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Home » Uncategorized » New article on interactions of general anesthetics with GABA(A) receptors in Journal of Biological Chemistry

New article on interactions of general anesthetics with GABA(A) receptors in Journal of Biological Chemistry

Research on the mechanism of general anesthesia from our collaboration with Dr. Roderic Eckenhoff’s grob-a+_sideup at University of Pennsylvania, is now in press at J Biol Chem:

“A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of GABAA Receptor Subunit Binding Selectivity in Synaptosomes” by  Kellie A. Woll, Sruthi Murlidaran, Benika J. Pinch, Jérôme Hénin, Xiaoshi Wang, Reza Salari, Manuel Covarrubias, William P. Dailey, Grace Brannigan, Benjamin A. Garcia, and Roderic G. Eckenhoff.

The experimental side of this work,  carried out at Penn and Thomas Jefferson University, involved using click chemistry and photoaffinity labeling to detect differences in binding of the general anesthetic propofol* to subunits forming the GABA(A) receptor.  The experiments were done in neurons, where general anesthesia actually takes place.

On the computational side, we used a sophisticated  MD technique called Alchemical Free Energy Perturbation to calculate affinities of propofol for sites found in each interface between subunits, and we determined how small changes in the amino acids forming the sites can result in large differences in how strongly the anesthetic binds.

This was challenging because the differences are subtle, but important because GABA(A) receptors across the human central nervous system have many subtle differences with dramatic effects.

*in experiments, actually a propofol analog with modifications necessary for the experimental technique.


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