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Molecular Pharmacology

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Research ArticleArticle

Stoichiometry of Sulfonylurea-Induced ATP-Sensitive Potassium Channel Closure

Henrik Dörschner, Edelweiss; Brekardin, Ingo Uhde, Christina Schwanstecher and Mathias Schwanstecher
Molecular Pharmacology June 1999, 55 (6) 1060-1066; DOI: https://doi.org/10.1124/mol.55.6.1060
Henrik Dörschner
Institut für Pharmakologie und Toxikologie, Universität Braunschweig, Mendelssohnstraβe 1, 38106 Braunschweig, Germany
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Edelweiss; Brekardin
Institut für Pharmakologie und Toxikologie, Universität Braunschweig, Mendelssohnstraβe 1, 38106 Braunschweig, Germany
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Ingo Uhde
Institut für Pharmakologie und Toxikologie, Universität Braunschweig, Mendelssohnstraβe 1, 38106 Braunschweig, Germany
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Christina Schwanstecher
Institut für Pharmakologie und Toxikologie, Universität Braunschweig, Mendelssohnstraβe 1, 38106 Braunschweig, Germany
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Mathias Schwanstecher
Institut für Pharmakologie und Toxikologie, Universität Braunschweig, Mendelssohnstraβe 1, 38106 Braunschweig, Germany
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Abstract

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 β-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.

Footnotes

    • Received January 13, 1999.
    • Accepted March 24, 1999.
  • Send reprint requests to: Dr. M. Schwanstecher, Institut für Pharmakologie und Toxikologie, Universität Braunschweig, Mendelssohnstraβe 1, 38106 Braunschweig, Germany. E-mail: M.Schwanstecher{at}tu-bs.de

  • This work was supported by grants from the Deutsche Forschungsgemeinschaft (M.S. and C.S.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (6)
Molecular Pharmacology
Vol. 55, Issue 6
1 Jun 1999
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Research ArticleArticle

Stoichiometry of Sulfonylurea-Induced ATP-Sensitive Potassium Channel Closure

Henrik Dörschner, Edelweiss; Brekardin, Ingo Uhde, Christina Schwanstecher and Mathias Schwanstecher
Molecular Pharmacology June 1, 1999, 55 (6) 1060-1066; DOI: https://doi.org/10.1124/mol.55.6.1060

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Research ArticleArticle

Stoichiometry of Sulfonylurea-Induced ATP-Sensitive Potassium Channel Closure

Henrik Dörschner, Edelweiss; Brekardin, Ingo Uhde, Christina Schwanstecher and Mathias Schwanstecher
Molecular Pharmacology June 1, 1999, 55 (6) 1060-1066; DOI: https://doi.org/10.1124/mol.55.6.1060
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