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Papers In Press, published online ahead of print August 4, 2005
Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD
Corresponding Author: mike.shipston{at}ed.ac.uk
The pore forming
J. Biol. Chem, 10.1074/jbc.M505383200
Submitted on May 17, 2005
Accepted on August 4, 2005
Fnctionally diverse complement of calcium-activated BK channel
-subunits generated from a single site of splicing
-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 demonstrate that alternative splicing at site of splicing C2 in the mouse BK channel C-terminus generates 5 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 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 (> 20mV at 1 
M [Ca2+]i) in half maximal voltage of activation compared to 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.
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