Description of Research Expertise:
MOLECULAR PHARMACOLOGY OF INHALED ANESTHETICS
Discovery of the general anesthetics is considered one of the most important medical advances of all time. They are used in over 100 million patients every year, and yet remain the most toxic and poorly understood of all drugs. The goal of my laboratory is a translational understanding of general anesthetic pharmacology, but focused at the most fundamental molecular level. This is a critical foundation on which the subsequent superstructure of molecular, cellular and organism understanding will be built. We have developed a wide variety of experimental approaches to study anesthetic binding to proteins, and the structural and dynamic consequences. Thus, photoaffinity labeling, fluorescence spectroscopy, amide hydrogen exchange, low-affinity elution chromatography and differential/isothermal calorimetry have all been introduced and validated for this purpose. We have moved from simple protein and peptide models to the most relevant and complex ion channels, enzymes, and receptors. We collaborate with Penn Chemistry (William Dailey, Ivan Dmochowski) to introduce novel reagents into our campaign to understand molecular anesthesia. Wide collaborations with many other departments and institutions have facilitated a rapid, multidisciplinary attack on some of the most fundamental questions in anesthetic pharmacology.
Our studies of general anesthetics have led to the observation that they can potently promote aggregation of selected peptides and proteins, as well as modulate the immune response. Since a common feature of most neurodegenerative disorders is aggregation of endogenous peptide, and neuroinflammation, the general anesthetics may accelerate the onset of neurodegeneration. Examination of the effects of anesthesia and surgery in a fully translational manner is a growing focus of our laboratory.
Woll Kellie A, Zhou Xiaojuan, Bhanu Natarajan V, Garcia Benjamin A, Covarrubias Manuel, Miller Keith W, Eckenhoff Roderic G: Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 (8): 4172-4189,2018.
Bensel Brandon M, Guzik-Lendrum Stephanie, Masucci Erin M, Woll Kellie A, Eckenhoff Roderic G, Gilbert Susan P: Common general anesthetic propofol impairs kinesin processivity. Proceedings of the National Academy of Sciences of the United States of America 114 (21): E4281-E4287,2017.
Woll Kellie A, Murlidaran Sruthi, Pinch Benika J, Hénin Jérôme, Wang Xiaoshi, Salari Reza, Covarrubias Manuel, Dailey William P, Brannigan Grace, Garcia Benjamin A, Eckenhoff Roderic G: A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of γ-Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes. The Journal of biological chemistry 291 (39): 20473-86,2016.
Ho J, Perez-Aguilar JM, Gao L, Saven JG, Matsunami H, Eckenhoff RG: Molecular recognition of ketamine by a subset of olfactory G protein–coupled receptors. Sci. Signal. 8 (370): 2015.
Weiser Brian P, Eckenhoff Roderic G: Propofol Inhibits SIRT2 Deacetylase through a Conformation-specific, Allosteric Site. The Journal of biological chemistry 290 (13): 8559-68,2015.
Tang Junxia X, Mardini Feras, Janik Luke S, Garrity Sean T, Li Rosie Q, Bachlani Gulnaz, Eckenhoff Roderic G, Eckenhoff Maryellen F: Modulation of murine Alzheimer pathogenesis and behavior by surgery. Annals of surgery 257 (3): 439-48,2013.
Emerson DJ, Weiser BP, Psonis J, Liao Z, Taratula O, Fiamengo A, Wang X, Sugasawa K, Smith A, Eckenhoff RG, Dmochowski IJ.: Direct modulation of microtubule stability contributes to anthracene general anesthesia.
J. Am. Chem. Soc. : 2013.
Hall Michael A, Xi Jin, Lor Chong, Dai Shuiping, Pearce Robert, Dailey William P, Eckenhoff Roderic G: m-Azipropofol (AziPm) a photoactive analogue of the intravenous general anesthetic propofol. Journal of medicinal chemistry 53 (15): 5667-75,2010.
Liu R, Loll PJ, Eckenhoff RG: Structural basis for high-affinity volatile anesthetic binding in a natural 4-helix bundle protein. FASEB J. 19 (6): 567-76,2005.
Eckenhoff RG, Johansson JS, Wei H, Carnini A, Kang B, Wei W, Pidikiti R, Keller JM, Eckenhoff MF: Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology 101 (3): 703-9,2004.
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