The objective of this research program is to characterize anesthetic actions on human brain ion channels and to understand the molecular forces by which anesthetics alter their functions. A new technique suitable for extensive single channel studies of scarce human brain material will be used, beginning with the study of voltage-dependent sodium channels. The effects of anesthetics or altered membrane composition on the steady-state properties of sodium channels in lipid bilayers will be examined. The first description of the responses of human brain sodium channels to clinical and other general anesthetics is to be provided. The concentrations at which these anesthetics have their effects are to be established and compared with those encountered during clinical anesthesia. Anesthetic sensitivities of human brain as opposed to peripheral sodium channels will be compared. The modulation of sodium channel function by steroid anesthetics and steroid-like compounds will be examined. Experiments will be conducted to establish that observed anesthetic actions on sodium channels are independent of the modifying alkaloid toxin. Combined with the results from future studies of other ion channels these data will be required in attempts to correlate clinically distinct anesthesia with differential actions of anesthetics on ion channels. Evidence for more than one action of general anesthetics suggested form macroscopic current measurements is to be confirmed on the molecular level. The thickness-tension hypothesis is to be tested and the involvement of calcium in the anesthetic response examined. The hypothesis that anesthetics can modify channel function indirectly by altering the lipid environment will be examined. Bilayer composition will be systematically altered in order to reproduce changes in membrane properties thought to be caused by anesthetics. It will be determined if anesthetic sensitivity depends on lipid environment. The characterization of anesthetic effects on the steady-state properties of sodium channels is a first step in the description of the total response of sodium channels to anesthetics. For a complete description future studies will be needed that describe anesthetic effects on the kinetics of sodium channels as they respond to transient membrane potentials. The present project will prepare the ground for such work and the future characterization of other human brain ion channels.
| Rehberg, B; Duch, D S; Urban, B W (1994) The voltage-dependent action of pentobarbital on batrachotoxin-modified human brain sodium channels. Biochim Biophys Acta 1194:215-22 |
| Wartenberg, H C; Wang, J; Rehberg, B et al. (1994) Molecular actions of pentobarbitone on sodium channels in lipid bilayers: role of channel structure. Br J Anaesth 72:668-73 |
| Urban, B W; Frenkel, C; Duch, D S et al. (1991) Molecular models of anesthetic action on sodium channels, including those from human brain. Ann N Y Acad Sci 625:327-43 |
| Chabala, L D; Urban, B W; Weiss, L B et al. (1991) Steady-state gating of batrachotoxin-modified sodium channels. Variability and electrolyte-dependent modulation. J Gen Physiol 98:197-224 |
