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Phospholipid Complexation of General Anesthetics A Wake Up Call

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2011-03-09
REGEN, Steven L
Türkyılmaz, Serhan
General anesthesia represents one of the most important advances in the history of medicine. Despite numerous attempts to determine how general anesthetics function at the molecular level, it remains to be established whether signaling proteins or the surrounding lipids serve as their primary targets. In this talk, I will discuss recent studies that we have carried out in which the effects of chloroform on phospholipid-sterol interactions in the liquid-ordered (lo) and the liquid-disordered (ld) phases have been quantified via the nearest-neighbor recognition (NNR) method. Using host membranes made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol, evidence has been obtained for 1/1 complexes being formed from chloroform and DPPC in both phases. At clinically-relevant concentrations (ca. 2 mM), chloroform was found to weaken cholesterol_DPPC interactions in the lo phase by 24.5 ± 5.5 cal/mol of lipid, while no effect could not be detected in the ld phase. Increasing the concentration of chloroform resulted in a convergence of nearest-neighbor interaction energies and the apparent formation of a common “liquid-anesthetic” (la) phase. The implications of these findings with regard to modern lipid theory of anesthesia will be discussed.