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J Physiol Volume 537, Number 1, 57-68, November 15, 2001
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Journal of Physiology (2001), 537.1, pp. 57-68
© Copyright 2001 The Physiological Society

Alternative splicing determines sensitivity of murine calcium-activated potassium channels to glucocorticoids


Lijun Tian, Martin S. L. Hammond, Hannah Florance, Ferenc A. Antoni * and Michael J. Shipston


Membrane Biology Group and MRC 'Membrane and Adapter Protein' COOP, Section of Biomedical Sciences, University of Edinburgh Medical School, Hugh Robson Building, Edinburgh EH8 9XD and * Department of Neuroscience, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK

  1. Large-conductance Ca2+- and voltage-activated potassium (BK) channels are important regulators of cellular excitability. Here, we present a patch-clamp electrophysiological analysis of splice-variant-specific regulation by the synthetic glucocorticoid dexamethasone (DEX) of BK channels consisting of cloned STREX or ZERO alpha-subunit variants expressed in human embryonic kidney (HEK 293) cells.
  2. STREX channels in isolated membrane patches were inhibited by protein kinase A (PKA) and this was blocked on pre-treatment of intact cells with DEX (100 nM) for 2 h.
  3. The effect of DEX required the synthesis of new mRNA and protein. Furthermore, it required protein phosphatase 2A (PP2A)-like activity intimately associated with the channels, as it was blocked by 10 nM okadaic acid but not by the specific protein phosphatase-1 inhibitor peptide PPI-2.
  4. ZERO variant channels that lack the STREX insert were activated by PKA but were not influenced by DEX. ZERO channels containing a mutant STREX domain (S4STREXA) were also activated by PKA. Importantly, DEX blocked PKA activation of S4STREXA channels in a PP2A-dependent manner.
  5. Taken together, the STREX domain is crucial for glucocorticoid regulation of BK channels through a PP2A-type enzyme. Moreover, glucocorticoids appear to induce a generic set of proteins in different types of cells, the actions of which depend on the expression of cell-specific targets.



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