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Title: Sodium channel activation mechanisms : insights from deuterium oxide and delta-9-tetrahydrocannabinol substitution 
Author: Alicata, Daniel Andrew
Date: 1990
Abstract: Schauf and Bullock (1979, 1982) demonstrated that solvent substitution with deuterium oxide (D2O) significantly affects both sodium channel activation and inactivation kinetics without corresponding changes in gating current or tail current rates. They concluded, (a) no significant component of gating current derives from the final channel opening step and, (b) channels must deactivate (during tail currents) by a different pathway from that used in channel opening. By contrast, Oxford (1981) found in squid axons that, when a depolarizing pulse is interrupted by a brief return to holding potential, subsequent reactivation is very rapid and shows almost monoexponential kinetics. Increasing the interpulse interval resulted in secondary activation rate returning towards control, sigmoid kinetics. He concluded that channels open and close via the same pathway. I have repeated both sets of observations, confirming the results obtained in both previous studies, despite the apparently contradictory conclusions reached by these authors. However, I find that secondary activation following a brief interpulse interval is insensitive to D20, although reactivation following longer interpulse intervals returns towards a D20-sensitivity similar to that of primary activation. I conclude that D20sensitive primary activation and D20-insensitive tail current deactivation involve separate pathways. However, D20-insensitive secondary activation involves reversal of the D20-insensitive deactivation step. Strichartz et al. (1978) were the first to investigate the effects of delta-9tetrahydrocannabinol (THC) on sodium channel conductance mechanisms under voltage-clamp conditions. The authors reported that THC modified channel conductance by slowing the activation kinetics of INa and suppressing ionic conductance (gNa) in a voltage-dependent manner. They also noted that channel inactivation processes were not affected by THC action. The authors concluded that the lengthening of !p and the shift in the voltage-dependence of peak gNa are both related to the relative kinetics of sodium activation and inactivation, and since inactivation was unaffected by THC, alterations of activation alone account for these observed changes. I have repeated the above observations, but I can confirm only one of the three results obtained in the previous studies. I find that THC affects both activation and inactivation kinetics. However, I find that the normalized F(Vm) curves are almost identical indicating no significant shift in surface charge following THC treatment.
Description: Thesis (Ph. D.)--University of Hawaii at Manoa, 1990. Includes bibliographical references (leaves 135-153) Microfiche. xi, 153 leaves, bound ill. 29 cm
Rights: All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Keywords: Sodium channels, Deuterium oxide, Tetrahydrocannabinol

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