Abstract
Quaternary ammonium compounds such as tetrabutylammonium (TBA) have been widely used to investigate the physical size and gating mechanisms at the intracellular entrance of cation-selective ion channel pores. Identification of a high-affinity blocker is often desirable for these studies where blocker on and off rates need to be comparable to the kinetics of channel gating. A hydrophobic derivative of TBA, called bbTBA, has been shown to block BK Ca2+- and voltage-gated K+ channels with high affinity and we have found a similar affinity to the prokaryotic homologue MthK (KD ∼ 1 μM). In this study, we are using single channel recordings to systematically explore MthK block by TBA, benzyl-tributylammonium (bTBA), and the high-affinity bbTBA that contains two hydrophobic rings. Addition of each hydrophobic ring to the blocker molecule increases the affinity for MthK by an order of magnitude. We discuss possible mechanisms for this marked enhancement of channel block and implications for the use of these blockers in gating studies.
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