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Vol. 55, Issue 5, 832-840, May 1999
Department of Pharmacology, University of Tübingen,
Tübingen, Germany (A.H., C.L-W., D.K., U.D., U.Q.); and
Department of Pharmacology II, Faculty of Medicine, Osaka University,
Osaka, Japan (Y.H., Y.K.)
KATP channels are heteromeric complexes of inwardly
rectifying K+ channel subunits and sulfonylurea receptors
(SURs). SUR2A and SUR2B, which differ within the carboxyl
terminal exon 38, are characteristic for the cardiac and smooth muscle
type channels, respectively. Here we compare binding of the tritiated
KATP channel opener, [3H]P1075, to membranes
from human embryonic kidney (HEK) cells transfected with murine SUR2A
and 2B at 37°C. Binding to both SURs required addition of
Mg2+ and ATP in the low micromolar range. In the presence
of MgATP, micromolar concentrations of MgADP, formed by the ATPase
activity of the membrane preparation, increased binding to SUR2A but
inhibited binding to SUR2B. Decreasing temperatures strongly reduced
[3H]P1075 binding to SUR2A, whereas binding to SUR2B was
increased in a bell-shaped manner. Kinetic experiments revealed a
faster dissociation of the [3H]P1075-SUR2A complex,
whereas the association rate constants for [3H]P1075
binding to SUR2A and 2B were similar. Openers inhibited [3H]P1075 binding to SUR2A with potencies 
4 times
lower than to SUR2B; in contrast, glibenclamide inhibited
[3H]P1075 binding to SUR2A 8 times more potently than
to SUR2B. The data suggest that SUR2A and 2B represent the opener
receptors of cardiac and vascular smooth muscle KATP
channels, respectively, and show that MgADP is an important modulator
of opener binding to SUR. The different carboxyl termini of SUR2A and
2B lead to differences in the MgADP dependence and the thermodynamics
of [3H]P1075 binding, as well as in the affinities for
openers and glibenclamide, underlining the importance of this part of
the molecule for KATP channel modulator binding.
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