PMID- 10342826
OWN - NLM
STAT- MEDLINE
DCOM- 19990608
LR  - 20190515
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 48
IP  - 6
DP  - 1999 Jun
TI  - Identification of the high-affinity tolbutamide site on the SUR1 subunit of the 
      K(ATP) channel.
PG  - 1341-7
AB  - ATP-sensitive potassium channels (K(ATP)) are formed from four pore-forming 
      Kir6.2 subunits complexed with four regulatory sulfonylurea receptor subunits 
      (SUR1 in pancreatic beta-cells, SUR2A in heart). The sensitivity of the channel 
      to different sulfonylureas depends on the SUR isoform. In particular, Kir6.2-SUR1 
      but not Kir6.2-SUR2A channels are blocked by tolbutamide with high affinity. We 
      made chimeras between SUR1 and SUR2A to identify the region of the protein 
      involved in high-affinity tolbutamide block. Chimeric SURs were coexpressed with 
      Kir6.2 in Xenopus oocytes, and macroscopic currents were measured in inside-out 
      membrane patches. High-affinity tolbutamide inhibition could be conferred on 
      SUR2A by replacing transmembrane domains (TMs) 14-16 with the corresponding 
      region of SUR1. Conversely, high-affinity tolbutamide inhibition of SUR1 was 
      abolished by replacing TMs 13-16 with the corresponding SUR2A sequence, or by 
      mutating a single serine residue within this region to tyrosine (S1237Y). Binding 
      of [3H]glibenclamide to membranes expressing SUR1 was abolished concomitantly 
      with the loss of high-affinity tolbutamide block. These results suggest that a 
      site in the COOH-terminal set of TMs of the SUR1 subunit of the K(ATP) channel is 
      involved in the binding of tolbutamide and glibenclamide.
FAU - Ashfield, R
AU  - Ashfield R
AD  - Nuffield Department of Clinical Biochemistry, John Radcliffe Hospital, Oxford, 
      UK.
FAU - Gribble, F M
AU  - Gribble FM
FAU - Ashcroft, S J
AU  - Ashcroft SJ
FAU - Ashcroft, F M
AU  - Ashcroft FM
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Abcc8 protein, rat)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Potassium Channels)
RN  - 0 (Potassium Channels, Inwardly Rectifying)
RN  - 0 (Receptors, Drug)
RN  - 0 (Sulfonylurea Compounds)
RN  - 0 (Sulfonylurea Receptors)
RN  - 61D2G4IYVH (Adenosine Diphosphate)
RN  - 982XCM1FOI (Tolbutamide)
RN  - SX6K58TVWC (Glyburide)
SB  - IM
MH  - *ATP-Binding Cassette Transporters
MH  - Adenosine Diphosphate/metabolism
MH  - Amino Acid Substitution
MH  - Animals
MH  - Binding Sites
MH  - COS Cells
MH  - Glyburide/metabolism
MH  - Hypoglycemic Agents/*metabolism
MH  - Potassium Channels/genetics/*metabolism
MH  - *Potassium Channels, Inwardly Rectifying
MH  - Rats
MH  - Receptors, Drug/genetics/*metabolism
MH  - Sulfonylurea Compounds/*metabolism
MH  - Sulfonylurea Receptors
MH  - Tolbutamide/*metabolism
MH  - Transfection
MH  - Xenopus
EDAT- 1999/05/26 00:00
MHDA- 1999/05/26 00:01
CRDT- 1999/05/26 00:00
PHST- 1999/05/26 00:00 [pubmed]
PHST- 1999/05/26 00:01 [medline]
PHST- 1999/05/26 00:00 [entrez]
AID - 10.2337/diabetes.48.6.1341 [doi]
PST - ppublish
SO  - Diabetes. 1999 Jun;48(6):1341-7. doi: 10.2337/diabetes.48.6.1341.