PMID- 10526167
OWN - NLM
STAT- MEDLINE
DCOM- 19991122
LR  - 20190621
IS  - 0014-5793 (Print)
IS  - 0014-5793 (Linking)
VI  - 459
IP  - 3
DP  - 1999 Oct 15
TI  - The tolbutamide site of SUR1 and a mechanism for its functional coupling to 
      K(ATP) channel closure.
PG  - 367-76
AB  - Micromolar concentrations of tolbutamide will inhibit (SUR1/K(IR)6. 2)(4) 
      channels in pancreatic beta-cells, but not (SUR2A/K(IR)6.2)(4) channels in 
      cardiomyocytes. Inhibition does not require Mg(2+) or nucleotides and is enhanced 
      by intracellular nucleotides. Using chimeras between SUR1 and SUR2A, we show that 
      transmembrane domains 12-17 (TMD12-17) are required for high-affinity tolbutamide 
      inhibition of K(ATP) channels. Deletions demonstrate involvement of the 
      cytoplasmic N-terminus of K(IR)6.2 in coupling sulfonylurea-binding with SUR1 to 
      the stabilization of an interburst closed configuration of the channel. The 
      increased efficacy of tolbutamide by nucleotides results from an impairment of 
      their stimulatory action on SUR1 which unmasks their inhibitory effects. The 
      mechanism of inhibition of beta-cell K(ATP) channels by sulfonylureas during 
      treatment of non-insulin-dependent diabetes mellitus thus involves two 
      components, drug-binding and conformational changes within SUR1 which are coupled 
      to the pore subunit through its N-terminus and the disruption of 
      nucleotide-dependent stimulatory effects of the regulatory subunit on the pore. 
      These findings uncover a molecular basis for an inhibitory influence of SUR1, an 
      ATP-binding cassette (ABC) protein, on K(IR)6.2, a ion channel subunit.
FAU - Babenko, A P
AU  - Babenko AP
AD  - Department of Molecular and Cellular Biology, Baylor College of Medicine, 
      Houston, TX 77030, USA. ababenko@bcm.tmc.edu
FAU - Gonzalez, G
AU  - Gonzalez G
FAU - Bryan, J
AU  - Bryan J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - FEBS Lett
JT  - FEBS letters
JID - 0155157
RN  - 0 (ABCC8 protein, human)
RN  - 0 (ABCC9 protein, human)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Nucleotides)
RN  - 0 (Potassium Channel Blockers)
RN  - 0 (Potassium Channels)
RN  - 0 (Potassium Channels, Inwardly Rectifying)
RN  - 0 (Receptors, Drug)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Sulfonylurea Compounds)
RN  - 0 (Sulfonylurea Receptors)
RN  - 982XCM1FOI (Tolbutamide)
SB  - IM
MH  - *ATP-Binding Cassette Transporters
MH  - Animals
MH  - COS Cells
MH  - Humans
MH  - Hypoglycemic Agents/pharmacology
MH  - Nucleotides/metabolism
MH  - Potassium Channel Blockers
MH  - Potassium Channels/genetics/*metabolism
MH  - *Potassium Channels, Inwardly Rectifying
MH  - Receptors, Drug/antagonists & inhibitors/genetics/*metabolism
MH  - Recombinant Fusion Proteins/metabolism
MH  - Sulfonylurea Compounds/metabolism
MH  - Sulfonylurea Receptors
MH  - Tolbutamide/*pharmacology
EDAT- 1999/10/20 00:00
MHDA- 1999/10/20 00:01
CRDT- 1999/10/20 00:00
PHST- 1999/10/20 00:00 [pubmed]
PHST- 1999/10/20 00:01 [medline]
PHST- 1999/10/20 00:00 [entrez]
AID - S0014-5793(99)01215-6 [pii]
AID - 10.1016/s0014-5793(99)01215-6 [doi]
PST - ppublish
SO  - FEBS Lett. 1999 Oct 15;459(3):367-76. doi: 10.1016/s0014-5793(99)01215-6.