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J. Biol. Chem., Vol. 280, Issue 39, 33599-33609, September 30, 2005

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Functionally Diverse Complement of Large Conductance Calcium- and Voltage-activated Potassium Channel (BK) -Subunits Generated from a Single Site of Splicing^*

Lie Chen1, Lijun Tian1, Stephen H.-F. MacDonald, Heather McClafferty, Martin S. L. Hammond, Jean-Marc Huibant, Peter Ruth, Hans-Guenther Knaus¶, and Michael J. Shipston2

From the Centre for Integrative Physiology, Membrane Biology Group, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, Scotland, United Kingdom, the University of Tuebingen, Tuebingen D727076, Germany, and the ^¶University of Innsbruck, Innsbruck A-6020, Austria

The pore-forming -subunits of large conductance calcium- and voltage-activated potassium (BK) channels are encoded by a single gene that undergoes extensive alternative pre-mRNA splicing. However, the extent to which differential exon usage at a single site of splicing may confer functionally distinct properties on BK channels is largely unknown. Here we demonstrated that alternative splicing at site of splicing C2 in the mouse BK channel C terminus generates five distinct splice variants: ZERO, e20, e21(STREX), e22, and a novel variant e23. Splice variants display distinct patterns of tissue distribution with e21(STREX) expressed at the highest levels in adult endocrine tissues and e22 at embryonic stages of mouse development. e23 is not functionally expressed at the cell surface and acts as a dominant negative of cell surface expression by trapping other BK channel splice variant -subunits in the endoplasmic reticulum and perinuclear compartments. Splice variants display a range of biophysical properties. e21(STREX) and e22 variants display a significant left shift (>20 mV at 1 µM [Ca²⁺]_i) in half-maximal voltage of activation compared with ZERO and e20 as well as considerably slower rates of deactivation. Splice variants are differentially sensitive to phosphorylation by endogenous cAMP-dependent protein kinase; ZERO, e20, and e22 variants are all activated, whereas e21 (STREX) is the only variant that is inhibited. Thus alternative pre-mRNA splicing from a single site of splicing provides a mechanism to generate a physiologically diverse complement of BK channel -subunits that differ dramatically in their tissue distribution, trafficking, and regulation.

Received for publication, May 17, 2005 , and in revised form, July 15, 2005.

^* This work was supported by the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains SD1 and SD2.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Centre for Integrative Physiology, Membrane Biology Group, Hugh Robson Bldg., University of Edinburgh, Edinburgh, Scotland EH8 9XD, UK. Tel.: 44-131-650-3253; Fax: 44-131-650-6527; E-mail: mike.shipston{at}ed.ac.uk.

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