TY - JOUR
T1 - Alternative Splicing Switches Potassium Channel Sensitivity to Protein Phosphorylation
AU - Tian, Lijun
AU - Duncan, Rory R.
AU - Hammond, Martin S.L.
AU - Coghill, Lorraine S.
AU - Wen, Hua
AU - Rusinova, Radda
AU - Clark, Alan G.
AU - Levitan, Irwin B.
AU - Shipston, Michael J.
PY - 2001/3/16
Y1 - 2001/3/16
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.C000741200
DO - 10.1074/jbc.C000741200
M3 - Article
C2 - 11244090
AN - SCOPUS:0035896535
SN - 0021-9258
VL - 276
SP - 7717
EP - 7720
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 11
ER -