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(Received for publication, March 19, 1996, and in revised form, May 24, 1996)
From the Department of Physiology, McGill University,
Montréal, Québec, H3G 1Y6, Canada
Plasma membrane Na+/H+
exchanger (NHE) isoforms NHE1 and NHE3 exhibit very different
sensitivities to amiloride and its 5-amino-substituted analogues,
benzoyl guanidinium derivatives (e.g.
(3-methylsulfonyl-4-piperidinobenzoyl)guanidine methanesulfonate
(HOE694)), and cimetidine. To define structural domains that confer
differential sensitivity to these antagonists, unique restriction
endonuclease sites were engineered into cDNAs for each isoform near
the regions that encode the putative membrane-spanning domains. These
new sites did not modify their pharmacological properties and allowed
several chimeric Na+/H+ exchangers to be
constructed by exchanging homologous segments. The modified parental
(E1
Volume 271, Number 33,
Issue of August 16, 1996
pp. 19922-19927
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
and E3) and chimeric molecules were stably expressed in
exchanger-deficient Chinese hamster ovary AP-1 cells and assayed for
their sensitivities to amiloride, ethylisopropylamiloride, HOE694, and
cimetidine. Most chimeras showed drug sensitivities corresponding to
the dominant parental segment. However, interchanging a 66-amino acid
segment containing the putative ninth transmembrane (M9) domain and its
adjacent loops caused reciprocal alterations in the sensitivities of
E1 and E3 to all antagonists. In addition, substituting the first
five putative membrane-spanning domains of E3 with the corresponding
region of E1 modestly reduced the transporter's sensitivity to
cimetidine but not the other compounds. These data indicate that the
protein segment between M8 and M10 may be a major site of interaction
with these antagonists, although other regions modestly influence
sensitivity to certain drugs.
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