Gambierol and n-alkanols inhibit Shaker Kv channel via distinct binding sites outside the K+ pore

Abstract

The marine polycyclic-ether toxin gambierol and 1-butanol (n-alkanol) inhibit Shaker-type Kv channels by interfering with the gating machinery. Competition experiments indicated that both compounds do not share an overlapping binding site but gambierol is able to affect 1-butanol affinity for Shaker through an allosteric effect. Furthermore, the Shaker-P475A mutant, which inverses 1-butanol effect, is inhibited by gambierol with nM affinity. Thus, gambierol and 1-butanol inhibit Shaker-type Kv channels via distinct parts of the gating machinery.

Hydrophobic Drug/Toxin Binding Sites in Voltage-Dependent K+ and Na+ Channels

“…A compound like gambierol (Figures 4 and 7) has been shown to mostly bind to the front side of the PD, while RTG ( Figures 5 and 7) PD57, and ICA74 ( Figure 6) also interact with the back side of the PD of an adjacent a-subunit. When mapping all the sites it appears that gambierol, ICA74, RTG, and PD57 bind to an analogues binding site present in different K v channel types ( Figure 7) (Schenzer et al, 2005;Kopljar et al, 2009;Lange et al, 2009;Perry et al, 2009;Garg et al, 2011;Martinez-Morales et al, 2016). This indicates that an analogues lipophilic binding site is conserved between the different K v channel types.…”

“…Additional determinants are a leucine and phenylalanine on S5: L348 and F351 in K v 3.1, respectively. K v 1 channels possess a threonine residue equivalent to T427 (T401 in K v 1.2), explaining their similar gambierol sensitivity (Cuypers et al, 2008;Kopljar et al, 2009;Martinez-Morales et al, 2016). These residues are mostly positioned on the front side of the PD (Figure 4).…”