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Vol. 59, Issue 3, 524-531, March 2001
Department of Molecular Physiology, National Cardiovascular Center
Research Institute, Osaka, Japan (T.I., S.K., Y.I., Y.T., M.S.); and
Department of Physiology, School of Medicine, Fukuoka University,
Fukuoka, Japan (A.U., I.I.)
KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea
methanesulfonate) is a potent and selective
Na+/Ca2+ exchange (NCX) inhibitor that is
3-fold more inhibitory to NCX3 than to NCX1 or NCX2. Here we searched
for amino acid residues that may form the KB-R7943 receptor in the
exchanger by analyzing the function of chimeras between NCX1 and NCX3
as well as of their site-directed mutants. We found that the highly
conserved 
-2 repeat of the exchanger is almost exclusively
responsible for the difference in drug response of the isoforms. Such
difference was mostly reproduced by single substitutions of residues in
the -2 repeat (V820G or Q826V in NCX1 and A809V or A809I in NCX3), suggesting their importance in drug sensitivity. Cysteine scanning mutagenesis of the -2 repeat of NCX1 identified one residue (Gly833) that caused a large (
30-fold) reduction in drug sensitivity. We
found that the Gly-to-Thr substitution caused even larger reduction in
drug sensitivity. Interestingly, extracellularly applied KB-R7943 at
0.8 µM markedly inhibited the whole-cell outward exchange current, whereas the drug applied intracellularly at 30 µM did not. These results suggest that KB-R7943 inhibits the exchanger from the external
side in intact cells and that a region of the -2 repeat of NCX1
containing Gly833 may participate in the formation of the drug
receptor. Because we suggested previously that Gly833 is accessible
from the inside of a cell, the results raised an interesting
possibility that this residue may alter its position during
Na+/Ca2+ exchange in such a way that it becomes
accessible to external drug.
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