to understand how proteins catalyze lipid bilayer fusion. His work has provided new insights into the function of SNARE proteins and synaptotagmin 1, particularly its role as a Ca2+ sensor triggering rapid synaptic vesicle exocytosis. The lab also employs proteoliposomes, light microscopy, single molecule fluorescence, atomic force microscopy, and DNA nanostructures to study the structure and dynamics of membrane fusion machinery. The neuronal cell biology subgroup focuses on the function of the seventeen isoforms of synaptotagmin, exploring their roles in regulating vesicle exocytosis, their targeting to various organelles, and their sorting within neurons. This work has led to discoveries such as identifying new membrane trafficking pathways in mammalian neurons. The team develops new methods to study membrane protein disruption and to track the life cycle of synaptic vesicle proteins. The synaptic transmission and plasticity subgroup investigates the molecular mechanisms of neurotransmitter release and synaptic plasticity using electrophysiological and optical approaches. Their research includes understanding spontaneous, synchronous, and asynchronous release, as well as how vesicle exocytosis converges to modulate synaptic transmission. They study short-term plasticity phenomena like facilitation and depression, and are extending their imaging efforts to include electron microscopy and optical approaches to explore 'kiss-and-run' exocytosis. Chapman’s work has contributed significantly to understanding the molecular basis of synaptic function and plasticity.

Research topics

• Biology
• Biochemistry
• Neuroscience
• Cell biology
• Pathology
• Genetics
• Materials science
• Chemistry
• Nanotechnology
• Psychology
• Biophysics
• Medicine

Selected publications

• Direct Observation of a Cross-Coupling Catalyst Intermediate via Single-Molecule Spectroscopy

  ChemRxiv · 2026-04-09

  articleOpen access

  Single-molecule measurements on molecular catalysts are uniquely poised to allow observation of unsynchronized chemical dynamics and transient intermediates that are not observable using traditional bulk techniques. However, single-molecule fluorescence spectroscopy is typically performed at nanomolar concentrations, far lower than typical synthetic conditions. Here, we use nanophotonic zero mode waveguides (ZMWs) to enable observation of the dynamics of a single operational catalyst under synthetically relevant reaction conditions. We deploy ZMWs to perform the direct observation of a previously hypothesized intermediate of Pd-PEPPSI (Pyridine-Enhanced Precatalyst Preparation, Stabilization, and Initiation), a well-known molecular C–C cross-coupling catalyst, by using a fluorescently labeled ligand to report on ligand binding and dissociation. Kinetic analysis of single-catalyst ligand dynamics reveals how the presence of cross-coupling reactants alters the underlying mechanism. This paradigm for single-molecule investigation of molecular catalysts at synthetically relevant concentrations is general for investigation of a wide variety of ligand and reactant dynamics.

  PublisherDOI

• Optimizing Multifunctional Fluorescent Ligands for Intracellular Labeling

  Qeios · 2025-02-07

  preprintOpen access

  Enzyme-based self-labeling tags enable covalent attachment of synthetic molecules to proteins inside living cells. A frontier of this field is designing multifunctional ligands that contain both fluorophores and affinity tags or pharmacological agents and can still efficiently enter cells. Self-labeling tag ligands with short linkers can enter cells readily but often show less activity due to steric issues; ligands with long linkers can be more potent but show lower cell permeability. Here, we overcome this tug-of-war between efficacy and cell-permeability by devising a rational strategy for making cell permeable multifunctional ligands for labeling HaloTag fusions. We found that the lactone–zwitterion equilibrium sconstant (_K_L–Z) of rhodamines inversely correlates with their distribution coefficients (log_D_7.4), suggesting that ligands based on dyes exhibiting low _K_L–Z and high log_D_7.4 values, such as Si-rhodamines, would efficiently enter cells. We designed cell-permeable multifunctional HaloTag ligands with a biotin moiety to purify mitochondria or a JQ1 appendage to translocate BRD4 from euchromatin to the nucleolus or heterochromatin. We discovered that translocation of BRD4 to constitutive heterochromatin in cells expressing HaloTag–HP1a fusion proteins can lead to apparent increases in transcriptional activity. These new reagents enable affinity capture and translocation of intracellular proteins in living cells and the use of Si-rhodamines and other low _K_L–Z/high log_D_7.4 dye scaffolds will facilitate the design of new multifunctional chemical tools for biology. SIGNIFICANCE STATEMENT: Understanding cellular processes requires tools to measure and manipulate proteins in living cells. Self- labeling tags, such as the HaloTag and SNAP-tag, enable modification of cellular proteins with synthetic molecules. Creating ligands for these systems that have more than one chemical motif remains challenging, however, due to competing demands between cell permeability and functionality. We discovered that multifunctional ligands based on Si-rhodamines efficiently entered cells and enabled affinity purification of mitochondria or translocation of nuclear proteins; the performance of these molecules could be verified by fluorescence microscopy. These compounds should be useful for a variety of biological experiments and our general framework will allow the design of other multifunctional ligands to study living systems.

  PublisherOA PDFDOI

• Alternative splicing of synaptotagmin 7 regulates oligomerization and short-term synaptic plasticity

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-28

  preprintOpen accessSenior authorCorresponding

  Synaptic plasticity is crucial for learning and memory. The presynaptic calcium sensor synaptotagmin 7 (syt7) regulates aspects of short-term plasticity (STP), but the underlying mechanisms remain unclear. Here, we show that alternative splicing of the syt7 juxtamembrane linker acts as a molecular switch at both biochemical and functional levels. The α and β variants undergo liquid-liquid phase separation to form condensates, while the γ variant forms aggregates. Using iGluSnFR imaging, we found that when expressed at equal levels, these three isoforms also diverge regarding their abilities to regulate two key aspects of STP: paired-pulse facilitation and synaptic depression. Further, MINFLUX super resolution microscopy demonstrated that syt7 forms clusters in the active zone, well-positioned to directly control synaptic vesicle dynamics. Thus, alternative splicing might fine-tune STP by differentially impacting syt7 oligomerization.

  PublisherOA PDFDOI

• Programmable Liposome Organization via DNA Origami Templates

  Journal of the American Chemical Society · 2025-07-02 · 6 citations

  articleOpen accessSenior authorCorresponding

  Liposomes are essential vehicles for membrane protein reconstitution and drug delivery, making them vital tools in both in vivo and in vitro studies. However, the lack of robust techniques for the precise arrangement of these synthetic vesicles limits their potential applications. Here, we present a modular polymerization platform based on square DNA origami to template the formation and organization of liposomes. By programming the sequence, number, position, chirality, and flexibility of sticky ends on each square, we assemble uniformly sized liposomes into diverse two-dimensional (2D) arrays, as well as finite lattices and rings. Additionally, we demonstrate stepwise assembly and targeted disassembly, enabling dynamic structural control. These complex liposome architectures represent a significant advancement in the fields of biotechnology, nanotechnology, and bottom-up biology.

  PublisherDOI

• Optimizing multifunctional fluorescent ligands for intracellular labeling

  Proceedings of the National Academy of Sciences · 2025-10-27

  articleOpen access

  Enzyme-based self-labeling tags enable the covalent attachment of synthetic molecules to proteins inside living cells. A frontier of this field is designing cell-permeable multifunctional ligands that contain fluorophores in combination with affinity tags or pharmacological agents. This is challenging since attachment of additional chemical moieties onto fluorescent ligands can adversely affect membrane permeability. To address this problem, we examined the chemical properties of rhodamine-based self-labeling tag ligands through the lens of medicinal chemistry. We found that the lactone–zwitterion equilibrium constant ( K L–Z ) of rhodamines inversely correlates with their distribution coefficients (log D 7.4 ), suggesting that ligands based on dyes exhibiting low K L–Z and high log D 7.4 values, such as Si-rhodamines, would efficiently enter cells. We designed cell-permeable multifunctional HaloTag ligands with a biotin moiety to purify mitochondria or a JQ1 appendage to translocate BRD4 within the nucleus. We found that translocation of BRD4 to constitutive heterochromatin in cells leads to apparent increases in transcriptional activity. These fluorescent reagents enable affinity capture and translocation of intracellular proteins in living cells, and our general design concepts will facilitate the design of multifunctional chemical tools for biology.

  PublisherOA PDFDOI

• Author Correction: Synaptotagmin-7 outperforms synaptotagmin-1 to promote the formation of large, stable fusion pores via robust membrane penetration

  Nature Communications · 2025-05-20

  erratumOpen accessSenior author
  PublisherOA PDFDOI

• Label-free detection and profiling of individual solution-phase molecules

  Nature · 2024-05-08 · 43 citations

  articleOpen access
  PublisherOA PDFDOI

• Author Response: Synaptotagmin 7 docks synaptic vesicles to support facilitation and Doc2α-triggered asynchronous release

  2024-03-01

  peer-reviewOpen access

  Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot be replenished on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse onward during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus providing synaptic vesicles for synchronous (syt1) and asynchronous (Doc2 and other unidentified sensors) release during ongoing transmission.

  PublisherDOI

• Structural insights into SV2A and the mechanism of racetam anticonvulsants

  Nature Structural & Molecular Biology · 2024-11-22 · 6 citations

  articleSenior authorCorresponding
  PublisherDOI

• Synaptotagmin 7 docks synaptic vesicles to support facilitation and Doc2α-triggered asynchronous release

  eLife · 2024-03-22 · 9 citations

  articleOpen access

  Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca 2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca 2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot be replenished on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse onward during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca 2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus providing synaptic vesicles for synchronous (syt1) and asynchronous (Doc2 and other unidentified sensors) release during ongoing transmission.

  PublisherDOI

Recent grants

• NIH Grant R01GM056827

  NIH · $2.2M · 2008

• NIH Grant R01NS072905

  NIH · $1.9M · 2017

• NIH Grant R21NS081549

  NIH · $396k · 2016

• Structure and dynamics of exocytotic fusion pores

  NIH · $4.6M · 2016–2024

• Synaptotagmin C2B Domain as a Ca2+ Sensing Module

  NIH · $7.7M · 2002–2028

Frequent coauthors

• Jason Vevea

  Howard Hughes Medical Institute

  66 shared

• Zhenyong Wu

  Shanghai Institute of Materia Medica

  59 shared

• Shigeki Watanabe

  Johns Hopkins University

  55 shared

• Grant F. Kusick

  Johns Hopkins Medicine

  55 shared

• Sumana Raychaudhuri

  Johns Hopkins University

  47 shared

• Kie Itoh

  Johns Hopkins Medicine

  47 shared

• Huan Bao

  46 shared

• Enfu Hui

  44 shared

Labs

• Chapman LabPI

Education

• PhD, Pharmacology

  University of Washington

  1992

• BS, Chemistry/biology

  Western Washington University

  1985