How do volatile anesthetics inhibit Ca(2+)-ATPases?
Volatile anesthetics at concentrations that are used in clinical practice to induce anesthesia selectively inhibit activity of the plasma membrane Ca(2+)-transport ATPase (Kosk-Kosicka, D., and Roszczynska, G. (1993) Anesthesiology 79, 774-780). We have investigated the mechanism of the inhibitory action of several anesthetics on the purified erythrocyte Ca(2+)-ATPase by employing fluorescence spectroscopy measurements that report changes in the environment of intrinsic tryptophans and of an extrinsic probe attached in the active site of the enzyme. We have shown that the observed inhibition of the Ca(2+)-dependent activation of the enzyme correlates well with the elimination of the Ca(2+)-induced conformation change that is important for the proper function of the enzyme. Analysis of the anesthetics effects on the total tryptophan fluorescence indicates a significant effect on enzyme conformation. Similar changes have been observed in the sarcoplasmic reticulum Ca(2+)-ATPase. We propose that volatile anesthetics inhibit Ca(2+)-ATPase by interacting with nonpolar sites in protein interior, in analogy to the binding demonstrated for myoglobin, hemoglobin, and adenylate kinase (Schoenborn, B. P., and Featherstone, R. M. (1967) Adv. Pharmacol. 5, 1-17; Tilton, R. F., Kuntz, I. D., and Petsko, G. A. (1984) Biochemistry 23, 2849-2857). Such binding is expected to modify conformational substate(s) of the enzyme and perturb its function. We view this process as an example of a general phenomena of interaction of small molecules with internal sites in proteins.
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000097:blood / Q000737:chemistry*; D004737:Enflurane / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000201:enzymology; D004912:Erythrocytes / Q000201:enzymology; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology; D007700:Kinetics; D008733:Methoxyflurane / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects*; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D014364:Tryptophan
D018685:Anesthetics, Inhalation; D008733:Methoxyflurane; D014364:Tryptophan; D004737:Enflurane; D007530:Isoflurane; D000252:Calcium-Transporting ATPases; D002118:Calcium; D006221:Halothane