Abstract
The block by the symmetric tetraethylammonium (TEA) ion derivatives tetrapropylammonium (TPrA), tetrabutylammonium (TBA), and tetrapentylammonium (TPeA) ions of fast chloride channels in acutely dissociated rat cortical neurons was studied with the excised inside-out configuration of the patch-clamp technique. When applied to the intracellular membrane surface, all three of the quaternary ammonium compounds (QAs) induced the appearance of short-lived closed states in a manner consistent with a blocking mechanism where the blocker preferentially binds to the open kinetic state and completely blocks ion current through the channel. The drug must leave the channel before the channel can return to a closed state. The mechanism of block was studied using one-dimensional dwell-time analysis. Kinetic models were fit to distributions of open and closed interval durations using the Q-matrix approach. The blocking rate constants for all three of the QAs were similar with values of approximately 12-20 x 10(6) M-1s-1. The unblocking rates were dependent on the size or hydrophobicity of the QA with the smallest derivative, TPrA, inducing a blocked state with a mean lifetime of approximately 90 microseconds, while the most hydrophobic derivative, TPeA, induced a blocked state with a mean lifetime of approximately 1 ms. Thus, it appears as though quaternary ammonium ion block of these chloride channels is nearly identical to the block of many potassium channels by these compounds. This suggests that there must be structural similarities in the conduction pathway between anion and cation permeable channels.