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See detailThe interactions of apamin and tetraethylammonium are differentially affected by single mutations in the pore mouth of small conductance calcium-activated potassium (SK) channels
Dilly, Sébastien ULg; Philippart, Fabian ULg; Lamy, Cédric et al

in Biochemical Pharmacology (2013), 85

Valine residues in the pore region of SK2 (V366) and SK3 (V520) were replaced by either an alanine or a phenylalanine to evaluate the impact on the interactions with the allosteric blocker apamin. Unlike ... [more ▼]

Valine residues in the pore region of SK2 (V366) and SK3 (V520) were replaced by either an alanine or a phenylalanine to evaluate the impact on the interactions with the allosteric blocker apamin. Unlike TEA which showed high sensitivity to phenylalanine mutated channels, the binding affinity of apamin to the phenylalanine mutants was strongly reduced. In addition, currents from phenylalanine mutants were largely resistant to block by apamin. On the other hand, when the valine residue was replaced by an alanine residue, an increase of the binding affinity and the amount of block by apamin was observed for alanine mutated SK2 channels, but not for mutated SK3 channels. Interestingly, the VA mutation reduced the sensitivity to TEA. In silico data confirmed these experimental results. Therefore, such mutations in the pore region of SK channels show that the three-dimensional structure of the SK tetramers can be disorganized in the outer pore region leading to reduced interaction of apamin with its target. [less ▲]

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See detailPhysiologie, pharmacologie et modélisation de canaux potassiques : zoom sur les canaux SK
Dilly, Sébastien ULg; Poncin, Sylvie; Lamy, Cédric et al

in Medecine Sciences : M/S (2012), 28

Various types of ion channels are involved in the control of neuronal activity. Among them, SK channels represent an interesting therapeutic target. Indeed, they underlie medium duration ... [more ▼]

Various types of ion channels are involved in the control of neuronal activity. Among them, SK channels represent an interesting therapeutic target. Indeed, they underlie medium duration afterhyperpolarizations in many types of neurons, thus inhibiting cell excitability. A thorough knowledge of the physiology of these channels and the discovery of non-peptidic selective modulators able to pass the blood-brain barrier are essential in view of developing future drugs for brain diseases such as those related to a dysfunction of dopaminergic and serotonergic systems. [less ▲]

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See detailInteractions of apamin with pore mutated SK3 channels
Dilly, Sébastien ULg; Lamy, Cédric; Poncin, Sylvie et al

Poster (2012, March 16)

In the present work, we have tested the impact of the replacement of valine residues in the pore region of SK3 (520) by either an alanine or a phenylalanine residue in terms of the interactions of apamin ... [more ▼]

In the present work, we have tested the impact of the replacement of valine residues in the pore region of SK3 (520) by either an alanine or a phenylalanine residue in terms of the interactions of apamin with these mutants in comparison with the corresponding native channels. Replacing valine residue at position 520 of the SK3 channel by a phenylalanine significantly increased the sensitivity of the channel to be blocked by tetraethylammonium (TEA) as previously reported. Indeed, an aromatic residue, such as a phenylalanine or a tyrosine, is frequently found in the pore region of several potassium channels more sensitive to TEA than SK channels. We measured the affinity (Kd) of apamin in saturation experiments and studied SK currents in transfected cells using patch clamp techniques. In parallel, molecular modelling techniques were used to examine the impact of these local modifications on the interaction of apamin with the corresponding channels. The presence of a phenylalanine in the pore region of potassium channels led to a higher sensitivity for TEA by creating more hydrophobic interactions as found by the docking procedure. In the in vitro binding experiments, the phenylalanine mutant (SK3VF) displayed a very low affinity for apamin. In patch clamp experiments, the SK current was only very partially blocked by apamin in the SK3VF mutant. Furthermore, apamin displayed an affinity and a blocking activity for the alanine mutant close to that for the corresponding native channels. In conclusion, the presence of a bulky and hydrophobic residue at a position near the pore mouth of SK3 channels has a negative impact on their interactions with apamin. [less ▲]

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