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Papers In Press, published online ahead of print March 21, 2006
Physiology; section Cell Physiology, Radboud Univ. Nijmegen Med. Center, Nijmegen 6500 HB
Corresponding Author: p.deen{at}ncmls.ru.nl
Excessive water uptake through Aquaporins (AQP) can be life-threatening and reversible AQP inhibitors are needed. Here, we determined the specificity, potency and binding site of tetra-ethyl ammonium (TEA) to block Aquaporin water permeability. Using oocytes, externally-applied TEA blocked AQP1/AQP2/AQP4 maximally 50% with Inhibitory-Concentration-50 values of 1.4, 6.2 and 9.8 M, respectively. Related tetra ammonium compounds yielded some (propyl) or no (methyl, butyl, pentyl) inhibition. TEA inhibition was lost upon a Tyr-to-Phe amino acid switch in the external water-pore of AQP1/AQP2/AQP4, while the water permeability of AQP3 and AQP5, which lack a corresponding Tyr, was not blocked by TEA. Consistent with experimental data, multi-nanosecond molecular dynamics simulations showed one stable binding site for TEA, but not TMA, in AQP1, resulting in a nearly 50% water permeability inhibition, which was reduced in AQP1-Y186F due to effects on the TEA inhibitory binding region. Moreover, in the simulation TEA interacted with charged residues in the C- [D128] and E- [D185] loop, and the A-[Y37, N42, T44] loop of the neighboring monomer, but not directly with Y186. The loss of TEA inhibition in oocytes expressing properly-folded AQP1-N42A or -T44A is in line with the computationally predicted binding mode. Our data reveal that the molecular interaction of TEA with AQP1 differs and is about 1000-fold more effective on AQPs than on potassium channels. Moreover, the observed experimental and simulated similarities open the way for rational design and virtual screening for AQP-specific inhibitors, with quaternary ammonium compounds in general, and TEA in particular as a lead compound.
J. Biol. Chem, 10.1074/jbc.M513072200
Submitted on December 7, 2005
Accepted on March 21, 2006
Quaternary ammonium compounds as water channel blockers: Specificity, potency and site of action
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