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

McCartney, C. E., McClafferty, H., Huibant, J.-M., Rowan, E. G., Shipston, M. J. and Rowe, I. C.M. (2005) A cysteine-rich motif confers hypoxia sensitivity to mammalian large conductance voltage- and Ca-activated K (BK) channel α-subunits. Proceedings of the National Academy of Sciences of the United States of America, 102(49), pp. 17870-17875. (doi: 10.1073/pnas.0505270102) (PMID:16306267) (PMCID:PMC1308893)

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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 α-subunits provides a powerful mechanism for generating functional diversity. Here, we demonstrate that the hypoxia sensitivity of BK channel α-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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rowe, Dr Iain
Authors: McCartney, C. E., McClafferty, H., Huibant, J.-M., Rowan, E. G., Shipston, M. J., and Rowe, I. C.M.
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:23 November 2005

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