西亚试剂:Allosteric block of K(Ca)2 channels by apamin
发布时间:2025-05-17
Allosteric block of K(Ca)2 channels by apamin
Cedric Lamy1, Samuel J. Goodchild2, Kate L. Weatherall2, David E. Jane2, Jean-Francois Liegeois1, Vincent Seutin1 and Neil V. Marrion2,*
1 University of Liege, Belgium;
2 University of Bristol, United Kingdom
Activation of small conductance calcium activated potassium (KCa2) channels can regulate neuronal firing and synaptic plasticity. They are characterised by their high sensitivity to the bee venom toxin apamin, but the mechanism of block is not understood. For example, apamin binds to both KCa2.2 and KCa2.3 with the same high affinity (KD ~ 5 pM for both subtypes), but requires significantly higher concentrations to block functional current (IC50s of ~100 pM and ~5 nM, respectively). This suggests that steps beyond binding are needed for channel block to occur. We have combined patch clamp and binding experiments on cell lines, with molecular modelling and mutagenesis, to gain more insight into the mechanism of action of the toxin. An outer pore histidine residue common to both subtypes was found to be critical for both binding and block by the toxin, but not for block by tetraethylammonium (TEA) ions. These data indicated that apamin blocks KCa2 channels by binding to a site distinct from that used by TEA, supported by finding that the onset of block by apamin was not affected by the presence of TEA. Structural modelling of ligand-channel interaction indicated that TEA binds deep within the channel pore, which contrasted with apamin being modelled to interact with the channel outer pore by utilizing the outer pore histidine residue. This multidisciplinary approach suggested that apamin does not behave as a classical pore blocker, but blocks using an allosteric mechanism that is consistent with observed differences between binding affinity and potency of block.
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