Inhibition of Martentoxin on Neuronal BK Channel Subtype (α+β4): Implications for a Novel Interaction Model

Martentoxin as a 37-residue peptide was capable of blocking large-conductance Ca2+-activated K+ (BK) channels in adrenal medulla chromaffin cells. This study investigated the pharmacological discrimination of martentoxin on BK channel subtypes. The results showed that the iberiotoxin-insensitive neuronal BK channels (α+β4) could be potently blocked by martentoxin (IC50 = ∼80 nM). In contrast, the iberiotoxin-sensitive BK channel consisting of only α-subunit was less sensitive to martentoxin. Distinctively, martentoxin inhibited neuronal BK channels (α+β4) with a novel interaction mode. Two possible interaction sites of neuronal BK channels (α+β4) might be responsible for the binding with martentoxin: one for trapping and the other located at the pore region for blocking. In addition, the inhibition of martentoxin on neuronal BK channels (α+β4) depended on cytoplasmic Ca2+ concentration. On the other hand, in vivo experiments from EEG recordings suggested that neuronal BK channels (α+β4) were the primary target of martentoxin. Therefore, this research not only sheds light on a unique ligand for neuronal BK channels (α+β4), but also highlights a novel model approach for the interaction between K+ channels and specific-ligands.