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J Biol Chem, Vol. 275, Issue 2, 717-720, January 14, 2000
From the Department of Molecular and Cellular Biology, Baylor
College of Medicine, Houston, Texas 77030
The differential responsiveness of
(SUR1/KIR6.2)4 pancreatic
ACCELERATED PUBLICATION
Pharmaco-topology of Sulfonylurea Receptors
SEPARATE DOMAINS OF THE REGULATORY SUBUNITS OF
KATP CHANNEL ISOFORMS ARE REQUIRED FOR SELECTIVE
INTERACTION WITH K+ CHANNEL OPENERS*
,
-cell
versus (SUR2A/KIR6.2)4 sarcolemmal
or (SUR2B/KIR6.0)4 smooth muscle cell
KATP channels to K+ channel openers
(KCOs) is the basis for the selective prevention of hyperinsulinemia,
myocardial infarction, and acute hypertension. KCO-stimulation of
KATP channels is a unique example of functional coupling between a transport ATPase and a K+ inward
rectifier. KCO binding to SUR is Mg-ATP-dependent and antagonizes the inhibition of (KIR6.0)4 pore
opening by nucleotides. Patch-clamping of matched chimeric human
SUR1-SUR2A/KIR6.2 channels was used to identify the SUR
regions that specify the selective response of sarcolemmal
versus -cell channels to cromakalim or pinacidil
versus diazoxide. The SUR2 segment containing the 12th through 17th predicted transmembrane domains, TMD12-17, confers sensitivity to the benzopyran, cromakalim, and the pyridine, pinacidil, whereas an SUR1 segment which includes TMD6-11 and the first
nucleotide-binding fold, NBF1, controls responsiveness to the
benzothiadiazine, diazoxide. These data are incorporated into a
functional topology model for the regulatory SUR subunits of
KATP channels.
*
The work was supported by grants from Juvenile Diabetes
Foundation International and American Heart Association (to A. P. B.)
and by National Institutes of Health grants (to J. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Tel.: 713-798-4996;
Fax: 713-790-0545; E-mail: ababenko@bcm.tmc.edu.
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