PMID- 10347249
OWN - NLM
STAT- MEDLINE
DCOM- 19990617
LR  - 20190607
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 55
IP  - 6
DP  - 1999 Jun
TI  - Stoichiometry of sulfonylurea-induced ATP-sensitive potassium channel closure.
PG  - 1060-6
AB  - Hypoglycemic sulfonylureas (e.g., glibenclamide, glipizide, and tolbutamide)
      exert their stimulatory effect on excitatory cells by closure of ATP-sensitive
      potassium (KATP) channels. These channels are heteromultimers composed with a 4:4
      stoichiometry of an inwardly rectifying K+ channel (KIR) subunit 6.x plus a
      sulfonylurea receptor (SUR). SUR1/KIR6.2 reconstitutes the neuronal/pancreatic
      beta-cell channel, whereas SUR2A/KIR6.2 and SUR2B/KIR6.1 (or KIR6.2) are proposed
      to reconstitute the cardiac and the vascular smooth muscle-type KATP channels,
      respectively. SUR2A and SUR2B are splice variants of a single gene differing only
      in their C-terminal 42 amino acids. Affinities of sulfonylureas for rat SUR2A,
      rat or human SUR2B, and a SUR2 chimera containing the C-terminal 42 amino acids
      of SUR1 did not differ significantly, implying that the C terminus does not form 
      part of the binding pocket. Consistent with these findings, reconstituted
      SUR2A/KIR6.2 and SUR2B/KIR6.2 channels revealed similar sensitivities for
      glibenclamide and tolbutamide. Dissociation constants of sulfonylureas for SUR2A 
      and SUR2B were 10- to 400-fold higher than for SUR1, however, amazingly the
      benzoic acid derivative meglitinide did not show lower affinity for SUR2
      isoforms. Potencies of glibenclamide, glipizide, tolbutamide, and meglitinide to 
      inhibit activity of SUR1/KIR6.2 and SUR2B/KIR6.2 channels were 3- to 6-fold
      higher than binding affinities of these drugs with concentration-inhibition
      relations being significantly steeper (Hill coefficients 1.23-1.32) than binding 
      curves (Hill coefficients 0.93-1.06). The data establish that the C terminus of
      SURs does not affect sulfonylurea affinity and sensitivity. We conclude that
      occupation of one of the four SUR sites per channel complex is sufficient to
      induce KATP channel closure.
FAU - Dorschner, H
AU  - Dorschner H
AD  - Institut fur Pharmakologie und Toxikologie, Universitat Braunschweig,
      Mendelssohnstrabetae 1, 38106 Braunschweig, Germany.
FAU - Brekardin, E
AU  - Brekardin E
FAU - Uhde, I
AU  - Uhde I
FAU - Schwanstecher, C
AU  - Schwanstecher C
FAU - Schwanstecher, M
AU  - Schwanstecher M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (ABCC8 protein, human)
RN  - 0 (ABCC9 protein, human)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Abcc8 protein, rat)
RN  - 0 (Abcc9 protein, rat)
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)
SB  - IM
MH  - *ATP-Binding Cassette Transporters
MH  - Animals
MH  - Binding, Competitive
MH  - COS Cells
MH  - Cricetinae
MH  - Dose-Response Relationship, Drug
MH  - Electrophysiology
MH  - Humans
MH  - *Potassium Channel Blockers
MH  - Potassium Channels/metabolism/physiology
MH  - *Potassium Channels, Inwardly Rectifying
MH  - Rats
MH  - Receptors, Drug/*antagonists & inhibitors/metabolism
MH  - Recombinant Fusion Proteins/antagonists & inhibitors/metabolism/physiology
MH  - Stereoisomerism
MH  - Sulfonylurea Compounds/*pharmacology
MH  - Sulfonylurea Receptors
EDAT- 1999/05/29 00:00
MHDA- 1999/05/29 00:01
CRDT- 1999/05/29 00:00
PHST- 1999/05/29 00:00 [pubmed]
PHST- 1999/05/29 00:01 [medline]
PHST- 1999/05/29 00:00 [entrez]
AID - 10.1124/mol.55.6.1060 [doi]
PST - ppublish
SO  - Mol Pharmacol. 1999 Jun;55(6):1060-6. doi: 10.1124/mol.55.6.1060.