The long term goal of this research is to determine the molecular mechanisms of anesthetic action through a detailed understanding of how and where inhalational anesthetics like halothane bind to proteins and other cellular constituents. We plan to use novel techniques developed in our laboratory to measure binding characteristics of halothane to a wide range of soluble proteins to examine the importance of protein structure on anesthetic binding, and then to determine the binding locations within these peptides to define anesthetic binding site character and heterogeneity. We will also examine reconstituted protein/lipid systems to determine selectivity of halothane binding between lipid and protein, and protein subunits to address the question of whether anesthetics act directly on protein or through an indirect effect on lipid. The binding heterogeneity of halothane to intact biological membranes from normal animals and anesthetic sensitive or resistant mutants will be measured at various levels of resolution (grossly -> microscopic -> molecular) to select out specific and potentially important binding regions or proteins. The determination of drug specific binding sites will lead to a better understanding of the mechanism of action, and this will undoubtedly lead to more efficacious and safer anesthetic drugs and practice. Further, improved understanding of the mechanisms of unconsciousness should lead to an improved understanding of consciousness.
| Vedula, L Sangeetha; Brannigan, Grace; Economou, Nicoleta J et al. (2009) A unitary anesthetic binding site at high resolution. J Biol Chem 284:24176-84 |
| Butts, Christopher A; Xi, Jin; Brannigan, Grace et al. (2009) Identification of a fluorescent general anesthetic, 1-aminoanthracene. Proc Natl Acad Sci U S A 106:6501-6 |
| Eckenhoff, R G (1998) Do specific or nonspecific interactions with proteins underlie inhalational anesthetic action? Mol Pharmacol 54:610-5 |
