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where V is membrane potential, VS is the potential at which = 0.5 (half of the channels are in the inactivated state), and k is a constant that includes the Boltzmann constant and describes the voltage sensitivity of the inactivation process (Hodgkin and Huxley, 1952).

This model ignores the fast-inactivated state, but interaction of the SCBIs with the channels is so slow, that it and the open state, O, can be ignored in the analysis. The observed enhancement of slow inacti-vation can be explained if we assume that the SCBI drug (D) binds selectively to an inactivated state, as also shown on the right-hand side in the model (Figure 9). Drug binding would then effectively remove channels from the I pool, which would be compensated for by mass action rearrangements among the other states, leading to net flux of more receptors from the R pool into the I and D • I pools. KI = [D] x [I]/[D • I] is defined as the equilibrium dissociation constant of the D • I complex.

In the presence of SCBI drug, two processes lead to the decrease in current upon depolarization: slow inactivation and drug binding. Fortunately, slow inactivation can be removed from the measurements by hyperpolarizing to —120 mV before applying the depolarizing pulse to measure the peak current. Figure 10a shows the time course of block after stepping from —120 mV to various depolarized potentials, in an axon equilibrated with 1 mM RH-1211. The pulse protocol, shown in the inset in panel A (Figure 10), includes a 500 ms hyperpolarizing

prepulse to —120 mV before each test pulse, which was long enough to completely remove slow inactivation, but not long enough to permit significant dissociation of D • I complexes, thus allowing direct assessment of block. The fraction of channels unblocked, fu, is plotted against time, and shows that block, which is equivalent to the formation of D • I complexes, occurs with a time constant of 5-6 min at 1 mM. The voltage dependence occurs only over the range where slow inactivation occurs, saturating near — 70 mV. This is seen clearly in Figure 10b, where fu is plotted against holding potential. In terms of the model shown above, fu = ([R] + [I])/( [R] + [D • I] + [I]). Substituting the above relations for KI and and eqn [1] into this expression, an equation for fu as a function of [D] and V can be derived:

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