Roderic G. Eckenhoff · University of Pennsylvania · PhdFit
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Roderic G. Eckenhoff
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University of Pennsylvania · Rehabilitation Medicine
Roderic G. Eckenhoff, MD, is the Austin Lamont Professor of Anesthesia in the Department of Anesthesiology and Critical Care at the University of Pennsylvania's Perelman School of Medicine. His research focuses on the molecular pharmacology of inhaled anesthetics, aiming to achieve a translational understanding of their fundamental molecular mechanisms. His laboratory employs various experimental approaches, including photoaffinity labeling, fluorescence spectroscopy, amide hydrogen exchange, chromatography, and calorimetry, to study anesthetic binding to proteins and the structural and dynamic consequences of these interactions. His work has moved from simple protein models to complex ion channels, enzymes, and receptors, often collaborating with Penn Chemistry to introduce novel reagents.
Dr. Eckenhoff's research has also revealed that general anesthetics can promote aggregation of peptides and proteins and modulate immune responses, which may influence the onset of neurodegenerative disorders. His studies include examining the effects of anesthesia and surgery on neurodegeneration in a translational context. He has contributed to the understanding of anesthetic effects on GABA receptors, amyloid-beta oligomerization, and neuroinflammation, and has published extensively on these topics. His work is integral to advancing knowledge in anesthetic pharmacology and brain health.
Proteins contain small pockets that form due to imperfections in residue packing or the rotational and conformational movement of amino acids. In this work, we used the fluorescent probe 1-aminoanthracene (AMA) to detect a small ligand pocket in the hydrophobic core of human proliferating cell nuclear antigen (PCNA), which is a critical protein for DNA replication and repair. Fluorescence measurements of AMA reported that the core of PCNA had a dielectric constant (ε) of 4, which was very apolar and similar to cyclohexane (ε = 2). Protein mutagenesis, photoaffinity labeling, and molecular dynamics simulations localized the binding site for AMA next to PCNA residues L90 and L101, which also interacted with general anesthetics (sevoflurane and propofol). The ligand binding site was cryptic, i.e., it formed transiently and was only detectable in certain structural states of PCNA. Ligand binding to the cryptic site on PCNA structurally stabilized the trimeric protein and reduced its ability to disassemble and reassemble its subunits. Thus, the cryptic site in PCNA's core serves to destabilize the assembled protein and promotes structural and oligomeric flexibility. Finally, the hydrophobic site is widely conserved among homologous β clamp proteins with a similar fold as PCNA. This work highlights how small fluorescent probes can reveal ligand sites within proteins, defines the chemical features of protein hydrophobic cores, and introduces a novel approach to modulate the oligomeric stability of PCNA.
Proceedings of the National Academy of Sciences · 2025-04-03 · 4 citations
articleOpen access
THIK1 tandem pore domain (K2P) potassium channels regulate microglial surveillance of the central nervous system and responsiveness to inflammatory insults. With microglia recognized as critical to the pathogenesis of neurodegenerative diseases, THIK1 channels are putative therapeutic targets to control microglia dysfunction. While THIK channels can principally be distinguished from other K2Ps by their distinctive inhibitory response to volatile anesthetics (VAs), molecular details governing THIK channel gating remain largely unexplored. Here, we report a 3.2 Å cryo-electron microscopy structure of the THIK1 channel in a closed conformation. A central pore gate located directly below the THIK1 selectivity filter is formed by inward-facing TM4 helix tyrosine residues that occlude the ion conduction pathway. VA inhibition of THIK requires closure of this central pore gate. Using a combination of anesthetic photolabeling, electrophysiology, and molecular dynamics simulation, we identify a functionally critical THIK1 VA binding site positioned between the central gate and a structured section of the THIK1 TM2/TM3 loop. Our results demonstrate the molecular architecture of the THIK1 channel and elucidate critical structural features involved in regulation of THIK1 channel gating and anesthetic inhibition.
The zebrafish (Danio rerio) is one of the most widely used research model organisms funded by the United States’ National Institutes of Health, second only to the mouse. Here, we discuss the advantages and unique qualities of this model organism. Additionally, we discuss key aspects of experimental design and statistical approaches that apply to studies using the zebrafish model organism. Finally, we list critical details that should be considered in the design of zebrafish experiments to enhance rigor and data reproducibility. These guidelines are designed to aid new researchers, journal editors, and manuscript reviewers in supporting the publication of the highest-quality zebrafish research. A review emphasizes the advantages of using zebrafish in research, outlines key differences in experimental approaches, and offers guidelines for designing studies in a way that enhances experimental rigor and reproducibility.
bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-21
preprintOpen access
Abstract Anesthetic and sedative drugs are small compounds known to bind to hundreds of proteins. One intriguing binding partner of propofol is the kinesin motor domain, kif5A, a neuronal mitochondrial transport protein. Here, we used zebrafish WT and kif5Aa KO larval behavioral assays to assess anesthetic sensitivity and combined that with zebrafish primary neuronal cell culture to probe for alteration in mitochondrial motility. We found that the loss of kif5Aa increases behavioral sensitivity to propofol and etomidate, with etomidate hypersensitivity greater than propofol. In contrast, kif5Aa KO animals were resistant to the behavioral effects of dexmedetomidine. Finally, WT and kif5Aa KO larvae responded similarly to the behavioral effects of ketamine. Propofol inhibited the anterograde motility of mitochondria in WT zebrafish neurons, while etomidate inhibited mitochondrial motility in both anterograde and retrograde directions; neither drug altered mitochondrial motility in the kif5Aa knockout (KO) neurons. In contrast, dexmedetomidine enhanced retrograde mitochondrial motility in both WT and kif5Aa KO animals. Finally, ketamine had little significant effect on mitochondrial motility in either mutant or WT animals. These data demonstrate that each anesthetic/sedative drug affects the motor protein machinery uniquely and is associated with unique changes in behavior. Understanding how different anesthetic compounds alter neuron motor proteins will be important in defining how anesthetics alter neuronal signaling and energetic dynamics.
British Journal of Anaesthesia · 2024-09-19 · 3 citations
articleOpen accessSenior author
BACKGROUND: release, increased sarcomere tension, and heat production. Propofol does not trigger MH and is commonly used for patients at risk of MH. The atomic-level interactions of any anaesthetic with RyR1 are unknown. METHODS: imaging of human skeletal myotubes. AziPm binding sites, reflecting propofol binding, were identified on RyR1 using photoaffinity labelling. Propofol binding affinity to a photoadducted site was predicted using molecular dynamics (MD) simulation. RESULTS: values of 55.8 μM and 1.4 μM in the V4828 pocket in open and closed RyR1, respectively. CONCLUSIONS: flux through RyR1.
Despite their frequent use across many clinical settings, general anesthetics are medications with lethal side effects and no reversal agents. A fluorinated analogue of propofol has previously been shown to antagonize propofol anesthesia in tadpoles and zebrafish, but little further investigation of this class of molecules as anesthetic antagonists has been conducted. A 13-member library of alkyl-fluorobenzene derivatives was tested in an established behavioral model of anesthesia in zebrafish at 5 days post fertilization. These compounds were examined for their ability to antagonize propofol and two volatile anesthetics, as well as their interaction with the anesthetic-binding model protein apoferritin. Two compounds provided significant antagonism of propofol, and when combined, were synergistic, suggesting more than one antagonist sensitive target site. These compounds did not antagonize the volatile anesthetics, indicating some selectivity amongst general anesthetics. For the compounds with the most antagonistic potency, similarities in structure and binding to apoferritin may be suggestive of competitive antagonism; however, this was not supported by a Schild analysis. This is consistent with multiple targets contributing to general anesthesia, but whether these are physiologic antagonists or are antagonists at only some subset of the many anesthetic potential targets remains unclear, and will require additional investigation.
bioRxiv (Cold Spring Harbor Laboratory) · 2024-01-12 · 2 citations
preprintOpen accessSenior author
Abstract As the primary Ca 2+ release channel in skeletal muscle sarcoplasmic reticulum (SR), mutations in the type 1 ryanodine receptor (RyR1) or its binding partners underlie a constellation of muscle disorders, including malignant hyperthermia (MH). In patients with MH mutations, exposure to triggering drugs such as the halogenated volatile anesthetics biases RyR1 to an open state, resulting in uncontrolled Ca 2+ release, sarcomere tension and heat production. Restoration of Ca 2+ into the SR also consumes ATP, generating a further untenable metabolic load. When anesthetizing patients with known MH mutations, the non-triggering intravenous general anesthetic propofol is commonly substituted for triggering anesthetics. Evidence of direct binding of anesthetic agents to RyR1 or its binding partners is scant, and the atomic-level interactions of propofol with RyR1 are entirely unknown. Here, we show that propofol decreases RyR1 opening in heavy SR vesicles and planar lipid bilayers, and that it inhibits activator-induced Ca 2+ release from SR in human skeletal muscle. In addition to confirming direct binding, photoaffinity labeling using m- azipropofol (AziP m ) revealed several putative propofol binding sites on RyR1. Prediction of binding affinity by molecular dynamics simulation suggests that propofol binds at least one of these sites at clinical concentrations. These findings invite the hypothesis that in addition to propofol not triggering MH, it may also be protective against MH by inhibiting induced Ca 2+ flux through RyR1.
