Abstract
The cytoskeleton is essential to cell morphology, cargo trafficking, and cell division. As the neuronal cytoskeleton is extremely complex, it is no wonder that a startling number of neurodegenerative disorders (including but not limited to Alzheimer’s disease, Parkinson’s disease and Huntington’s disease) share the common feature of a dysfunctional neuronal cytoskeleton. Recently, concern has been raised about a possible link between anesthesia, post-operative cognitive dysfunction, and the exacerbation of neurodegenerative disorders. Experimental investigations suggest that anesthetics bind to and affect cytoskeletal microtubules, and that anesthesia-related cognitive dysfunction involves microtubule instability, hyper-phosphorylation of the microtubule-associated protein tau, and tau separation from microtubules. However, exact mechanisms are yet to be identified. In this paper the interaction of anesthetics with the microtubule subunit protein tubulin is investigated using computer-modeling methods. Homology modeling, molecular dynamics simulations and surface geometry techniques were used to determine putative binding sites for volatile anesthetics on tubulin. This was followed by free energy based docking calculations for halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) on the tubulin body, and C-terminal regions for specific tubulin isotypes. Locations of the putative binding sites, halothane binding energies and the relation to cytoskeleton function are reported in this paper.
Highlights
Despite the extensive electrophysiological studies regarding the effects of inhaled anesthetics on membrane ion channels and receptor proteins [1,2,3] the exact molecular mode of action of anesthetics remains uncertain
Summary Anesthetic binding to tubulin may be important for the mechanism of anesthetic action, and for anesthetic side effects related to post-operative cognitive dysfunction and/or exacerbation of neurodegenerative diseases
The size of the tubulin macromolecule, its numerous preexisting non-polar, hydrophobic cavities, and the generally weak binding of volatile anesthetics hinder the experimental investigation of this molecular mechanism of interaction
Summary
Despite the extensive electrophysiological studies regarding the effects of inhaled anesthetics on membrane ion channels and receptor proteins [1,2,3] the exact molecular mode of action of anesthetics remains uncertain. In addition to altering the function of membrane ion channels and receptors in vitro [4,5,6,7,8,9,10,11,12,13,14], the inhaled anesthetics are known to affect enzymes [15,16,17] as well as many cytoplasmic proteins in the mammalian central nervous system [18,19,20,21,22], providing multiple targets for their actions including side effects Among these cytoplasmic proteins is tubulin, the component protein of cytoskeletal microtubules. MTs have been shown to modulate both sodium and calcium current within neurons [26,27,28,29,30]
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