Differential inhibition of a transient K+ current by chlorpromazine and 4-aminopyridine in neurones of the rat dorsal root ganglia.

1. K+ currents were recorded from neurones of the newborn rat cultured dorsal root ganglia, by a whole cell variation of the patch-clamp technique. 2. Chlorpromazine (CPZ), a neuroleptic, reversibly reduced the amplitude of the transient K+ current (referred to as 'IT' hereafter) with a dissociation constant (Kd) of 4.5 microM. The inhibition of the delayed rectifier K+ current (IDR) was much less potent (Kd, 120 microM). CPZ (100 microM) had no effect on the inward rectifier K+ current. 3. The blocking action of CPZ on IT was about seven times more potent than that of 4-aminopyridine (4-AP) which had a Kd of 31 microM. The inhibition of IT followed one-to-one binding stoichiometry with both drugs. 4. The decay time course of IT was not affected by CPZ, whereas 4-AP markedly accelerated the decay phase of IT. 5. The steady-state inactivation curve of IT was shifted in the negative direction (about 5 mV) by CPZ, whereas the curve was shifted in the positive direction (about 13 mV) by 4-AP. 6. The recovery from inactivation as measured by a conventional double pulse protocol was described by two exponential components in the control solution. CPZ markedly reduced the first component and slowed down the recovery from inactivation. In contrast, in the presence of 4-AP, the peak amplitude of IT was rather increased by a preceding IT possibly through voltage-dependent unbinding of 4-AP molecules. 7. These results indicate that CPZ has a preferential blocking action on IT and the mechanism underlying this block is markedly different from the mechanism underlying the blocking action of 4-AP.