An inhibitory action of ASIC1a peptide on BK channels

Abstract

Acid Sensing Ion Channels contain a sequence that is identical to scorpion toxins blocking potassium channels, and this sequence is critical for ASICs' inhibition of large conductance calcium‐ and voltage‐activated potassium (BK) channels (Petroff et al., PNAS 2008, 118(4), 1571). In this study, a peptide containing the ASIC1a toxin‐like sequence (without the Cys to avoid peptide aggregation) also reduced BK current amplitude. Mutating the peptide sequence replacing Arg and Lys with Ala prevented BK inhibition. Peptide inhibition was reversible and concentration‐dependent, and although pH 6 solution only marginally reversed inhibition the rate at which current increased following peptide washout was faster at pH 6 than 7.4. Moreover, the peptide competed with the known BK channel blocker, tetraethyl ammonium. Extracellular K+is known to reduceIbTx and CTx block. Raising the K+ and Rb+ concentrations, but not Na+, Cs+, Li+ or Ca2+, reduced BK inhibition by the peptide. A parallel exists inCTx block ofShaker K+ channels; external K+, but not Na+ reduced block, indicating the presence of an extracellular K+ coordination site located near the toxin binding site. In addition, the peptide inhibition of BK channels was voltage‐dependent only in the presence of intracellular K+. These data suggest that ASIC1a peptide interacts with the K+ conduction pathway in the BK channel and may act as a BK channel blocker.