Reference : The interactions of apamin and tetraethylammonium are differentially affected by sing...
Scientific journals : Article
Engineering, computing & technology : Computer science
Human health sciences : Pharmacy, pharmacology & toxicology
http://hdl.handle.net/2268/137829
The interactions of apamin and tetraethylammonium are differentially affected by single mutations in the pore mouth of small conductance calcium-activated potassium (SK) channels
English
Dilly, Sébastien mailto [Université de Liège - ULiège > GIGA-Neurosciences/C.I.R.M > Pharmacologie/Chimie Pharmaceutique > >]
Philippart, Fabian mailto [Université de Liège - ULiège > GIGA-Neurosciences > Pharmacologie > >]
Lamy, Cédric mailto [Université de Liège - ULiège > GIGA-Neurosciences > Pharmacologie > >]
Poncin, Sylvie mailto [Université de Liège - ULiège > GIGA-Neurosciences > Pharmacologie > >]
Snyders, Dirk mailto [University of Antwerp > Department of Biomedical Sciences > Laboratory for Molecular Biophysics > >]
Seutin, Vincent mailto [Université de Liège - ULiège > GIGA-Neurosciences > Pharmacologie > >]
Liégeois, Jean-François mailto [Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique >]
2013
Biochemical Pharmacology
Elsevier Science
85
560-569
Yes (verified by ORBi)
International
0006-2952
Oxford
United Kingdom
[en] Small conductance calcium-activated ; potassium channel ; Apamin ; TEA ; Single mutation ; Site-directed mutagenesis ; Docking
[en] 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.
Giga-Neurosciences / C.I.R.M.
Belgian Science Policy (IAP 6/31 to D.S. and V.S.) ; F.R.S-FNRS (grant No. 9.4560.03 to V.S. and J.-F-L.) ; Walloon Region and UCB (SPW DGO6 PPP NEUREDGE convention 816859)
Researchers ; Professionals ; Students
http://hdl.handle.net/2268/137829
10.1016/j.bcp.2012.12.015

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