A cysteine-rich motif confers hypoxia sensitivity to mammalian large conductance voltage- and Ca-activated K (BK) channel alpha-subunits

Claire E. McCartney, Heather McClafferty, Jean-Marc Huibant, Edward.G. Rowan, Michael J. Shipston, Iain C.M. Rowe

Research output: Contribution to journalArticle

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Abstract

Cellular responses to hypoxia are tissue-specific and dynamic. However, the mechanisms that underlie this differential sensitivity to hypoxia are unknown. Large conductance voltage- and Ca-activated K (BK) channels are important mediators of hypoxia responses in many systems. Although BK channels are ubiquitously expressed, alternative pre-mRNA splicing of the single gene encoding their pore-forming alpha-subunits provides a powerful mechanism for generating functional diversity. Here, we demonstrate that the hypoxia sensitivity of BK channel alpha-subunits is splice-variant-specific. Sensitivity to hypoxia is conferred by a highly conserved motif within an alternatively spliced cysteine-rich insert, the stress-regulated exon (STREX), within the intracellular C terminus of the channel. Hypoxic inhibition of the STREX variant is Ca-sensitive and reversible, and it rapidly follows the change in oxygen tension by means of a mechanism that is independent of redox or CO regulation. Hypoxia sensitivity was abolished by mutation of the serine (S24) residue within the STREX insert. Because STREX splice-variant expression is tissue-specific and dynamically controlled, alternative splicing of BK channels provides a mechanism to control the plasticity of cellular responses to hypoxia.
Original languageEnglish
Pages (from-to)17870-17876
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume102
Issue number49
DOIs
Publication statusPublished - 2005

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Large-Conductance Calcium-Activated Potassium Channels
Cysteine
Exons
RNA Precursors
Alternative Splicing
Carbon Monoxide
Hypoxia
Serine
Oxidation-Reduction
Oxygen
Mutation

Keywords

  • alternative splicing
  • oxygen sensing
  • pharmacology
  • hypoxia

Cite this

McCartney, Claire E. ; McClafferty, Heather ; Huibant, Jean-Marc ; Rowan, Edward.G. ; Shipston, Michael J. ; Rowe, Iain C.M. / A cysteine-rich motif confers hypoxia sensitivity to mammalian large conductance voltage- and Ca-activated K (BK) channel alpha-subunits. In: Proceedings of the National Academy of Sciences . 2005 ; Vol. 102, No. 49. pp. 17870-17876.
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A cysteine-rich motif confers hypoxia sensitivity to mammalian large conductance voltage- and Ca-activated K (BK) channel alpha-subunits. / McCartney, Claire E.; McClafferty, Heather; Huibant, Jean-Marc; Rowan, Edward.G.; Shipston, Michael J.; Rowe, Iain C.M.

In: Proceedings of the National Academy of Sciences , Vol. 102, No. 49, 2005, p. 17870-17876.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A cysteine-rich motif confers hypoxia sensitivity to mammalian large conductance voltage- and Ca-activated K (BK) channel alpha-subunits

AU - McCartney, Claire E.

AU - McClafferty, Heather

AU - Huibant, Jean-Marc

AU - Rowan, Edward.G.

AU - Shipston, Michael J.

AU - Rowe, Iain C.M.

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N2 - Cellular responses to hypoxia are tissue-specific and dynamic. However, the mechanisms that underlie this differential sensitivity to hypoxia are unknown. Large conductance voltage- and Ca-activated K (BK) channels are important mediators of hypoxia responses in many systems. Although BK channels are ubiquitously expressed, alternative pre-mRNA splicing of the single gene encoding their pore-forming alpha-subunits provides a powerful mechanism for generating functional diversity. Here, we demonstrate that the hypoxia sensitivity of BK channel alpha-subunits is splice-variant-specific. Sensitivity to hypoxia is conferred by a highly conserved motif within an alternatively spliced cysteine-rich insert, the stress-regulated exon (STREX), within the intracellular C terminus of the channel. Hypoxic inhibition of the STREX variant is Ca-sensitive and reversible, and it rapidly follows the change in oxygen tension by means of a mechanism that is independent of redox or CO regulation. Hypoxia sensitivity was abolished by mutation of the serine (S24) residue within the STREX insert. Because STREX splice-variant expression is tissue-specific and dynamically controlled, alternative splicing of BK channels provides a mechanism to control the plasticity of cellular responses to hypoxia.

AB - Cellular responses to hypoxia are tissue-specific and dynamic. However, the mechanisms that underlie this differential sensitivity to hypoxia are unknown. Large conductance voltage- and Ca-activated K (BK) channels are important mediators of hypoxia responses in many systems. Although BK channels are ubiquitously expressed, alternative pre-mRNA splicing of the single gene encoding their pore-forming alpha-subunits provides a powerful mechanism for generating functional diversity. Here, we demonstrate that the hypoxia sensitivity of BK channel alpha-subunits is splice-variant-specific. Sensitivity to hypoxia is conferred by a highly conserved motif within an alternatively spliced cysteine-rich insert, the stress-regulated exon (STREX), within the intracellular C terminus of the channel. Hypoxic inhibition of the STREX variant is Ca-sensitive and reversible, and it rapidly follows the change in oxygen tension by means of a mechanism that is independent of redox or CO regulation. Hypoxia sensitivity was abolished by mutation of the serine (S24) residue within the STREX insert. Because STREX splice-variant expression is tissue-specific and dynamically controlled, alternative splicing of BK channels provides a mechanism to control the plasticity of cellular responses to hypoxia.

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