BLOCK OF NEURONAL CHLORIDE CHANNELS BY TETRAETHYLAMMONIUM ION DERIVATIVES

The block by the symmetric tetraethylammonium (TEA) ion derivatives te trapropylammonium (TPrA), tetrabutylammonium (TEA), and tetrapen-tylam monium (TPeA) ions of fast chloride channels in acutely dissociated ra t cortical neurons was studied with the excised inside-out configurati on of the patch-clamp technique. When applied to the intracellular mem brane surface, all three of the quaternary ammonium compounds (QAs) in duced the appearance of short-lived closed states in a manner consiste nt 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-dimen sional dwell-time analysis. Kinetic models were fit to distributions o f open and closed interval durations using the Q-matrix approach. The blocking rate constants for all three of the QAs were similar with val ues of similar to 12-20 X 10(6) M(-1)s(-1). The unblocking rates were dependent on the size or hydrophobicity of the QA with the smallest de rivative, TPrA, inducing a blocked state with a mean lifetime of simil ar to 90 mu s, while the most hydrophobic derivative, TPeA, induced a blocked state with a mean lifetime of similar to 1 ms. Thus, it appear s as though quaternary ammonium ion block of these chloride channels i s nearly identical to the block of many potassium channels by these co mpounds. This suggests that there must be structural similarities in t he conduction pathway between anion and cation permeable channels.