ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 and Kir6.2 with diminished PIP 2 sensitivity

Emily B. Pratt, Show-Ling Shyng

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

ATP-sensitive potassium (K ATP) channels are inhibited by ATP and activated by phosphatidylinositol-4,5-bisphosphate (PIP 2). Both channel subunits Kir6.2 and sulfonylurea receptor 1 (SUR1) contribute to gating: while Kir6.2 interacts with ATP and PIP 2, SUR1 enhances sensitivity to both ligands. Recently, we showed that a mutation, E128K, in the N-terminal transmembrane domain of SUR1 disrupts functional coupling between SUR1 and Kir6.2, leading to reduced ATP and PIP 2 sensitivities resembling channels formed by Kir6.2 alone. We show here that when E128K SUR1 was coexpressed with Kir6.2 mutants known to disrupt PIP 2 gating, the resulting channels were surprisingly stimulated rather than inhibited by ATP. To explain this paradoxical gating behavior, we propose a model in which the open state of doubly mutant channels is highly unstable; ATP binding induces a conformational change in ATP-unbound closed channels that is conducive to brief opening when ATP unbinds, giving rise to the appearance of ATP-induced stimulation.

Original languageEnglish (US)
JournalChannels
Volume5
Issue number4
StatePublished - Jul 2011

Fingerprint

Sulfonylurea Receptors
KATP Channels
Adenosine Triphosphate
Phosphatidylinositols
Potassium
Ligands

Keywords

  • ATP
  • Gating
  • K channel
  • Kir6.2
  • PIP
  • Sulfonylurea receptor 1

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

Cite this

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abstract = "ATP-sensitive potassium (K ATP) channels are inhibited by ATP and activated by phosphatidylinositol-4,5-bisphosphate (PIP 2). Both channel subunits Kir6.2 and sulfonylurea receptor 1 (SUR1) contribute to gating: while Kir6.2 interacts with ATP and PIP 2, SUR1 enhances sensitivity to both ligands. Recently, we showed that a mutation, E128K, in the N-terminal transmembrane domain of SUR1 disrupts functional coupling between SUR1 and Kir6.2, leading to reduced ATP and PIP 2 sensitivities resembling channels formed by Kir6.2 alone. We show here that when E128K SUR1 was coexpressed with Kir6.2 mutants known to disrupt PIP 2 gating, the resulting channels were surprisingly stimulated rather than inhibited by ATP. To explain this paradoxical gating behavior, we propose a model in which the open state of doubly mutant channels is highly unstable; ATP binding induces a conformational change in ATP-unbound closed channels that is conducive to brief opening when ATP unbinds, giving rise to the appearance of ATP-induced stimulation.",
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T1 - ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 and Kir6.2 with diminished PIP 2 sensitivity

AU - Pratt, Emily B.

AU - Shyng, Show-Ling

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N2 - ATP-sensitive potassium (K ATP) channels are inhibited by ATP and activated by phosphatidylinositol-4,5-bisphosphate (PIP 2). Both channel subunits Kir6.2 and sulfonylurea receptor 1 (SUR1) contribute to gating: while Kir6.2 interacts with ATP and PIP 2, SUR1 enhances sensitivity to both ligands. Recently, we showed that a mutation, E128K, in the N-terminal transmembrane domain of SUR1 disrupts functional coupling between SUR1 and Kir6.2, leading to reduced ATP and PIP 2 sensitivities resembling channels formed by Kir6.2 alone. We show here that when E128K SUR1 was coexpressed with Kir6.2 mutants known to disrupt PIP 2 gating, the resulting channels were surprisingly stimulated rather than inhibited by ATP. To explain this paradoxical gating behavior, we propose a model in which the open state of doubly mutant channels is highly unstable; ATP binding induces a conformational change in ATP-unbound closed channels that is conducive to brief opening when ATP unbinds, giving rise to the appearance of ATP-induced stimulation.

AB - ATP-sensitive potassium (K ATP) channels are inhibited by ATP and activated by phosphatidylinositol-4,5-bisphosphate (PIP 2). Both channel subunits Kir6.2 and sulfonylurea receptor 1 (SUR1) contribute to gating: while Kir6.2 interacts with ATP and PIP 2, SUR1 enhances sensitivity to both ligands. Recently, we showed that a mutation, E128K, in the N-terminal transmembrane domain of SUR1 disrupts functional coupling between SUR1 and Kir6.2, leading to reduced ATP and PIP 2 sensitivities resembling channels formed by Kir6.2 alone. We show here that when E128K SUR1 was coexpressed with Kir6.2 mutants known to disrupt PIP 2 gating, the resulting channels were surprisingly stimulated rather than inhibited by ATP. To explain this paradoxical gating behavior, we propose a model in which the open state of doubly mutant channels is highly unstable; ATP binding induces a conformational change in ATP-unbound closed channels that is conducive to brief opening when ATP unbinds, giving rise to the appearance of ATP-induced stimulation.

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KW - PIP

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