Alternative splicing switches potassium channel sensitivity to protein phosphorylation

Lijun Tian, Rory Duncan, Martin S. L. Hammond, Lorraine S. Coghill, Hua Wen, Radda Rusinova, Alan G. Clark, Irwin B. Levitan, Michael J. Shipston

Research output: Contribution to journalArticle

173 Citations (Scopus)

Abstract

Alternative exon splicing and reversible protein phosphorylation of large conductance calcium-activated potassium (BK) channels represent fundamental control mechanisms for the regulation of cellular excitability. BK channels are encoded by a single gene that undergoes extensive, hormonally regulated exon splicing. In native tissues BK channels display considerable diversity and plasticity in their regulation by cAMP-dependent protein kinase (PKA). Differential regulation of alternatively spliced BK channels by PKA may provide a molecular basis for the diversity and plasticity of BK channel sensitivities to PKA. Here we demonstrate that PKA activates BK channels lacking splice inserts (ZERO) but inhibits channels expressing a 59-amino acid exon at splice site 2 (STREX-1). Channel activation is dependent upon a conserved C-terminal PKA consensus motif (S869), whereas inhibition is mediated via a STREX-1 exon-specific PKA consensus site. Thus, alternative splicing acts as a molecular switch to determine the sensitivity of potassium channels to protein phosphorylation.

Original languageEnglish
Pages (from-to)7717-7720
Number of pages4
JournalJournal of Biological Chemistry
Volume276
Issue number11
DOIs
Publication statusPublished - 16 Mar 2001

Keywords

  • Alternative Splicing
  • Animals
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Exons
  • Mice
  • Phosphorylation
  • Potassium Channels
  • Proteins
  • Structure-Activity Relationship

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    Tian, L., Duncan, R., Hammond, M. S. L., Coghill, L. S., Wen, H., Rusinova, R., Clark, A. G., Levitan, I. B., & Shipston, M. J. (2001). Alternative splicing switches potassium channel sensitivity to protein phosphorylation. Journal of Biological Chemistry, 276(11), 7717-7720. https://doi.org/10.1074/jbc.C000741200