Alternative splicing switches potassium channel sensitivity to protein phosphorylation.
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.
Membrane Biology Group & Medical Research Council Membrane and Adapter Protein Co-operative Group, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG, United Kingdom.
L
L
Tian
R R
RR
Duncan
M S
MS
Hammond
L S
LS
Coghill
H
H
Wen
R
R
Rusinova
A G
AG
Clark
I B
IB
Levitan
M J
MJ
Shipston
D017398:Alternative Splicing; D000818:Animals; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D005091:Exons; D051379:Mice; D010766:Phosphorylation; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship
D015221:Potassium Channels; D011506:Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases