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Vol. 60, Issue 1, 190-199, July 2001
Department of Pharmacology, University of Tübingen,
Tübingen, Germany
ATP-dependent K+ channels are composed of pore-forming
subunits of the Kir6.x family and of sulfonylurea
receptors (SURs). SUR1, expressed in pancreatic 
-cells, has a higher
affinity for sulfonylureas, such as glibenclamide, than SUR2B,
expressed in smooth muscle. This difference is mainly caused by serine
1237 in SUR1 corresponding to tyrosine 1206 in SUR2B. To increase the affinity of SUR2B for glibenclamide, the mutant SUR2B(Y1206S) was
constructed. In whole-cell patch-clamp experiments, glibenclamide inhibited the channel formed by coexpression of mutant SUR2B with Kir6.1 or 6.2 in human embryonic kidney cells with IC50
values of 2.7 and 13 nM, respectively (wild-type, 43 and 167 nM). In intact cells, [3H]glibenclamide bound to mutant SUR2B
with a KD value of 4.7 nM (wild-type, 32 nM); coexpression with Kir6.1 or 6.2 increased affinity by 4- and
8-fold, respectively. Binding of the opener [3H]P1075 to
SUR2B(Y1206S) was the same as to wild-type and was unaffected by
coexpression. In cells, the ratio of glibenclamide:P1075 sites was 
1:1; in membranes, it varied with the MgATP concentration. Heterologous competition curves were generally biphasic; the shape of
the curve depended on the Kir-subtype. The effects of coexpression were
weakened or abolished when binding assays were conducted in membranes.
It is concluded that the mutation Y1206S increases the affinity of
SUR2B for and the channel sensitivity toward glibenclamide by 7- to
15-fold. The interaction of glibenclamide (but not opener) with mutant
SUR2B is modified by coexpression with Kir6.x in a manner depending on the Kir subtype and on the integrity of the cell.
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